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Sample records for antibody rituximab radioimmunotherapy

  1. I-131 rituximab (chimeric anti Cd 20 mab) radioimmunotherapy of non-Hodgkins lymphoma

    International Nuclear Information System (INIS)

    Full text: Commercially available anti-CD 20 monoclonal antibody, rituximab (MabThera) may be efficiently radioiodinated with 131I using standard Chloramine-T methodology in a hospital radiopharmacy, under appropriate regulatory authority approvals. Multicentre clinical trials of 131I-rituximab radioimmunotherapy have been performed in patients with relapsed or refractory low grade non-Hodgkins lymphoma with therapeutically effective administered activities being determined on the basis of individualised prospective patient dosimetry. A non-myeloablative regimen of 131I-radioimmunotherapy predicated upon a maximum prescribed dose of 0.75 Gy to whole body has been used to minimise myelotoxicity in patients undergoing radioimmunotherapy, even when they have been heavily pre-treated with chemotherapy and/or there is tumour infiltration of bone marrow greater than 25%. Provided that baseline leucocytes exceeded an absolute neutrophil count of 1.5 x 109/L and platelets > 100 x 109 /L, the incidence of grade IV haematological toxicity was 16% for neutrophils and 4 % for platelets which was self-limited. The red marrow radiation absorbed dose in selected patients receiving 131I activities estimated to deliver 0.75 Gy to whole body was calculated to be less than 2 Gy using Monte Carlo methodology on post therapy CT/SPECT imaging. Predictive dosimetry was performed by serial whole body imaging following IV administration of a standard 200 MBq 131I-rituximab tracer and determination of individual pharmacokinetics of the radiolabelled antibody in each patient. A standard dose of 375 mg/m2 unlabelled rituximab (MabThera) was administered IV immediately prior to the tracer and therapy doses of 131I-rituximab to minimise nonspecific uptake of the radiolabelled antibody and to optimise the tumour to background activity. The administration of a standard course of 4 cycles of cold rituximab (MabThera) in association with the prescribed maximum activity of 131I-rituximab constitutes

  2. Radioimmunotherapy with engineered antibody fragments

    International Nuclear Information System (INIS)

    Authors have developed and begun evaluating radiometal-chelated (213Bi) engineered antibody fragments as radioimmunotherapy agents that target the HER2/neu (c-erbB-2) antigen. The diabody format was found to have 40-fold greater affinity for HER2/neu and to be associated with significantly greater tumor localization than is achieved with scFv molecule. It is shown that short-lived isotopes like 213Bi would be most effective when used in conjunction with antibodies that targeted diffuse malignancies (leukemia or lymphoma) or when used for very rapid pretargeted radioimmunotherapy application in which the radioisotope is conjugated to a very small ligand

  3. Standard Operating Procedure for Prospective Individualised Dosimetry for [131]I-rituximab Radioimmunotherapy of Non-Hodgkin's Lymphoma

    OpenAIRE

    Calais, Phillipe J.; Turner, J. Harvey

    2012-01-01

    Radioimmunotherapy (RIT) is an attractive therapy for non-Hodgkin's lymphoma (NHL) as it allows targeted tumor irradiation which provides a cytotoxic effect significantly greater than that of the immune-mediated effects of a non-radioactive, or ‘cold’, antibody alone. Anti-CD20 antibodies such as rituximab are ideal for RIT, as not only is it easily iodinated, but the CD20 antigen is found on more than 95% of B-cell NHL. A standard operating procedure (SOP) has been formulated for personalize...

  4. Standard Operating Procedure for Prospective Individualised Dosimetry for ([131])I-rituximab Radioimmunotherapy of Non-Hodgkin's Lymphoma.

    Science.gov (United States)

    Calais, Phillipe J; Turner, J Harvey

    2012-09-01

    Radioimmunotherapy (RIT) is an attractive therapy for non-Hodgkin's lymphoma (NHL) as it allows targeted tumor irradiation which provides a cytotoxic effect significantly greater than that of the immune-mediated effects of a non-radioactive, or 'cold', antibody alone. Anti-CD20 antibodies such as rituximab are ideal for RIT, as not only is it easily iodinated, but the CD20 antigen is found on more than 95% of B-cell NHL. A standard operating procedure (SOP) has been formulated for personalized prospective dosimetry for safe, effective outpatient (131)I-rituximab RIT of NHL. Over five years, experience of treatment of outpatients with (131)I-rituximab was analyzed with respect to critical organ radiation dose in patients and radiation exposure of their carers. This radiation safety methodology has been refined; and offers the potential for safe, practical application to outpatient (131)I-rituximab RIT of lymphoma in general and in developing countries in particular. Given endorsement and sanction of this SOP by local regulatory authorities the personalized dosimetry paradigm will facilitate incorporation of RIT into the routine clinical practice of therapeutic nuclear oncology worldwide. PMID:23372448

  5. Standard Operating Procedure for In-house Preparation of 131I-rituximab for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    OpenAIRE

    Pickford, Matthew D.; Turner, J. Harvey

    2012-01-01

    A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of 131I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear ...

  6. Radioimmunotherapy using {sup 131}I-rituximab in patients with advanced stage B-cell non-Hodgkin's lymphoma: initial experience

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    Bienert, Maren; Reisinger, Ingrid; Humplik, Beatrice I.; Reim, Christel; Kroessin, Thomas; Avril, Norbert; Munz, Dieter L. [Charite - Universitaetsmedizin Berlin, Clinic for Nuclear Medicine, Berlin (Germany); Srock, Stefanie; Pezzutto, Antonio [Charite - Universitaetsmedizin Berlin, Department of Haematology and Oncology, Berlin (Germany)

    2005-10-01

    The aim of this study was to evaluate the safety, toxicity and therapeutic response of non-myeloablative radioimmunotherapy using {sup 131}I-rituximab in previously heavily treated patients with B-cell non-Hodgkin's lymphoma (B-NHL). Nine patients with relapsed, refractory or transformed B-NHL received ten radioimmunotherapies. Patients had a median of 5 (range 2-7) prior standard therapies. Four patients had received prior high-dose chemotherapy followed by autologous stem cell transplantation, and eight had received prior rituximab therapy. Histopathology consisted of four mantle cell, one follicular and four diffuse large B-cell lymphomas. Rituximab, a monoclonal chimeric anti-CD20 antibody (IDEC-C2B8), was labelled with {sup 131}I using the Iodogen method. The administered activity (2,200{+-}600 MBq) was based on a dosimetrically calculated 45 cGy total-body radiation dose. All patients received an infusion of 2.5 mg/kg of rituximab prior to administration of the radiopharmaceutical. No acute adverse effects were observed after the administration of{sup 131}I-rituximab. Radioimmunotherapy was safe in our patient group and achieved one complete response ongoing at 14 months and two partial responses progressing at 12 and 13 months after treatment. One partial responder was re-treated with radioimmunotherapy and achieved an additional progression-free interval of 7 months. Four non-responders with bulky disease died 4.8{+-}2.0 months after therapy. Three patients had an elevated serum lactate dehydrogenase (LDH) level prior to radioimmunotherapy and none of the patients responded. Of two patients who received radioimmunotherapy as an additional treatment after salvage chemotherapy, one continues to be disease-free at 9 months and one relapsed at 5 months' follow-up. Reversible grade 3 or 4 haematological toxicity occurred in seven of nine patients. Median nadirs were 35 days for platelets, 44 days for leucocytes and 57 days for erythrocytes. (orig.)

  7. Standard Operating Procedure for In-house Preparation of (131)I-rituximab for Radioimmunotherapy of Non-Hodgkin's Lymphoma.

    Science.gov (United States)

    Pickford, Matthew D; Turner, J Harvey

    2012-09-01

    A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of (131)I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements. PMID:23372447

  8. Preparation and quality control of 177Lu-DOTA-Rituximab for radioimmunotherapy of relapsed and refractory B-cell NHL patients

    International Nuclear Information System (INIS)

    Full text of publication follows. Background: the prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumor-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumor cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immuno-conjugate of Rituximab and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab was desalted with sodium bi-carbonate (0.1 M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in-vitro stability and pyrogenicity were studied. Immunoreactivity of 177Lu-DOTA-Rituximab was assessed using RAMOS cells. The radio-immuno-conjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: an average of 4.02 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single Rituximab antibody. The radiochemical purity of the labelled antibody was >95 % with preserved affinity for CD20 antigen. The final preparation was stable up to ∼120 hours when tested under different conditions. Bacterial endotoxin level in the sample was less than the permissible levels(<0.2 EU/ml). A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Conclusion: a favorable radiochemical purity, stability and biodistribution of the radiolabelled immuno-conjugate indicated that 177Lu-DOTA-antiCD20 antibody-Rituximab might be a promising therapeutic agent for the treatment of relapsed and refractory Non Hodgkin's Lymphoma. (authors)

  9. Radioimmunotherapy in refractory b-cell nonhodgkins lymphoma with I-131-labeled chimeric anti cd-20 c2b8 (I-131 rituximab): preliminary result

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    Kang, Hye Jin; Park, Yeon Hee; Kim, Sung Eun and others [Korea University Medical School, Seoul (Korea, Republic of)

    2005-07-01

    Recently, the native chimeric human-mouse anti CD-20 antibody IDEC-C2B8 (Rituximab) has been widely applied in NHL. This ongoing phase study was to evaluate whether radioimmunotherapy (RIT) with I-131 rituximab is effective in refractory B-cell NHL. Inclusion criteria were as follows: B-cell NHL with relapsed or refractory to primary standard therapy, measurable disease, adequate hematologic, renal, and hepatic function, informed consent. The rituximab (Mabthera, Roach) was radiolabeled with iodine-131(I-131) using a modified chloramine T method with high radiochemical purity (95%) and preservation of immuno-reactivity. All patients received loading doses of unlabeled rituximab (median, 40 mg: range, 20{approx}70 mg) immediately prior to administration of therapeutic dose (51.4{approx}152.2 MBq/kg), and then underwent gamma camera scan. 11 patients were enrolled (4 low-grade B-cell NHL, 7 DLBCL, median age 63 years). Patients had received a median of three prior chemotherapy regimens. The objective response rate was 36.4% (1 CR, 3 PRs). These all responses were observed in low-grade B-cell NHL, except one with DLBCL. Adverse events were primarily hematologic toxicities; the incidence of grade 3/4 neutropenia, thrombocytopenia, and anemia was 27.3%, 45.5%, and 18.2%, respectively. The treatment-related mortality was observed in one patient, who had been previously treated with high-dose chemotherapy plus TBI with autologous stem cell transplantation. RIT with I-131 rituximab seems to be effective tolerable in refractory low-grade B-cell NHL, although modest activity in refractory DLBCL. Further studies to define the efficacy of I-131 rituximab in DLBCL are warranted.

  10. Initial evaluation of 227Th-p-benzyl-DOTA-rituximab for low-dose rate α-particle radioimmunotherapy

    International Nuclear Information System (INIS)

    Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with β-emitting isotopes. In contrast to β-emitters, the shorter range and high linear energy transfer (LET) of α particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of α-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The α-emitting radioimmunoconjugate 227Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the α-particle-emitting nuclide 227Th alone, the chelated form, 227Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate 227Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of 227Th-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the 227Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of 227Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with 227Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of 227Th-DOTA-p-benzyl-rituximab

  11. Current research status of radioimmunotherapy monoclonal antibody drug

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) was one of the most important progresses in the field of cancer therapy over the past 20 years. It has been successfully applied in the treatment of blood system tumors such as NHL. For the utilization of RIT in therapy of solid tumors, however, development of more effective monoclonal antibodies, labeling methods and so on are needed. The current status of radionuclides, monoclonal antibodies and drugs commonly used in the RIT were briefly reviewed. (authors)

  12. Tumour targeting and radiation dose of radioimmunotherapy with {sup 90}Y-rituximab in CD20+ B-cell lymphoma as predicted by {sup 89}Zr-rituximab immuno-PET: impact of preloading with unlabelled rituximab

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    Muylle, Kristoff [Vrije Universiteit Brussel, MIMA Research Group, Brussels (Belgium); Universite Libre de Bruxelles, Department of Nuclear Medicine, Jules Bordet Institute, Brussels (Belgium); Flamen, Patrick; Guiot, Thomas; Ghanem, Ghanem; Meuleman, Nathalie; Bourgeois, Pierre; Vanderlinden, Bruno; Vaes, Melanie; Bron, Dominique [Universite Libre de Bruxelles, Jules Bordet Institute, Brussels (Belgium); Vugts, Danielle J.; Dongen, Guus A.M.S. van [VU University Medical Centre, Amsterdam (Netherlands); Everaert, Hendrik [Vrije Universiteit Brussel, UZ Brussel, Brussels (Belgium); Vrije Universiteit Brussel, MIMA Research Group, Brussels (Belgium)

    2015-07-15

    To compare using immuno-PET/CT the distribution of {sup 89}Zr-labelled rituximab without and with a preload of unlabelled rituximab to assess the impact of preloading with unlabelled rituximab on tumour targeting and radiation dose of subsequent radioimmunotherapy with {sup 90}Y-labelled rituximab in CD20+ B-cell lymphoma. Five patients with CD20+ B-cell lymphoma and progressive disease were prospectively enrolled. All patients underwent three study phases: initial dosimetric phase with baseline {sup 89}Zr-rituximab PET/CT imaging without a cold preload, followed 3 weeks later by a second dosimetric phase with administration of a standard preload (250 mg/m{sup 2}) of unlabelled rituximab followed by injection of {sup 89}Zr-rituximab, and a therapeutic phase 1 week later with administration of unlabelled rituximab followed by {sup 90}Y-rituximab. PET/CT imaging and tracer uptake by organs and lesions were assessed. With a cold rituximab preload, the calculated whole-body dose of {sup 90}Y-rituximab was similar (mean 0.87 mSv/MBq, range 0.82-0.99 mSv/MBq) in all patients. Without a preload, an increase in whole-body dose of 59 % and 87 % was noted in two patients with preserved circulating CD20+ B cells. This increase in radiation dose was primarily due to a 12.4-fold to 15-fold higher dose to the spleen without a preload. No significant change in whole-body dose was noted in the three other patients with B-cell depletion. Without a preload, consistently higher tumour uptake was noticed in patients with B-cell depletion. Administration of the standard preload of unlabelled rituximab impairs radioconjugate tumour targeting in the majority of patients eligible for radioimmunotherapy, that is patients previously treated with rituximab-containing therapeutic regimens. This common practice may need to be reconsidered and further evaluated as the rationale for this high preload has its origin in the ''prerituximab era''. (orig.)

  13. Design and manufacture of monoclonal antibodies for radioimmunotherapy

    International Nuclear Information System (INIS)

    Appropriate design and manufacture of monoclonal antibodies is fundamental to their use for radioimmunotherapy. Besides the right selection of antibody specificity and affinity, recombinant antibodies can be designed to simplify manufacture and minimise unwanted side effects. Although many innovative new technologies have been developed in recent years, antibodies are still most commonly produced from mammalian cells and purified by column chromatography. Purification methods have to be designed and validated to remove potential contaminants, especially retroviruses which in principle might be present in mammalian cell lines. Adherence to relevant Good Manufacturing Practice is mandatory in the production of any medicinal product and there are numerous guidelines regarding the manufacture of antibodies. This article outlines some methods used for fermentation, purification and quality control of antibodies intended for radiolabelling

  14. Radioimmunotherapy of infection with 213Bi-labeled antibodies

    OpenAIRE

    Dadachova, Ekaterina

    2008-01-01

    Bismuth-213 (213Bi) (physical half-life 46 min) is a beta-emitter (97%) and an alpha-emitter (3%) which decays to short lived alpha-emitter Polonium-213 and could therefore be used as an in vivo generator of alpha particles with the energy of around 8 MeV. 213Bi has been successfully used during the last decade in both clinical and pre-clinical work for radioimmunotherapy (RIT) of cancer with 213Bi-labeled monoclonal antibodies (mAbs). RIT has been proposed as a novel techonology for treatmen...

  15. Feasibility and toxicity of concomitant radio/immunotherapy with MabThera (Rituximab registered) for patients with non-Hodgkin's lymphoma. Results of a prospective phase I/II study

    International Nuclear Information System (INIS)

    Purpose: Non-Hodgkin's lymphomas (NHL) have a high radio- and chemosensitivity. Although initially responsive, approximately 50% of low grade B-cell lymphomas relapse after 10-15 years. Besides chemo- and radiotherapy, rituximab, a mouse/human chimeric antibody targeting CD20 antigen on the surface of B-cell lymphoma cells, is another treatment approach. In vitro data showed potentiation of radiation-induced apoptosis by addition of rituximab. The purpose of this study was to evaluate the feasibility and toxicity of radiotherapy with concomitant application of rituximab in NHL patients. Patients and Methods: A total of 21 patients with B-cell lymphoma (stage I: n = 11; II: n = 5; III: n = 1; IV: n = 4) were included in this study, treated with radiotherapy of 30-40 Gy and weekly application of rituximab (375 mg/m2). Nine patients had R-CHOP chemotherapy previously, 1 patient leuceran chemotherapy, and 2 patients an initial treatment with 6 cycles of rituximab. Mean time of follow-up was 41.7 months. Results: No grade 4 toxicity or treatment-related death was observed. In 1 patient, rituximab application had to be stopped after 3 cycles due to radiation-induced side effects. No late toxicities were reported. All patients were in complete remission after treatment. Progression or relapse was observed in 6 patients (28%); the mean time to progression was 27 months. The mean overall survival (OS) was 53 months. Conclusion: Combined radio/immunotherapy is feasible and safe. Treatment was well tolerated, no late toxicities were observed, and treatment outcome is promising. Randomized trials are necessary to clarify the benefit of this treatment approach and its applicability. (orig.)

  16. Feasibility and toxicity of concomitant radio/immunotherapy with MabThera (Rituximab {sup registered}) for patients with non-Hodgkin's lymphoma. Results of a prospective phase I/II study

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    Haidenberger, Alfred; Popper, Bela-Andre; Skvortsova, Ira; Lukas, Peter [Medical Univ. Innsbruck (Austria). Dept. of Radiotherapy/Radiooncology; Fromm-Haidenberger, Sabine [Hospital Gmunden (Austria). Inst. of Radiology; Vries, Alexander de [Hospital Feldkirch (Austria). Dept. of Radiotherapy/Radiooncology; Steurer, Michael; Kantner, Johanna; Gunsilius, Eberhard [Medical Univ. Innsbruck (Austria). Dept. of Hematology

    2011-05-15

    Purpose: Non-Hodgkin's lymphomas (NHL) have a high radio- and chemosensitivity. Although initially responsive, approximately 50% of low grade B-cell lymphomas relapse after 10-15 years. Besides chemo- and radiotherapy, rituximab, a mouse/human chimeric antibody targeting CD20 antigen on the surface of B-cell lymphoma cells, is another treatment approach. In vitro data showed potentiation of radiation-induced apoptosis by addition of rituximab. The purpose of this study was to evaluate the feasibility and toxicity of radiotherapy with concomitant application of rituximab in NHL patients. Patients and Methods: A total of 21 patients with B-cell lymphoma (stage I: n = 11; II: n = 5; III: n = 1; IV: n = 4) were included in this study, treated with radiotherapy of 30-40 Gy and weekly application of rituximab (375 mg/m{sup 2}). Nine patients had R-CHOP chemotherapy previously, 1 patient leuceran chemotherapy, and 2 patients an initial treatment with 6 cycles of rituximab. Mean time of follow-up was 41.7 months. Results: No grade 4 toxicity or treatment-related death was observed. In 1 patient, rituximab application had to be stopped after 3 cycles due to radiation-induced side effects. No late toxicities were reported. All patients were in complete remission after treatment. Progression or relapse was observed in 6 patients (28%); the mean time to progression was 27 months. The mean overall survival (OS) was 53 months. Conclusion: Combined radio/immunotherapy is feasible and safe. Treatment was well tolerated, no late toxicities were observed, and treatment outcome is promising. Randomized trials are necessary to clarify the benefit of this treatment approach and its applicability. (orig.)

  17. High-dose radioimmunotherapy in refractory b-celI non-Hodgikin's lymphoma with I-131-labeled chimeric anti CD-20 C2B8 (I-131 rituximab): pilot trial

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    Kim, Sung Eun; Park, Yeon Hee; Cheon, Gi Jeong; Ryoo, Baek Yeol; Lee, Seung Sook; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Science, Seoul (Korea, Republic of)

    2004-07-01

    The native chimeric human-mouse anti CD-20 antibody IDEC-C2B8 (rituximab) is therapeutically applied in relapsed or refractory NHL. This ongoing pilot study was to evaluate whether high-dose radioimmunotherapy (RIT) with I-131 rituximab is therapeutically effective in refractory B-cell NHL. 5 patients (5 male, aged 50.89{+-}16.89) with chemorefractory NHL of B-cell origin (2 diffuse large B cell, 1 burkitt's lymphoma, and 2 mantle cell Iymphoma) oe, with a life expectancy of at least 3 months, and with a Kamofsky performance score of 60 and above were studied. The chimeric IgG1 anti CD 20 monoclonal antibody rituximab (mabthera, Roche) was radiolabelled with iodine-131 (I-131) using a modified chloaramine T method with high radiochemical purity (95%{+-}0.9) and preservation of immunoreactivity. All patients received therapeutic loading doses of unlabelled rituximab (18.5 MBq/kg) immediately prior to administration of therapeutic dose (3.7 GBq-8.5 GBq), and then underwent gamma camera scan and pre-and post-RIT FDG PET (within 7 day and day 30). Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but all patients recovered at 6 weeks after treatment. Non hematologic toxicity was restricted to mild-to moderate nausea, fever, transient bilirubin, or liver enzyme elevation. Two (8.5 GBq) with mantle cell lymphoma and one with burkitt's lymphoma experienced good partial remissions, and one (5.5 GBq, DLBL) with bulky disease had a partial remission, and one patient (3.7 GBq, DLBL) with bulky disease had a mixed response. High-dose RIT with I-131 labelled rituximab seems to be effective and moderate toxicity. Further follow-up to monitor the long-term outcome are indicated.

  18. Study of conjugation and radiolabeling of monoclonal antibody rituximab for use in radionuclide therapy

    International Nuclear Information System (INIS)

    Lymphomas are tumors originated from the transformation of a lymphocyte in the lymphatic system. The most common lymphoma is the Non-Hodgkin Lymphoma (NHL). Advances in immunology and molecular biology have been improving NHL's detection and treatment strategies development, such as Radioimmunotherapy (RIT). Rituximab is an anti-CD20 monoclonal antibody used as immunotherapeutic to treat refractory or relapsed NHL. The goal of the present work was to conjugate this antibody to DOTA-NHS-ester bifunctional chelator and to radiolabel it with 177Lu radioisotope in order to develop a radio immunotherapeutic agent for NHL's treatment. Different rituximab to DOTA molar ratios (1:5, 1:10, 1:20, 1:50, 1:250, 1:500 and 1:1000) were evaluated in order to determine the best condition for obtaining the highest radiochemical purity of radio immunotherapeutic. The stability of the unlabeled immuno conjugated was evaluated by high performance liquid chromatography (HPLC) for up to 240 days in different storage conditions. The stability of the labeled preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C. The binding to serum proteins was also determined. In vivo studies were performed in healthy Swiss mice, in order to characterize the biological properties of labeled conjugate. Finally, preliminary studies of radio immuno conjugated competitive binding to CD20 positive Raji cells were carried out in order to analyze if the process of conjugation and radiolabeling compromises the immunoreactivity of the antibody. The conjugation applying lower antibody to chelator molar ratios (1:5, 1:10 and 1:20) showed high stability when stored for up to 240 days in different conditions. The HPLC analysis showed that the monoclonal antibody conjugated in molar ratio 1:50 was labeled with higher radiochemical purity (> 95%) when purified in PD-10 column. This conjugate showed reasonable stability at 2-8 degree C. The analysis of the stability

  19. Study of conjugation and radiolabeling of monoclonal antibody rituximab for use in radionuclide therapy; Estudo da conjugacao e radiomarcacao do anticorpo monoclonal rituximab para aplicacao em terapia radionuclidica

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    Massicano, Adriana Vidal Fernandes

    2011-07-01

    Lymphomas are tumors originated from the transformation of a lymphocyte in the lymphatic system. The most common lymphoma is the Non-Hodgkin Lymphoma (NHL). Advances in immunology and molecular biology have been improving NHL's detection and treatment strategies development, such as Radioimmunotherapy (RIT). Rituximab is an anti-CD20 monoclonal antibody used as immunotherapeutic to treat refractory or relapsed NHL. The goal of the present work was to conjugate this antibody to DOTA-NHS-ester bifunctional chelator and to radiolabel it with {sup 177}Lu radioisotope in order to develop a radio immunotherapeutic agent for NHL's treatment. Different rituximab to DOTA molar ratios (1:5, 1:10, 1:20, 1:50, 1:250, 1:500 and 1:1000) were evaluated in order to determine the best condition for obtaining the highest radiochemical purity of radio immunotherapeutic. The stability of the unlabeled immuno conjugated was evaluated by high performance liquid chromatography (HPLC) for up to 240 days in different storage conditions. The stability of the labeled preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C. The binding to serum proteins was also determined. In vivo studies were performed in healthy Swiss mice, in order to characterize the biological properties of labeled conjugate. Finally, preliminary studies of radio immuno conjugated competitive binding to CD20 positive Raji cells were carried out in order to analyze if the process of conjugation and radiolabeling compromises the immunoreactivity of the antibody. The conjugation applying lower antibody to chelator molar ratios (1:5, 1:10 and 1:20) showed high stability when stored for up to 240 days in different conditions. The HPLC analysis showed that the monoclonal antibody conjugated in molar ratio 1:50 was labeled with higher radiochemical purity (> 95%) when purified in PD-10 column. This conjugate showed reasonable stability at 2-8 degree C. The analysis

  20. Radioimmunotherapy with {sup 131}I-Rituximab in a Patient with Diffuse Large B-Cell Lymphoma Relapsed After Treatment with {sup 90}Y-Ibritumomab Tiuxetan

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    Kang, Geon Wook; Kang, Hye Jin; Shin, Dongyeop; Gu, Ha Ra; Choi, Hong Seok; Lim, Sang Moo [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    2013-12-15

    We report a case that demonstrates the efficacy of radioimmunotherapy (RIT) with radioiodinated rituximab ({sup 131}I-rituximab) for relapsed diffuse large B-cell lymphoma (DLBCL). A 79-year-old male patient with DLBCL initially achieved a complete response (CR) after six cycles of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. However, the lymphoma relapsed 20 months later. Although the patient had achieved a second and a third CR after two cycles of {sup 90}Y-ibritumomab tiuxetan, he experienced a third relapse approximately 3 years later. Between March and June 2011, the patient received three cycles of {sup 131}I-rituximab. Although he had achieved partial response after the second cycle, the disease progressed after the third cycle, and the total progression. Free survival was thus 5 months. The patient suffered only relatively mild toxicity (grade 1 thrombocytopenia) during treatment. RIT with {sup 131}I-rituximab is therefore potentially effective in patients with relapsed DLBCL, even after the failure of {sup 90}Y-ibritumomab tiuxetan therapy.

  1. Radioimmunotherapy of the lymphoma; Radioimmunotherapie du lymphome

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    Bodet-Milin, C.; Kraeber-Bodere, F. [Hotel Dieu, Service de Medecine Nucleaire, 44 - Nantes (France); Kraeber-Bodere, F. [Centre Regional de Lutte Contre le Cancer Rene-Gauducheau, Service de Medecine Nucleaire, 44 - Nantes (France)

    2006-09-15

    The radioimmunotherapy is a kind of internal radiotherapy using as vectorization agent a monoclonal antibody, recognizing an antigen expressed by tumor cells, coupled to a radioisotope. Developed now from more than twenty years, its efficiency is demonstrated in hematology for the treatment of the B lymphomas. The murine monoclonal antibody ( anti -CD20) and labelled with Yttrium 90 can be used in clinical routine in the treatment of recurrences of L.N.H. of low grade CD20 positive among the adults resistant or relapsing after treatment by rituximab, leading to response rate about 70 to 80 % with 20 to 30 % of complete response. The benefits of the R.I.T. will be probably more significant in first therapy line, in strengthening after a treatment by chemo- immunotherapy or in the frame of myelo ablative protocols. (N.C.)

  2. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins

    OpenAIRE

    Querol, Luis; Rojas-García, Ricard; Diaz-Manera, Jordi; Barcena, Joseba; Pardo, Julio; Ortega-Moreno, Angel; Sedano, Maria Jose; Seró-Ballesteros, Laia; Carvajal, Alejandra; Ortiz, Nicolau; Gallardo, Eduard; Illa, Isabel

    2015-01-01

    Objective: To describe the response to rituximab in patients with treatment-resistant chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against paranodal proteins and correlate the response with autoantibody titers. Methods: Patients with CIDP and IgG4 anti–contactin-1 (CNTN1) or anti–neurofascin-155 (NF155) antibodies who were resistant to IV immunoglobulin and corticosteroids were treated with rituximab and followed prospectively. Immunocytochemistry was used to detec...

  3. Validation of prospective whole-body bone marrow dosimetry by SPECT/CT multimodality imaging in {sup 131}I-anti-CD20 rituximab radioimmunotherapy of non-Hodgkin's lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Boucek, Jan A. [Fremantle Hospital, Department of Nuclear Medicine, Fremantle (Australia); Turner, J. Harvey [Fremantle Hospital, Department of Nuclear Medicine, Fremantle (Australia); University of Western Australia, School of Medicine and Pharmacology (Australia)

    2005-04-01

    Radioimmunotherapy (RIT) for relapsed non-Hodgkin's lymphoma is emerging as a promising treatment strategy. Myelosuppression is the dose-limiting toxicity and may be particularly problematic in patients heavily pretreated with chemotherapy. Reliable dosimetry is likely to minimise toxicity and improve treatment efficacy, and the aim of this study was to elucidate the complex problems of dosimetry of RIT by using an integrated SPECT/CT system. As a part of a clinical trial of {sup 131}I-anti-CD20 rituximab RIT of non-Hodgkin's lymphoma, we employed a patient-specific prospective dosimetry method utilising the whole-body effective half-life of antibody and the patient's ideal weight to calculate the administered activity for RIT corresponding to a prescribed radiation absorbed dose of 0.75 Gy to the whole body. A novel technique of quantitation of bone marrow uptake with hybrid SPECT/CT imaging was developed to validate this methodology by using post-RIT extended imaging and data collection. A strong, statistically significant correlation (p=0.001) between whole-body effective half-life of antibody and effective marrow half-life was demonstrated. Furthermore, it was found that bone marrow activity concentration was proportional to administered activity per unit weight, height or body surface area (p<0.001). The results of this study show the proposed whole-body dosimetry method to be valid and clinically applicable for safe, effective RIT. (orig.)

  4. The radiolabeled monoclonal antibodies in immunoscintigraphy and radioimmunotherapy: current state and perspectives

    International Nuclear Information System (INIS)

    The antibodies can be satisfactorily labelled with technitium-99 m or indium-111 for tumor immunoscintigraphy. The immunoscintigraphy is not useful for the primary tumor diagnosis. It can be useful for the diagnosis of the some cancer extension and for recurrent tumor visualization. The immunoscintigraphy is widely competed with Positron Emission Tomography (PET) which gives accurate results. In the future the immunoscintigraphy, in pre-therapeutic stage, contribute to the estimation of the dose delivered to the tumor and to normal organs for adopting or not a radioimmunotherapy. The antibodies can also be labeled with Iodine-131 for an application in radioimmunotherapy (RIT). The RIT is efficient in the non-Hodgkin's lymphoma treatment because of their great radiosensitivity. Until now the results have been very modest in solid tumor treatment but methodological and biotechnological progresses have to improve the efficiency especially for the small tumors. In the future iodine-131 which requires the confinement (very expensive) of patients will be substituted by yttrium-90 beta emitter, more energetic than iodine-131 and can be injected in walking case. In the long term, the alpha emitter radionuclides (astatine-211 or bismuth-213) can be used for hematologic cancer treatment. In conclusion the future of radiolabeled monoclonal antibodies is essentially therapeutic. The radioimmunotherapy associated to the chemotherapy give promising perspectives for the radiosensitive cancer treatment and in general small solid tumor treatment (F.M.)

  5. Successful pregnancy after rituximab in a women with recurrent in vitro fertilisation failures and anti-phospholipid antibody positive.

    LENUS (Irish Health Repository)

    Ng, C T

    2012-02-01

    We report a case of successful pregnancy after rituximab in a patient with a history of in vitro fertilisation (IVF) failures and positive anti-cardiolipin antibody (ACA). Following a course of rituximab, her ACA became negative and she successfully conceived with IVF treatment. This is the first case in literature describing the use of rituximab therapy in this clinical scenario.

  6. An approach for conjugation of 177 Lu- DOTA-SCN- Rituximab (BioSim & its evaluation for radioimmunotherapy of relapsed & refractory B-cell non Hodgkins lymphoma patients

    Directory of Open Access Journals (Sweden)

    Parul Thakral

    2014-01-01

    Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177 Lu-DOTA-antiCD20 antibody-Rituximab (BioSim in patients of relapsed and refractory non Hodgkin′s lymphoma can be considered.

  7. Preparation and radiolabeling of a lyophilized (kit) formulation of DOTA-rituximab with 90Y and 111In for domestic radioimmunotherapy and radioscintigraphy of Non-Hodgkin’s Lymphoma

    OpenAIRE

    Gholipour, Nazila; Jalilian, Amir Reza; Khalaj, Ali; Johari-Daha, Fariba; Yavari, Kamal; Sabzevari, Omid; Khanchi, Ali Reza; AKHLAGHI, MEHDI

    2014-01-01

    Background On the basis of results of our previous investigations on 90Y-DTPA-rituximab and in order to fulfil national demands to radioimmunoconjugates for radioscintigraphy and radioimmunotherapy of Non-Hodgkin’s Lymphoma (NHL), preparation and radiolabeling of a lyophilized formulation (kit) of DOTA-rituximab with 111In and 90Y was investigated. Methods 111In and 90Y with high radiochemical and radionuclide purity were prepared by 112Cd (p,2n)111In nuclear reaction and a locally developed ...

  8. B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study

    DEFF Research Database (Denmark)

    El Fassi, Daniel; Nielsen, Claus H; Bonnema, Steen J; Hasselbalch, Hans K; Hegedüs, Laszlo

    2007-01-01

    Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might be of...

  9. B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study

    DEFF Research Database (Denmark)

    El Fassi, Daniel; Nielsen, Claus H; Bonnema, Steen J; Hasselbalch, Hans C; Hegedüs, Laszlo

    2007-01-01

    CONTEXT: Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might b...

  10. Radioimmunotherapy of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Non-Hodgkin's lymphomas (NHL) are malignancies derived from lymphocytes with approximately 80% involving B-cell lymphocytes and 95% of B-cell lymphomas expressing the CD20 antigen on the tumor cell surface membrane. Although NHL is considered a curable disease, many patients especially those with indolent NHL relapse and eventually die. For patients with limited stage disease, conventional radiation therapy is utilized. For advanced stage disease combination chemotherapy and Rituximab, a chimeric anti-CD20 monoclonal antibody is the standard therapy. Radioimmunotherapy is a recent addition for treatment of NHL and utilizes a tumor cell targeting monoclonal antibody chemically linked to a therapeutic radionuclide delivering radiation to tumor cells while limiting toxicity to normal cells. The advantage of radioimmunotherapy is the ability to treat multiple tumor sites throughout the body following intravenous infusion. The most common radionuclides used for radioimmunotherapy have been 131Iodine (I-131) and more recently 90Yttrium (Y-90). Y-90 is bound to the monoclonal antibody using metal chelating groups while I-131 is directly linked to the antibody. Phase I, II and III therapy trials of I-131 or Y-90 labeled anti-CD20 monoclonal antibodies have shown radioimmunotherapy to be safe and highly effective in the treatment of B-cell NHL. Transient hematologic toxicity with nadirs occurring at 7 to 9 weeks and lasting approximately 1 to 2 weeks has been the only side-effects. The response rates from radioimmunotherapy have been higher than for the unlabeled antibody therapy (Y-90 anti-CD20 vs. Rituximab response rates = 80% vs. 56% ( p = 0.002) and complete response (CR) rates were 30% and 16% respectively (p=0.04). Radiolabeled anti-CD20 monoclonal antibodies are now being used alone or in combination with chemotherapy, external beam radiation or stem cell transplantation for treating patients with NHL. Radioimmunotherapy has become a value new treatment for patients

  11. In Vitro Cytotoxicity of Low-Dose-Rate Radioimmunotherapy by the Alpha-Emitting Radioimmunoconjugate Thorium-227-DOTA-Rituximab

    International Nuclear Information System (INIS)

    Purpose: To determine whether the low-dose-rate α-particle-emitting radioimmunoconjugate 227Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. Methods and Materials: CD20-positive lymphoma cell lines were treated with 227Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with 227Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. Results: There was a specific targeted effect on cell growth of the 227Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with 227Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL 227Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 105 to 107 cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy α-particle radiation from 227Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. Conclusions: The low-dose-rate radioimmunoconjugate 227Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

  12. Cuban Monoclonal Antibodies for Radioimmunodiagnosis and Radioimmunotherapy of Cancer Diseases

    International Nuclear Information System (INIS)

    The Centre of Molecular Immunology produces monoclonal antibodies for treating cancer diseases. We are mainly focus on two target systems; one is the epidermal growth factor receptor (EGF-R) because there is a tremendous relationship between the EGF/EGF-R system and several human tumours such as lung, head and neck, ovarian breast and brain cancers; the second one is the ganglioside system, the relevance of certain gangliosides in tumour growth and metastatic dissemination has been well documented, GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues. Nimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) that was obtained by complementarity-determining regions grafting of a murine mAb (ior egf/r3) to a human framework having remarkable antiproliferative, pro-apoptotic, and antiangiogenic effects. A Phase I clinical trial was performed to evaluate the toxicity and clinical effect of an intracavitary (intracerebral) administration of a single dose of nimotuzumab (h-R3) labelled with increasing doses of 188Re. All patients bearing astrocytomas grade III/IV should be treated previously with conventional therapies and have an EGF-R overexpression in the tumour, demonstrated by immunohistochemical study. Maximal tolerated dose was 3 mg of the h-R3 labelled with 10 mCi of 188Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5% of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas. GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues according to immunohistochemical studies, using either polyclonal or monoclonal antibodies. But both immunohistochemical and biochemical methods have strongly suggested its over-expression in human breast and colon

  13. Radioimmunotherapy: A Specific Treatment Protocol for Cancer by Cytotoxic Radioisotopes Conjugated to Antibodies

    Directory of Open Access Journals (Sweden)

    Hidekazu Kawashima

    2014-01-01

    Full Text Available Radioimmunotherapy (RIT represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments or peptides. In a clinical field, two successful examples of this treatment protocol are currently extended by 90Y-ibritumomab tiuxetan (Zevalin and 131I-tositumomab (Bexxar, both of which are anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hodgkin lymphoma patients. In addition, some beneficial observations are obtained in preclinical studies targeting solid tumors. To date, in order to reduce the unnecessary exposure and to enhance the therapeutic efficacy, various biological, chemical, and treatment procedural improvements have been investigated in RIT. This review outlines the fundamentals of RIT and current knowledge of the preclinical/clinical trials for cancer treatment.

  14. Simultaneous radiotherapy and radioimmunotherapy of malignant gliomas with anti-EGFR antibody labelled with iodine 125. Preliminary results

    International Nuclear Information System (INIS)

    In this paper we present the preliminary results of a prospective trial of the efficacy of simultaneous radiotherapy and anti-EGFR 125I radioimmunotherapy of malignant gliomas with 2 years' total survival as the end-point, raising the question whether anti-EGFR 125I radioimmunotherapy influences the disease-free survival in these patients. Patients with anaplastic astrocytoma or primary glioblastoma were previously treated by a macroscopically radical neurosurgical approach and randomized either to radiotherapy + radioimmunotherapy arm or treated by radiotherapy alone. Seven patients were included in the group with radioimmunotherapy, among them five with GBM and two with AA, and five patients in the control arm. Patients were irradiated to 60 Gy using three-dimensional conformal noncoplanar techniques. Anti-EGFR 125I monoclonal antibody 425 radioimmunotherapy (50 mCi/course) was started during 4. week of radiotherapy and was repeated three times in one week intervals. Time of follow-up ranges between 2 and 10 months in the anti-EGFR 125I radioimmunotherapy arm and 4 and 9 months in the control arm. Recurrence was diagnosed in all patients in the EGFR 125I group with a lethal outcome in two of them and in 4 patients in the control group. Median time to recurrence was 2 and 5 months respectively. Taking into account early recurrences observed, we propose to continue the studies on the efficacy of adjuvant anti-EGFR 125I radioimmunotherapy in a selected group of patients in whom the greatest benefit may be expected on the basis of molecular studies, among them EGFR expression investigation. (author)

  15. Two courses of rituximab (anti-CD20 monoclonal antibody) for recalcitrant pemphigus vulgaris

    DEFF Research Database (Denmark)

    Faurschou, A.; Gniadecki, R.

    2008-01-01

    Background Pemphigus vulgaris (PV) is a severe autoimmune blistering disease involving the skin and mucous membranes. The response to therapy varies greatly amongst patients and treatment may be challenging. Rituximab is a chimeric monoclonal antibody that selectively targets cell surface antigen...

  16. Radioimmunotherapy with 90Y-labeled monoclonal antibodies in a nude mouse ovarian cancer model

    International Nuclear Information System (INIS)

    Tumor stroma contains much fibrin, and so monoclonal antifibrin antibody can accumulate in tumors. We treated nude mice bearing human ovarian carcinoma xenografts with 90Y-labeled monoclonal antifibrin antibody Fab fragments administered intratumorally. The survival time vs. a control group was significantly prolonged and tumor growth rate was decreased. Another group of animals was treated with 90Y-labeled OC 125-monoclonal antibody; these mice received the antibodies intratumorally, intraperitoneally or intravenously. The survival time was longest in the intratumorally treated group. There was no significant difference in survival between 90Y-labeled OC 125 and antifibrin in the intratumorally treated animal groups. The tissue activity distribution studies revealed that bone marrow is the critical organ. Intratumorally injected monoclonal 90Y-antifibrin antibodies were retained at least 36 h (up to 50% of injected activity per gram tumor tissue) in the xenograft after one treatment, causing cell death. Beta-camera imaging and immunohistochemistry were performed for studies of the correlation between 90Y activity and fibrin distribution in tumor specimens. These results were in concordance. In conclusion, intratumoral administration seems suitable for radioimmunotherapy, with an antibody that targets stromal structures. The accumulation can be successfully monitored by a beta-camera. (orig.)

  17. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura

    DEFF Research Database (Denmark)

    Braendstrup, Peter; Bjerrum, Ole W; Nielsen, Ove J;

    2005-01-01

    . Recent studies have shown that rituximab, a chimeric anti-CD20 monoclonal antibody, is useful in the treatment of these patients, with overall response rates of about 50%. Most published reports have included a small number patients including case reports. The present study reports the results of a...... retrospective Danish multicenter study of rituximab in the treatment of adult patients with refractory ITP. Thirty-five patients (median age 52 years, range 17-82 years, 17 males) were included. One patient had immune thrombocytopenia and neutropenia. All patients had received prednisolone (Pred). Next to Pred...

  18. Advantage of dose fractionation in monoclonal antibody-targeted radioimmunotherapy

    International Nuclear Information System (INIS)

    Monoclonal antibody (MAb) B72.3 IgG was radiolabeled with 131I and administered to female athymic NCr-nu mice bearing the LS-174T human colon adenocarcinoma xenograft to determine if fractionation of MAb dose had any advantage in tumor therapy. In the LS-174T xenograft, only approximately 30%-60% of tumor cells express the B72.3-reactive TAG-72 antigen. The LS-174T xenograft was used to reflect the heterogeneity of the TAG-72 antigen often seen in biopsy specimens from patients. In contrast to a single 600-muCi dose of 131I-B72.3 IgG where 60% of the animals died from toxic effects, two 300-muCi doses of 131I-B72.3 IgG reduced or eliminated tumor growth in 90% of mice, with only 10% of the animals dying from toxic effects. Dose fractionation even permitted escalation of the dose to three doses of 300 muCi of 131I-B72.3 IgG, resulting in even more extensive tumor reduction or elimination and minimal toxic effects. The use of an isotype-matched control MAb revealed a nonspecific component to tumor growth retardation, but the use of the specific B72.3 IgG demonstrated a much greater therapeutic effect. Tumors that had escaped MAb therapy were analyzed for expression of the B72.3-reactive TAG-72 antigen with the use of the immunoperoxidase method; they were shown to have the same antigenic phenotype as the untreated tumors. We verified tumor elimination by killing the test animals after a 7-week observation period and performing histologic examination of tumor sites. We also monitored toxic effects by histologic examination of numerous organs. These studies thus demonstrate the advantage of dose fractionation of a radiolabeled MAb for tumor therapy. We anticipate that the concept of dose fractionation can be practically applied in radioimmunotherapeutic clinical trials with the development and use of recombinant-chimeric MAbs and modified constructs

  19. Preparation & in vitro evaluation of 90Y-DOTA-rituximab

    OpenAIRE

    Mythili Kameswaran; Usha Pandey; Ashutosh Dash; Grace Samuel; Meera Venkatesh

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin′s lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with [90] Y and in vitro and in vivo ev...

  20. Preparation & in vitro evaluation of 90 Y-DOTA-rituximab

    OpenAIRE

    Mythili Kameswaran; Usha Pandey; Ashutosh Dash; Grace Samuel; Meera Venkatesh

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin′s lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with [90] Y and in vitro and in vivo ev...

  1. Development of a radioscandium immunoconjugate for radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Moghaddam-Banaem, L.; Jalilian, A.R.; Pourjavid, M.R.; Radfar, E.; Bahrami-Samani, A.; Yavari, K.; Mazidi, M.; Ghannadi-Maragheh, M. [Nuclear Science and Technology Research Institute (NSTRI), Tehran (IR). Radiopharmaceutical Research and Development Lab. (RRDL)

    2012-07-01

    Developing monoclonal antibodies labeled with beta-emitters has led to the introduction of important agents in radioimmunotherapy. In this work, Sc-46 chloride was obtained by thermal neutron activation flux of natural metallic scandium sample followed by dissolution in acidic media (radionuclidic purity via beta and gamma ray spectroscopy, 99.9; radiochemical purity via ITLC, > 99%) and used in radiolabeling of rituximab after conjugation with DOTA-NHS-ester. The specific activity was however not high. The conjugates were purified by molecular filtration and used in the radiolabeling. The radiochemical purity (ITLC), stability studies (ITLC and size exclusion chromatography), determination of average number of DOTA conjugated per mAb (chelate: antibody ratio, 5.8:1) and gel electrophoresis of [{sup 46}Sc]Sc-DOTA-anti-CD20 were determined followed by biodistribution studies for {sup 46}Sc and [{sup 46}Sc]Sc-DOTA-anti-CD20 i n wild type rats up to 72 h. The binding of the radiolabeled antibody was showed to be 60% on Raji cells. The final compound was stable in presence of PBS at 37 C and room temperature. The accumulation of the radiolabeled antibody in liver, spleen, kidney, heart and other tissues demonstrates a pattern similar to the other radiolabeled anti-CD20 immunoconjugates. The present study shows the possibility of antibody labeling for future use in radioimmunotherapy by {sup 47}Sc. (orig.)

  2. Radioimmunotherapy of Non-Hodgkin's Lymphoma. The interaction of radiation and antibody with lymphoma cells

    International Nuclear Information System (INIS)

    Whilst many patients with indolent Non-Hodgkin's Lymphoma (NHL) can achieve clinical remissions to first-line chemotherapy and/or radiotherapy, most will relapse. Current treatment options for relapsing patients are limited since most patients become resistant to repeated chemotherapy. Death usually occurs within 10 years of diagnosis. Overall, these disappointing results have not changed significantly in a quarter of a century and clearly advocate the urgent priority to research into potential new therapeutic approaches into this diverse and increasingly prevalent group of human tumours. Radioimmunotherapy (RIT) is currently under investigation as a new approach for the treatment of this disease. In this form of treatment, radionuclide-labeled monoclonal antibodies are able to deliver selective systemic irradiation by recognising tumour-associated antigens. The use of RIT with radiolabeled anti-CD20 antibodies in patients with recurrent B-cell lymphoma has resulted in extremely high rates of durable complete remissions. The optimal approach and mechanisms of action of successful RIT remain however largely unknown. The work described in this thesis has focused on clarifying some of the important determinants and mechanisms of effective RIT of syngeneic B-cell lymphoma, both in vivo and in vitro. A successful animal model of RIT in B cell lymphomas was established by initially generating a panel of antibodies against mouse B cell antigens. The in vitro characteristics of these antibodies have been compared with their subsequent performance, in biodistribution studies and RIT in vivo. For the first time in an in vivo model the relative contributions of antibody and irradiation are described. Some antibodies including anti-MHC Class II were shown to be effective delivery vehicles of low doses of Iodine-131. These antibodies, which appear to be inactive delivery vehicles can cure animals with low burdens of tumour. However antibodies such as anti-idiotype and anti-CD40

  3. Low-Dose Rituximab Therapy for Antibody-Mediated Rejection in a Highly Sensitized Heart-Transplant Recipient

    OpenAIRE

    Aggarwal, Ashim; Pyle, Joseph; Hamilton, John; Bhat, Geetha

    2012-01-01

    Antibody-mediated rejection is the B-cell–mediated production of immunoglobulin G antibody against the transplanted heart. The currently available therapies for antibody-mediated rejection have had marginal success, and chronic manifestations of rejection can result in an increased risk of graft vasculopathy and perhaps require repeat transplantation. Rituximab, a monoclonal antibody directed against the CD20 receptor of B-lymphocytes and approved as therapy for lymphoma, can be used in heart...

  4. Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT registered)

    International Nuclear Information System (INIS)

    A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT registered) application. Preclinical and clinical results are described. 90Y and 177Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated. High radiochemical purity (>99%) was routinely achieved with 90Y or 177Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both 90Y- and 177Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of ∝85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was ∝12 mGy/MBq. These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials. (orig.)

  5. Preparation & in vitro evaluation of 90 Y-DOTA-rituximab

    Directory of Open Access Journals (Sweden)

    Mythili Kameswaran

    2016-01-01

    Full Text Available Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin′s lymphoma (NHL. Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA to rituximab, its radiolabelling with [90] Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Methods: Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90 Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Results: Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with [90] Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90 Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with [90] Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant K d for 90 Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of [90] Y-DOTA-rituximab. Interpretation & conclusions: p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90 Y was

  6. Low-Dose Rituximab Therapy for Antibody-Mediated Rejection in a Highly Sensitized Heart-Transplant Recipient

    Science.gov (United States)

    Aggarwal, Ashim; Pyle, Joseph; Hamilton, John; Bhat, Geetha

    2012-01-01

    Antibody-mediated rejection is the B-cell–mediated production of immunoglobulin G antibody against the transplanted heart. The currently available therapies for antibody-mediated rejection have had marginal success, and chronic manifestations of rejection can result in an increased risk of graft vasculopathy and perhaps require repeat transplantation. Rituximab, a monoclonal antibody directed against the CD20 receptor of B-lymphocytes and approved as therapy for lymphoma, can be used in heart-transplant patients for the management of antibody-mediated rejection. We present the case of a 52-year-old woman with high allosensitization (pre-transplantation panel reactive antibody level, 72%) who underwent successful orthotopic heart transplantation. Postoperatively, her acute antibody-mediated rejection with concomitant cellular rejection was successfully treated with low-dose rituximab. The patient died 5 months later because of multiple other medical problems. The present case suggests a role for low-dose rituximab as therapy for antibody-mediated rejection in heart-transplant patients. PMID:23304051

  7. Bivalent fragment of the ior-CEA1 antibody. A challenge to the positive CEA tumors radioimmunotherapy

    International Nuclear Information System (INIS)

    The directed radiotherapy of the solid tumors with fragments recombinants of radiolabelled antibodies is a topic of current investigation, so much at preclinical level as clinical. This work describes the preclinical characterization of a new fragment type diabody of the AcMo ior CEA1 that has been labelled with 131 I for their use in the diagnosis and the therapy of CEA positive tumors. The radiolabelling methodology used allows the incorporation of more than 90% of the radio iodine to the molecule without committing the capacity of recognition of its antigen significantly. The combination of the favourable properties pharmacy kinetic and high selective accumulation in the tumor, they make of the diabody anti CEA an appropriate candidate for the radioimmunodiagnosis and the radioimmunotherapy of tumors that expresses CEA (Author)

  8. Radioimmunotherapy of fungal infection with 213-Bi- and 188-Re-labeled antibody

    International Nuclear Information System (INIS)

    Aim: Radioimmunotherapy (RIT) is a therapeutic modality that utilizes monoclonal antibodies (mAb) radiolabeled with therapeutic radioisotopes to selectively deliver lethal doses of radiation to cells. We hypothesized that 18B7 mAb (murine IgG1), specific for Cryptoccocus neoformans (CN) polysaccharide capsule, may be used to deliver fungicidal doses of radioisotopes to the sites of CN infection in vitro and in vivo. Materials and Methods: 18B7 mAb was radiolabeled with either the beta-emitter 188-Rhenium (188Re) or with the alpha-emitter 213-Bismuth (213Bi). The biodistribution of radiolabeled 18B7 was measured in BALB/c mice with and without intratracheal CN infection. For in vitro killing assays 105 CN cells/well were treated with 0-3.2 μCi 213Bi-18B7 (3 h incubation), 32 μCi 188Re-18B7 (48 h incubation) or with radiolabeled IgG1 MOPC21 as a control and minimal inhibitory concentrations (MIC) were determined. To compare the activity of radiolabeled mAb's against CN infection with an established antifungal drug, we evaluated the susceptibility of CN strain to Amphoterecin B. In vivo therapy of CN was conducted in groups of 10 A/JCr mice infected intravenously with 105 CN cells 24 h prior to treatment with 50-200 μCi 213Bi- or 188Re-18B7, 213Bi- or 188Re-MOPC21, unlabeled 18B7 or saline. Student's t test for unpaired data was used to analyze in vitro data, and log-rank test - for animal survival data. Results: MAb 18B7 preserved its immunoreactivity post-labeling and delivered 10% ID/g to the lungs of the CN-infected BALB/c mice in 24 h after injection. Two-log reduction in colony forming units (CFU) was achieved in treatment of CN with 213Bi-18B7 and 188Re-18B7, which compared favorably with Amphoterecin B. MIC's were determined to be 0.4 μCi/1.5 mg and 4 μCi/1.25 mg mAb for 213Bi-18B7 and 188Re-18B7, respectively. The fungicidal activity of irrelevant mAb 213Bi-or 188Re-MOPC21 was negligible (P213Bi-18B7 and of 100 μCi 188Re-18B7 significantly (P<0

  9. Guideline for radioimmunotherapy of rituximab relapsed or refractory CD20{sup +} follicular B-cell non-Hodgkin's lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, M.; Behr, T.; Gruenwald, F.; Knapp, W.H. [Deutsche Gesellschaft fuer Nuklearmedizin (DGN) (Germany); Truemper, L.; Schilling, C. von [Deutsche Gesellschaft fuer Haematologie und Onkologie e.V., Muenchen (Germany)

    2004-10-01

    This guideline is a prerequisite for the quality management in the treatment of non-Hodgkin-lymphomas using radioimmunotherapy. It is based on an interdisciplinary consensus and contains background information and definitions as well as specified indications and detailed contraindications of treatment. Essential topics are the requirements for institutions performing the therapy. For instance, presence of an expert for medical physics, intense cooperation with all colleagues committed to treatment of lymphomas, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how the treatment has to be carried out technically. Here, quality control and documentation of labelling are of greatest importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with those colleagues (haematology-oncology) who propose, in general, radioimmunotherapy under consideration of the development of the disease. (orig.)

  10. Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging

    Energy Technology Data Exchange (ETDEWEB)

    Orcutt, Kelly Davis; Slusarczyk, Adrian L. [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Cieslewicz, Maryelise [Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Ruiz-Yi, Benjamin [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Bhushan, Kumar R. [Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Frangioni, John V. [Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Wittrup, K. Dane, E-mail: wittrup@mit.ed [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States)

    2011-02-15

    Introduction: In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelates for use in PRIT applications. Methods: We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to DOTA, reformatted as a single chain variable fragment (scFv). Results: Modeling predicts that for high antigen density and saturating bsAb dose, a hapten-binding affinity of 100 pM is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nM to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2{+-}1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen, pretargeted high-affinity scFv results in significantly higher tumor retention of a {sup 111}In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. Conclusions: We have engineered a versatile, high-affinity, DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals.

  11. Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging

    International Nuclear Information System (INIS)

    Introduction: In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelates for use in PRIT applications. Methods: We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to DOTA, reformatted as a single chain variable fragment (scFv). Results: Modeling predicts that for high antigen density and saturating bsAb dose, a hapten-binding affinity of 100 pM is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nM to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2±1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen, pretargeted high-affinity scFv results in significantly higher tumor retention of a 111In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. Conclusions: We have engineered a versatile, high-affinity, DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals.

  12. Preliminary report on the clinical application of 131I-chTNT monoclonal antibody radio-immunotherapy in patients with re-operated glioma

    International Nuclear Information System (INIS)

    Objective: To study the safety and therapeutic efficacy of 131I-chTNT monoclonal antibody radio-immunotherapy (RIT) via intratumoral Ommaya reservoir placed during re-operation in patients with glioma. Methods: Twelve patients with recurrent glioma (WHO stage III-IV) underwent second operation(tumor de-bulking) and Ommaya reservoir was placed in the residual cavity. 131I-chimeric tumor necrosis treatment (131I-chTNT) monoclonal antibody 1.5 ml (1110 MBq) was injected into the reservoir as radio-immunotherapy two weeks after the operation and the injection was repeated another two weeks later. Blood chemistry (with hepatic, renal and thyroid functions), brain CT and MR imaging were studied before operation, 3 months and 6 months later. The karnofsky scores were noticed. Results: As shown with the imaging studies, the total treatment response rate was 66.67% (CR 50% and PR 16.67%). General condition was satisfactory and laboratory studies were within normal ranges. There were no serious untoward reactions. Conclusion: Administration of 131I-chTNT monoclonal antibody via Ommaya reservoir as radio-immunotherapy post-operatively was safe and effective in patients with recurrent glioma. The process warranted further study. (authors)

  13. Spotlight on rituximab in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis: current perspectives

    Directory of Open Access Journals (Sweden)

    Moog P

    2015-11-01

    Full Text Available Philipp Moog, Klaus Thuermel Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Abstract: A 54-year-old patient presented to his general practitioner because of strong muscle pain in both thighs. Inflammatory parameters (CRP 16.3 mg/dL and white blood cells (15 g/L were elevated. The patient reported a weight loss of 10 kg in 4 weeks. There was no fever or any other specific symptoms. Urine dipstick examination and computed tomography of the chest were unremarkable. Because of increasing symptoms, the patient was referred to our department. Magnetic resonance tomography showed diffuse inflammatory changes of the muscles of both thighs. Neurological examination and electrophysiology revealed axonal sensorimotor neuropathy and ground-glass opacities of both lungs had occurred. Serum creatinine increased to 229 µmol/L within a few days, with proteinuria of 3.3 g/g creatinine. Kidney biopsy showed diffuse pauci-immune proliferative glomerulonephritis. Proteinase 3-specific antineutrophil cytoplasmic antibodies were markedly increased. Birmingham Vasculitis Activity Score was 35. Within 2 days, serum creatinine further increased to 495 µmol/L. Plasma exchange, high-dose glucocorticosteroids, and hemodialysis were started. The patient received cyclophosphamide 1 g twice and rituximab 375 mg/m2 four times according to the RITUXVAS protocol. Despite ongoing therapy, hemodialysis could not be withdrawn and had to be continued over 3 weeks until diuresis normalized. Glucocorticosteroids were tapered to 20 mg after 2 months, and serum creatinine was 133 µmol/L. However, nephritic urinary sediment reappeared. Another dose of 1 g cyclophosphamide was given, and glucocorticosteroids were raised for another 4 weeks. After 6 months, the daily prednisolone dose was able to be tapered to 5 mg. Serum creatinine was 124 µmol/L, proteinuria further decreased to 382 mg/g creatinine, and the Birmingham

  14. Rituximab in Combination with Corticosteroids for the Treatment of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A NICE Single Technology Appraisal

    OpenAIRE

    Latimer, Nicholas R.; Carroll, Christopher; Wong, Ruth; Tappenden, Paul; Venning, Michael C.; Luqmani, Raashid

    2014-01-01

    As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of rituximab (Roche Products) to submit evidence of the clinical and cost effectiveness of rituximab in combination with corticosteroids for treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as...

  15. Bismuth-212-labeled anti-Tac monoclonal antibody: alpha-particle-emitting radionuclides as modalities for radioimmunotherapy

    International Nuclear Information System (INIS)

    Anti-Tac, a monoclonal antibody directed to the human interleukin 2 (IL-2) receptor, has been successfully conjugated to the alpha-particle-emitting radionuclide bismuth-212 by use of a bifunctional ligand, the isobutylcarboxycarbonic anhydride of diethylenetriaminepentaacetic acid. The physical properties of 212Bi are appropriate for radioimmunotherapy in that it has a short half-life, deposits its high energy over a short distance, and can be obtained in large quantities from a radium generator. Antibody specific activities of 1-40 microCi/microgram (1 Ci = 37 GBq) were achieved. Specificity of the 212Bi-labeled anti-Tac was demonstrated for the IL-2 receptor-positive adult T-cell leukemia line HUT-102B2 by protein synthesis inhibition and clonogenic assays. Activity levels of 0.5 microCi or the equivalent of 12 rad/ml of alpha radiation targeted by anti-Tac eliminated greater than 98% the proliferative capabilities of HUT-102B2 cells with more modest effects on IL-2 receptor-negative cell lines. Specific cytotoxicity was blocked by excess unlabeled anti-Tac but not by human IgG. In addition, an irrelevant control monoclonal antibody of the same isotype labeled with 212Bi was unable to target alpha radiation to cell lines. Therefore, 212Bi-labeled anti-Tac is a potentially effective and specific immunocytotoxic reagent for the elimination of IL-2 receptor-positive cells. These experiments thus provide the scientific basis for use of alpha-particle-emitting radionuclides in immunotherapy

  16. Using anti-VEGF monoclonal antibody and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer

    International Nuclear Information System (INIS)

    Objective: To study the biodistribution of 131I-anti-VEGF monoclonal antibody (Sc-7269)-- Dextran Magnetic Nanoparticles (DMN) in nude mice bearing human liver cancer where an external magnetic field was focused on, and to evaluate its therapeutic effects and security. Methods: 18 nude mice bearing human liver cancer where an external magnetic field was focused on, were used for the biodistribution study after intratumoral injection (n=9) or intravenous injection (n=9) of 131I-Sc-7269--DMN Another 25 tumor-bearing nude mice were divided into five groups, four groups of them were treated with 7.4 MBq/0.1 ml 131I-Sc-7269-DMN, 131I-Sc-7269, 131I- DMN and 131I by a single intratumoral injection, respectively. And an external magnetic field was bound to the tumor of the nude mice that were rejected 131I-Sc-7269--DMN or 131I-DMN. For control study, the remaining one group was injected with Hanks' balanced salt solution. Tumor Growth Delay (TGD) and tumor inhibition rate were observed as antitumor effect. Peripheral white blood cells counts anti the loss of body weight were tested as an indicator of systemic toxicity. Results: The retention percentages of radioactivity (% injected dose per gram, %ID/g) in tumors after intratumoral injection were 104.06%ID/g, 101.58%ID/g and 100.96%ID/g at 4, 24 and 48 h, respectively, while in the case of intravenous injection, the lower %ID/g values were 85.33%ID/g, 89.67%ID/g and 90.00%ID/g, respectively(P131I-Sc-7269--DMN (13.3±3.3d) was the longest, and tumor inhibition rate (89.0%) was the highest, when compared with other groups. However, systemictoxicity was not significantly increased in 131I-Sc-7269-DMN-treated mice as monitqred by the decrease in peripheral white blood cells counts and the loss of body weight. Conclusions: The radioimmunotherapy of intratumoral injection of 131I-Sc-7269-DMN may be safe and efficient for the treatment of liver cancer. Furthermore, the radioimmunotherapy using DMN as a 'carder system' may be a

  17. Radioimmunotherapy of Non-Hodgkin's Lymphoma. The interaction of radiation and antibody with lymphoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Illidge, T.M

    1999-06-01

    Whilst many patients with indolent Non-Hodgkin's Lymphoma (NHL) can achieve clinical remissions to first-line chemotherapy and/or radiotherapy, most will relapse. Current treatment options for relapsing patients are limited since most patients become resistant to repeated chemotherapy. Death usually occurs within 10 years of diagnosis. Overall, these disappointing results have not changed significantly in a quarter of a century and clearly advocate the urgent priority to research into potential new therapeutic approaches into this diverse and increasingly prevalent group of human tumours. Radioimmunotherapy (RIT) is currently under investigation as a new approach for the treatment of this disease. In this form of treatment, radionuclide-labeled monoclonal antibodies are able to deliver selective systemic irradiation by recognising tumour-associated antigens. The use of RIT with radiolabeled anti-CD20 antibodies in patients with recurrent B-cell lymphoma has resulted in extremely high rates of durable complete remissions. The optimal approach and mechanisms of action of successful RIT remain however largely unknown. The work described in this thesis has focused on clarifying some of the important determinants and mechanisms of effective RIT of syngeneic B-cell lymphoma, both in vivo and in vitro. A successful animal model of RIT in B cell lymphomas was established by initially generating a panel of antibodies against mouse B cell antigens. The in vitro characteristics of these antibodies have been compared with their subsequent performance, in biodistribution studies and RIT in vivo. For the first time in an in vivo model the relative contributions of antibody and irradiation are described. Some antibodies including anti-MHC Class II were shown to be effective delivery vehicles of low doses of Iodine-131. These antibodies, which appear to be inactive delivery vehicles can cure animals with low burdens of tumour. However antibodies such as anti-idiotype and anti

  18. Clinical scale preparation and evaluation of 131I-Rituximab for Non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) with anti CD20 MoAb conjugated to a β- emitting radioisotope like 131I or 90Y has the added advantage of delivering radiation not only to tumor cells that bind the antibody but also due to a crossfire effect, to neighboring tumor cells inaccessible to the antibody. In order to make available an indigenous radioimmunotherapeutic agent for Non Hodgkin's Lymphoma (NHL), radioiodinated Rituximab has been prepared and evaluated at a clinical scale. Radioiodination of Rituximab was performed by the conventional Chloramine T method using 7.4 GBq Na131I in a lead shielded plant. Six batches of radioiodination were prepared and characterized by electrophoresis and HPLC to evaluate the reproducibility of the product. The product remained stable retaining the radiochemical purity > 95% upto 5 days after radioiodination. In vitro cell binding studies and biodistribution studies in normal Swiss mice have indicated the potential of this molecule as a radioimmunotherapeutic agent for NHL. (orig.)

  19. Rituximab for autoimmune blistering diseases: recent studies, new insights

    OpenAIRE

    Lunardon, Luisa; Payne, Aimee S.

    2012-01-01

    Rituximab, an anti-CD20 monoclonal antibody, has been successfully used off-label for treatment of autoimmune blistering diseases. We discuss rituximab mechanisms of action, host factors that may affect response to rituximab, and the efficacy and safety of rituximab in autoimmune blistering diseases, incorporating recent data on the use of rituximab in other autoimmune disease patients.

  20. Stability of 188Re Labeled antibody for radioimmunotherapy and the effect of stabilizing agents

    International Nuclear Information System (INIS)

    For clinical application of beta-emitter labeled antibody, high specific activity is important. Carrier-free 188Re from 188W/ 188Re generator is an ideal radionuclide for this purpose. However, low stability of 188Re labeled antibody, especially in high specific activity, due to radiolytic decomposition by high energy (2.1 MeV) beta ray was problem. We studied the stability of 188Re labeled antibody, and stabilizing effect of several stabilizers. Pre-reduced monoclonal antibody (CEA79.4) was labeled with 188Re by incubating with generator-eluted 188Re-perrhenate in the presence of stannous tartrate for 2 hr at room temperature. Radiochemical purity of each preparation was determined by chromatography. Human serum albumin was added to the labeled antibodies (2%). Stability of 188Re-CEA79.4 was investigated in the presence of ascorbic acid, ethanol, or Tween 80 as stabilizing agents. Labeling efficiencies were 88±4% (n=12). Specific activities of 1.25 ∼4.77 MBq/μg were obtained. If stored after purging with N2, all the preparations were stable for 10 hr. However, stability decreased in the presence of air. Perrhenate and 188Re-tartrate was major impurity in declined preparation. Colloid-formation was not a significant problem in all cases. Addition of ascorbic acid stabilized the labeled antibodies either under N2 or under air by reducing the formation of perrhenate. High specific activity 188Re labeled antibody is unstable, especially, in the presence of oxygen. Addition of ascorbic acid increased the stability

  1. Selection of monoclonal antibody E48 IgG or U36 IgG for adjuvant radioimmunotherapy in head and neck cancer patients.

    OpenAIRE

    van Bree, R.; Roos, J C; Plaizier, M. A.; Quak, J.J.; Van Kamp, G J; den Hollander, W.; Snow, G. B.; van Dongen, G. A.

    1997-01-01

    Preliminary data from recent clinical radioimmunoscintigraphy studies indicate that 99mTc-labelled murine monoclonal antibodies (MAbs) E48 and U36 have a similar ability to target squamous cell carcinoma of the head and neck (HNSCC) selectively. In the present study we describe additional aspects of murine and chimeric MAb (mMAb and cMAb) E48 and U36, which might influence the selection of one MAb for adjuvant radioimmunotherapy. To make direct comparison possible, ten patients received 11.2 ...

  2. Combination therapy with rituximab and cyclophosphamide in the treatment of anti-neutrophil cytoplasmic antibodies (ANCA) positive pulmonary hemorrhage: case report

    OpenAIRE

    Lehman Thomas JA; Baird Emily M; Worgall Stefan

    2011-01-01

    Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with pulmonary hemorrhage is rare in childhood. Standard treatment includes corticosteroids and cyclophosphamide (CYC), which is associated with a high level of toxicity. We report a white female with ANCA positive pulmonary hemorrhage who was treated with cyclophosphamide (CYC) and rituximab (RTX) combination therapy.

  3. {sup 99m}Tc-rituximab radiolabelled by photo-activation: a new non-Hodgkin's lymphoma imaging agent

    Energy Technology Data Exchange (ETDEWEB)

    Gmeiner Stopar, T.; Fettich, J.; Hojker, S. [University Medical Centre Ljubljana, Department for Nuclear Medicine, Ljubljana (Slovenia); Mlinaric-Rascan, I. [University of Ljubljana, Faculty of Pharmacy, Ljubljana (Slovenia); Mather, S.J. [St Bartholomew' s Hospital, Cancer Research UK, Department Nuclear Medicine, London (United Kingdom)

    2006-01-01

    Rituximab was the first chimeric monoclonal antibody to be approved for treatment of indolent B-cell non-Hodgkin's lymphoma (NHL). It is directed against the CD20 antigen, which is expressed by 95% of B-cell NHLs. The aim of this study was to explore the possibility of radiolabelling rituximab with {sup 99m}Tc for use as an imaging agent in NHL for early detection, staging, remission assessment, monitoring for metastatic spread and tumour recurrence, and assessment of CD20 expression prior to (radio)immunotherapy. Rituximab was purified from Mabthera solution (Roche), photo-activated at 302 nm by UV irradiation and radiolabelled with {sup 99m}Tc. The effectiveness of the labelling method was evaluated by determination of the number of free thiol groups per photoreduced antibody, radiochemical purity and in vitro stability of {sup 99m}Tc-rituximab. On average, 4.4 free thiol groups per photoreduced antibody were determined. Radiolabelling yields greater than 95% were routinely observed after storage of the photo-activated antibody at -80 C for 195 days. The direct binding assay showed preserved ability of {sup 99m}Tc-rituximab to bind to CD20, with an average immunoreactive fraction of 93.3%. The internalisation rate was proven to be low, with only 5.3% of bound {sup 99m}Tc-rituximab being internalised over 4 h at 37 C. Our results demonstrate that {sup 99m}Tc-rituximab of high radiochemical purity and with preserved binding affinity for the antigen can be prepared by photoreduction and that the method shows good reproducibility. {sup 99m}Tc-rituximab will be further explored as an imaging agent applicable in NHL for the purposes mentioned above. (orig.)

  4. Sequential radioimmunotherapy with 177Lu- and 211At-labeled monoclonal antibody BR96 in a syngeneic rat colon carcinoma model

    DEFF Research Database (Denmark)

    Eriksson, Sophie E; Elgström, Erika; Bäck, Tom;

    2014-01-01

    UNLABELLED: Alpha-particle emitters, such as astatine-211 (211At), are generally considered suitable for the treatment of small cell clusters due to their short path length, while beta-particle emitters, for example, Lutetium-177 (177Lu), have a longer path length and are considered better for...... small, established tumors. A combination of such radionuclides may be successful in regimens of radioimmunotherapy. In this study, rats were treated by sequential administration of first a 177Lu-labeled antibody, followed by a 211At-labeled antibody 25 days later. METHODS: Rats bearing solid colon...... carcinoma tumors were treated with 400 MBq/kg body weight 177Lu-BR96. After 25 days, three groups of animals were given either 5 or 10 MBq/kg body weight of 211At-BR96 simultaneously with or without a blocking agent reducing halogen uptake in normal tissues. Control animals were not given any 211At-BR96...

  5. Melanin-targeting antibody as a potential agent for radioimmunotherapy of melanoma

    International Nuclear Information System (INIS)

    Aim: Melanoma is a cancer of increasing incidence for which new methods of treatment and imaging are urgently needed. Currently there is no effective therapy for metastatic melanoma as this tumor is resistant to radiation and chemotherapy. The majority of human melanomas are pigmented with melanin. Here we investigated the possibility of using a melanin-binding antibody (mAb 6D2) which was originally developed against fungal melanin as a delivery vehicle for RIT of pigmented melanoma. Materials and Methods: MAb 6D2 (IgM type) was generated from hybridomas obtained from mice immunized with melanin isolated from Cryptococcus neoformans. The mAb was radiolabeled with 213Bi or 111In via bifunctional chelator CHXA'' and with 188Re - via 'direct labeling'. The immunoreactivity of radiolabeled 6D2 mAb towards fungal melanin was tested by immunofluorescence. Cell binding of 213Bi-6D2, 188Re-6D2 and irrelevant IgM 12A1 was evaluated by incubating 2 μg/mL mAb with 0.23-2 x 106 human slightly pigmented melanoma cells SK-28-MEL (whole or lysed) which were grown with or without 110 μM L-tyrosine to promote melanin formation. In vivo binding of 111In-6D2 was studied by scintigraphic imaging in nude mice injected IP with 2.8 x 106 SK-28-MEL cells 24 h before 111In-6D2; biodistribution of 188Re-6D2 was performed in nude mice bearing SK-28-MEL xenografted tumors. Results: The immunoreactivity of radiolabeled 6D2 mAb to melanin was demonstrated by immunofluorescence. Cell binding of 213Bi-6D2 and 188Re-6D2 was higher for the melanoma cells grown with 110 μM L-tyrosine suggesting melanin-specific binding. There was no significant difference (P>0.05) in binding to the whole or lysed cells which may be due to reactivity with melanin or precursors found on the cell surface. In mice injected IP with SK-28-MEL cells there was more retention of 111In-6D2 in intraperitoneal cavity compared to irrelevant 111In-IgM and control animals with no tumor cells. The biodistribution of 188Re-6D2 m

  6. Single Chain Fv Constructs of Anti-Ganglioside GD2 Antibodies for Radioimaging and Radioimmunotherapy

    International Nuclear Information System (INIS)

    of its broad and usually homogeneous distribution in human solid tumors, and most importantly, their absence on cell membranes of normal human tissues. In separate experiments, we have shown that T-cells transduced with the herpes simplex viral thymidine kinase (HSV-tk) gene can be radiolabeled with 131I-FIAU to a safe nuclear radiation dose. Using a dicistronic construct we are inserting chimeric immune receptor plus HSV-tk into T-cells to allow such their trafficking to be radioactively monitored. We plan to study the role of cytokines, chemoreceptors and CD4 helper T-cells in recruiting CD8+ transduced T-cells to the tumor site. These studies should provide us with an adoptive cell therapy approach to target cytotoxicity to human tumors, and a lymphocyte tracking tool to study delivery to the tumor sites, to determine if they proliferate locally and/or recirculate. Such pharmacologic information is crucial for optimizing gene-modified T-cells in future clinical trials. Single chain FV constructs of anti-ganglioside GD2 antibodies for radioimaging

  7. Radioimmunotherapy with Zevalin in Patients with Non-Hodgkin's Lymphoma

    International Nuclear Information System (INIS)

    Full text: The aim of this prospective study was to asses the value of new radioimmunotherapy treatment with Zevalin (IgG1 monoclonal antibody covalently bound to tiuxetan and labeled with Y-90) for adult patients with refractory or relapsed CD20+ follicular B-cell non- Hodgkin's lymphoma (NHL). This multicentric study included eight patients (median age 55 years, range 51-59 years) from five hospitals in Croatia. The treatment involved a day 1 infusion of rituximab 250 mg /m2; a second infusion of rituximab on day 8, followed by 'slow push' 10 minute infusion of Zevalin (median dose 1020 MBq; range 820- 1177 MBq). On follow-up 12 weeks after treatment response was achieved in six patients (75%). In three patients tumor mass was completely disappeared (complete response), and in other three patients tumor mass was significantly decreased (partial response). Hematological toxicity was observed in three patients and manifested with infections requiring hospitalization. One patient died because of extreme pancytopenia and Candida sepsis, in spite of support with granulocyte colony-stimulating factor. The median time to lowest blood counts was four weeks after Zevalin injection. Acute and non-hematological side effects were not observed. Our preliminary results confirmed Zevalin as a very effective therapy for patients with refractory or relapsed CD20+ follicular B-cell NHL. One should be aware of hematologic toxicity; therefore the close follow-up is required. (author)

  8. Rituximab Injection

    Science.gov (United States)

    ... a certain type of medication called a tumor necrosis factor (TNF) inhibitor. Rituximab is also used with ... redness, tenderness, swelling or warmth of area of skin chest tightness Rituximab may cause other side effects. ...

  9. Nature of the bifunctional chelating agent used for radioimmunotherapy with yttrium-88 monoclonal antibodies: critical factors in determining in vivo survival and organ toxicity

    International Nuclear Information System (INIS)

    One factor that is critical to the potential effectiveness of radioimmunotherapy is the design of radiometal-chelated antibodies that will be stable in vivo. Stability in vivo depends on the condition that both the chelate linkage and radiolabeling procedures not alter antibody specificity and biodistribution. In addition, synthesis and selection of the chelating agent is critical for each radiometal in order to prevent inappropriate release of the radiometal in vivo. In the present study, we compare the in vivo stability of seven radioimmunoconjugates that use different polyaminocarboxylate chelating agents to complex yttrium-88 to the mouse anti-human interleukin-2 receptor monoclonal antibody, anti-Tac. Chelate linkage and radiolabeling procedures did not alter the immunospecificity of anti-Tac. In order to assess whether yttrium was inappropriately released from the chelate-coupled antibody in vivo, iodine-131-labeled and yttrium-88 chelate-coupled antibodies were simultaneously administered to the same animals to correlate the decline in yttrium and radioiodinated antibody activity. The four stable yttrium-88 chelate-coupled antibodies studied displayed similar iodine-131 and yttrium-88 activity, indicating minimal elution of yttrium-88 from the complex. In contrast, the unstable yttrium-88 chelate-coupled antibodies had serum yttrium-88 activities that declined much more rapidly than their iodine-131 activities, suggesting loss of the radiolabel yttrium-88 from the chelate. Furthermore, high rates of yttrium-88 elution correlated with deposition in bone. Four chelating agents emerged as promising immunotherapeutic reagents: isothiocyanate benzyl DTPA and its derivatives 1B3M, MX, and 1M3B

  10. Preclinical Evaluation of 90Y Labelled Rituximab and ERIC-1: Two Antibodies for Tumour Therapy. Chapter 5

    International Nuclear Information System (INIS)

    The project described in this chapter focuses on harnessing the great potential of radionuclide therapy, using various vehicles to transport radionuclides into tumour tissues. The main aim of the project was to make specific vehicle molecules whose tumour affinity and suitability for radioactive coupling have been proven through laboratory trials on animals and cell cultures at the Department of Nuclear Medicine, University of Cologne, Germany, and to label them with 90Y. The vectors to transport radionuclides into tumour tissue for treatment were antibodies against lymphomas and neuroblastomas. Tumour pretargeting has shown clear advantages over the direct application of labelled antibodies with regard to tumour to background ratios. The pretargeting strategy would be first evaluated on cell cultures and the results then transferred to in vivo experiments on tumour bearing mice. Briefly, the first component of a three step pretargeting strategy would consist of the biotinylated antibody. This would include the protocol for determination of the number of biotin molecules per antibody. Using this technique, a stock of biotinylated antibody in lyophilized form can be built up, ready for further experiments. In the second step, commercially available avidin streptavidin would be used. The third and final step is the binding of radiolabelled (188Re, 90Y) biotin to the tumour cells through the avidin antibody bridge, after administration of a clearing agent. Initial evaluations of the potential radiopharmaceuticals have been carried out by in vitro experiments on cell lines expressing the corresponding antigen. The work done so far for the three step pretargeting method can be summarized as follows: —— Yttrium-90 labelling of biotin DOTA; —— Coupling of biotinylated rituximab to CD20 positive Raji cells; —— Successful labelling of cells conjugated with a complex of biotinylated antibody and avidin with 90Y DOTA biotin; —— First animal experiments with

  11. Radiolabeling parameters of {sup 177}Lu-DOTA-RITUXIMAB

    Energy Technology Data Exchange (ETDEWEB)

    Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de, E-mail: adriana.avfernandes@gmail.com [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2013-07-01

    Cancer treatment using radioimmunotherapy (RIT) has been the focus of much research in the last two decades. In RIT, a radioisotope is coupled to a monoclonal antibody (mAb) to form a tumor-specific target agent to improve the cytocidal effect of the mAbs. RIT allows the systemic delivery of radiation to disease target by mAbs while sparing normal tissues. Rituximab® (Mabthera - Roche) is a chimeric mouse-human monoclonal antibody; it selectively binds with high affinity to the CD20 antigen, a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and in more than 90% of B cell non-Hodgkin's lymphomas (NHL). The conjugation and radiolabeling process involve special conditions of pH and temperature, long processes of manipulation and mixing. All this process can damage the antibody structure and compromise its clinical application. Therefore, these parameters must be largely studied. The aim of this work was to evaluate the best radiolabeling conditions of DOTA-rituximab. Briefly, 10 mg of antibody previously purified by ultrafiltration device was conjugated with DOTA-NHS-ester (Macrocyclics) in 50 fold molar excess. The reaction was conducted for 1 hour in phosphate buffer pH 8.0 and gently mixing at room temperature, remaining for 24 hours under refrigeration. The immunoconjugated was purified by size exclusion column and ultrafiltration device. The radiolabeled parameters studied were: immunoconjugated mass, activity of {sup 177}LuCl{sub 3}, reaction time, temperature and pH. The radiochemical purity of the preparations was determined using analysis by thin layer chromatography (TLC-SG plates). The best studied condition presented radiochemical purity above 95% and the integrity of antibody was preserved. (author)

  12. Initial experience with locoregional radioimmunotherapy using 131I-labelled monoclonal antibodies against tenascin (BC-4) for treatment of glioma (WHO III and IV)

    International Nuclear Information System (INIS)

    Aim: None of the established treatments (surgery, radiotherapy, chemotherapy) for malignant glioma has improved its very poor prognosis. Adjuvant locoregional radioimmunotherapy (RIT) represents a new therapeutic approach. We present our initial experience with this therapeutic tool with respect to adverse effects, biokinetics and clinical follow-up. Methods: Following surgery and radiotherapy, 12 patients with glioma (4, WHO stage III; 8, WHO stage IV) underwent 1-5 RIT-cycles (average dose 1100 MBq 131labelled monoclonal BC-4 antibodies) at six week intervals. Follow-up included serial FDG-PET and MRI investigations. Evaluation of biokinetics included whole body scans, together with analysis of blood, urine and fluid from the tumor cavity. Results: Following RIT, four patients experienced temporary seizures, which, in one case, were associated with temporary aphasia. Eight patients developed HAMA (human anti-mouse anti-bodies) during follow-up. Mean biologic half-life of the radiopharmaceutical in the resection cavity was 3.9 d (range: 1.0-10.2 d) and remained stable intraindividually during further RIT-cycles. The antibody/radionuclide conjugate remain stable in the tumor cavity for at least 5 d. Median survival presently stands at 18.5 months compared to 9.7 months in a historical patient group (n=89) undergoing conventional therapeutic strategies. Five patients show no signs of recurrence. In three patients with post-surgical evidence of residual tumor, one patient showed partial remission, one stable disease, and one progressive disease during RIT. Four patients without evidence of residual tumor mass at the beginning of RIT developed recurrence during therapy. Conclusions: Initial experience demonstrates that locoregional RIT is a well tolerated treatment modality that may represent a promising new approach in the management of patients with malignant glioma. Advantages of local application include passage of the blood-brain barrier, high concentration of

  13. The characteristics of human antibody targeting the Epidermal Growth Factor Receptor in vivo for radioimmunotherapy in a small animal model

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Jung; Choi, Tae Hyun; Kim, Byoung Soo; Cheon, Gi Jeong [Korea Institue of Radiological and Medical Sciences, Seoul (Korea, Republic of); Hong, Kwang Won; Chang, Ki Hwan; Shin, Yong Won; Ryoo, Kyung Hwan; Shin, Yong Nam; Kim, Se Ho [Green Cross Corp., Yongin (Korea, Republic of)

    2010-05-15

    The identification of epidermal growth factor receptor (EGFR) as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including Erbitux for colon cancer. Many therapeutic approaches are aimed at the EGFR. Erbitux is example of monoclonal antibody inhibitors. The monoclonal antibodies block the extracellular ligand binding domain. EGFR4-2, IgG human monoclonal antibody, has been developed on the basis of human antibody gene library in Green Cross Corp. Small animal imaging is useful for preclinical evaluation of radiolabeled antibody to see biodistribution and targeting ability at serial time points in same animals

  14. Radioimmunotherapy for pancreatic carcinoma using 131I-labeled monoclonal antibody Nd2 in xenografted nude mice

    International Nuclear Information System (INIS)

    We investigated the biodistribution, radiolocalization, and radioimmunotherapeutic potential of 131I-labeled Nd2 in athymic nude mice bearing human pancreatic carcinoma xenografts. 131I-Nd2 was accumulated at high levels in the tumor, in contrast to blood, liver, spleen, and other normal organs. The tumor was clearly delineated in scintigraphs. The volumes of tumors of mice injected with 7.4 MBq of 131I-Nd2 were 80% less than those of tumors before injection of radiolabeled Nd2. Fibrous or vacuolar degeneration was seen in histological sections of tumors of 7-week-treated mice. The growth of tumors in mice treated with misonidazole, a hypoxic cell radiosensitizer, and then injected twice with 3.7 MBq of 131I-Nd2 was suppressed over 7 weeks. Neither leucocytopenia nor thrombocytopenia was severe after injection of radiolabeled Nd2. Thus 131I-labeled Nd2 may have clinical application in the radioimmunotherapy of pancreatic cancer. (author)

  15. Rituximab-Induced Hypersensitivity Pneumonitis

    OpenAIRE

    Tonelli, Adriano R.; Lottenberg, Richard; Robert W Allan; Sriram, P.S

    2008-01-01

    Rituximab is a chimeric anti-CD20 monoclonal antibody used to treat CD20+ non-Hodgkin's lymphoma. Although pulmonary adverse reactions such as cough, rhinitis, bronchospasm, dyspnea and sinusitis are relatively common, other respiratory conditions like cryptogenic organizing pneumonia, interstitial pneumonitis and diffuse alveolar hemorrhage have rarely been reported. Only 2 possible cases of rituximab-associated hypersensitivity pneumonitis have been described to date. We present a case of h...

  16. Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers

    International Nuclear Information System (INIS)

    Human monoclonal antibodies (MAbs) are needed for colon cancer radioimmunotherapy (RIT) to allow for repeated injections. Carcinoembryonic antigen (CEA) being the reference antigen for immunotargeting of these tumors, we developed human anti-CEA MAbs. XenoMouse®-G2 animals were immunized with CEA. Among all the antibodies produced, two of them, VG-IgG2κ and VG-IgM, were selected for characterization in vitro in comparison with the human-mouse chimeric anti-CEA MAb X4 using flow cytometry, surface plasmon resonance, and binding to radiolabeled soluble CEA and in vivo in human colon carcinoma LS174T bearing nude mice. Flow cytometry analysis demonstrated binding of MAbs on CEA-expressing cells without any binding on NCA-expressing human granulocytes. In a competitive binding assay using five reference MAbs, directed against the five Gold CEA epitopes, VG-IgG2κ and VG-IgM were shown to be directed against the Gold 4 epitope. The affinities of purified VG-IgG2κ and VG-IgM were determined to be 0.19 ± 0.06 × 108 M-1 and 1.30 ± 0.06 × 108 M-1, respectively, as compared with 0.61 ± 0.05 × 108 M-1 for the reference MAb X4. In a soluble phase assay, the binding capacities of VG-IgG2κ and VG-IgM to soluble CEA were clearly lower than that of the control chimeric MAb X4. A human MAb concentration of about 10-7 M was needed to precipitate approximatively 1 ng 125I-rhCEA as compared with 10-9 M for MAb X4, suggesting a preferential binding of the human MAbs to solid phase CEA. In vivo, 24 h post-injection, 125I-VG-IgG2κ demonstrated a high tumor uptake (25.4 ± 7.3%ID/g), close to that of 131I-X4 (21.7 ± 7.2%ID/g). At 72 h post-injection, 125I-VG-IgG2κ was still concentrated in the tumor (28.4 ± 11.0%ID/g) whereas the tumor concentration of 131I-X4 was significantly reduced (12.5 ± 4.8%ID/g). At no time after injection was there any accumulation of the radiolabeled MAbs in normal tissues. A pertinent analysis of VG-IgM biodistribution was not possible in this

  17. In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Decker, Mario de [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent (Belgium); Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands)], E-mail: mario.dedecker@health.wa.gov.au; Bacher, Klaus; Thierens, Hubert [Department of Medical Physics and Radiation Protection, Ghent University, Ghent (Belgium); Slegers, Guido [Department of Medical Imaging of Domestic Animals, Ghent University, Ghent (Belgium); Dierckx, Rudi A. [Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands); Vos, Filip de [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent (Belgium)

    2008-07-15

    Alemtuzumab (Campath, Berlex) is a humanized IgG1 rat monoclonal antibody directed against the cell surface CD52 antigen, found on lymphocytes and monocytes. It is being developed for the treatment of chronic lymphocytic leukemia (CLL), autoimmune disease and for the prevention of transplant rejection. This study focused on synthesis, quality control, in vitro evaluation and biodistrubution of {sup 188}Re-labeled alemtuzumab for radioimmunotherapy of B-cell CLL. {sup 188}Re-alemtuzumab was synthesized using a direct radiolabeling method. Reduction of the intramolecular disulfide bonds of the antibody was performed with tris-(carboxyethyl)-phosphine (Pierce), using a 1:60 molar excess. Reaction took place at room temperature for 20 min. A PD-10 desalting column was used to purify the reduced antibody from excess phospine. Complexation and transchelation of {sup 188}ReO{sub 4}{sup -} was achieved using sodium gluconate as weak chelator and SnCl{sub 2} as reducing agent. Quality control was done using instant thin-layer chromatography. Binding assays were performed on a CD52-positive cell line (HuT-78). Female NMRI mice were injected intravenously with 20 {mu}g radiolabeled alemtuzumab and killed at preset time intervals for biodistribution studies. Tissues were dissected, weighed and counted for determination of radioactivity. Data were expressed as percentage injected activity per gram of tissue (% IA/g tissue) or as percentage injected activity (% IA). {sup 188}Re-alemtuzumab was prepared achieving high radiochemical yields. Labeling efficiency of more than 95% can be obtained using optimal reaction conditions. {sup 188}Re-alemtuzumab showed good in vitro stability, remaining intact at 24 h after radiolabeling. In mice, {sup 188}Re-alemtuzumab showed high uptake in the blood (25.10{+-}1.36% IA at 1 h p.i.), followed by a biexponential clearance (t{sub 1/2{alpha}}=4.790 h and t{sub 1/2{beta}}=55.45 h). Increased uptake was observed in kidneys and heart (9

  18. Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA Gold 4 epitope and designed for radioimmunotherapy (RIT of colorectal cancers

    Directory of Open Access Journals (Sweden)

    Pugnière Martine

    2004-10-01

    Full Text Available Abstract Background Human monoclonal antibodies (MAbs are needed for colon cancer radioimmunotherapy (RIT to allow for repeated injections. Carcinoembryonic antigen (CEA being the reference antigen for immunotargeting of these tumors, we developed human anti-CEA MAbs. Methods XenoMouse®-G2 animals were immunized with CEA. Among all the antibodies produced, two of them, VG-IgG2κ and VG-IgM, were selected for characterization in vitro in comparison with the human-mouse chimeric anti-CEA MAb X4 using flow cytometry, surface plasmon resonance, and binding to radiolabeled soluble CEA and in vivo in human colon carcinoma LS174T bearing nude mice. Results Flow cytometry analysis demonstrated binding of MAbs on CEA-expressing cells without any binding on NCA-expressing human granulocytes. In a competitive binding assay using five reference MAbs, directed against the five Gold CEA epitopes, VG-IgG2κ and VG-IgM were shown to be directed against the Gold 4 epitope. The affinities of purified VG-IgG2κ and VG-IgM were determined to be 0.19 ± 0.06 × 108 M-1 and 1.30 ± 0.06 × 108 M-1, respectively, as compared with 0.61 ± 0.05 × 108 M-1 for the reference MAb X4. In a soluble phase assay, the binding capacities of VG-IgG2κ and VG-IgM to soluble CEA were clearly lower than that of the control chimeric MAb X4. A human MAb concentration of about 10-7 M was needed to precipitate approximatively 1 ng 125I-rhCEA as compared with 10-9 M for MAb X4, suggesting a preferential binding of the human MAbs to solid phase CEA. In vivo, 24 h post-injection, 125I-VG-IgG2κ demonstrated a high tumor uptake (25.4 ± 7.3%ID/g, close to that of 131I-X4 (21.7 ± 7.2%ID/g. At 72 h post-injection, 125I-VG-IgG2κ was still concentrated in the tumor (28.4 ± 11.0%ID/g whereas the tumor concentration of 131I-X4 was significantly reduced (12.5 ± 4.8%ID/g. At no time after injection was there any accumulation of the radiolabeled MAbs in normal tissues. A pertinent analysis of

  19. Review of (90Y-ibritumomab tiuxetan as first-line consolidation radio-immunotherapy for B-cell follicular non-Hodgkin’s lymphoma

    Directory of Open Access Journals (Sweden)

    Christos Emmanouilides

    2009-10-01

    Full Text Available Christos EmmanouilidesDepartment of Medical Oncology, Interbalkan Hospital, Thessaloniki, GreeceAbstract: Several studies have indicated that radioimmunotherapy is an effective and clinically relevant complementary therapeutic approach for patients with B-cell non-Hodgkin’s lymphoma (NHL and may convert partial to complete response when given as consolidation after induction chemotherapy. Yttrium-90(90Y-ibritumomab tiuxetan (90Υ-ΙΤ, Zevalin®, Y2B8 has documented efficacy for both indolent and aggressive NHL. Patients considered eligible for 90Y-IT treatment should satisfy several screening criteria. A recently completed randomized study for patients with follicular lymphoma has demonstrated that 90Y-ibritumomab consolidation also produced a marked prolongation of the median time to progression from 13.5 to 37 months, while partial responders seem to derive relatively more benefit. Other published and ongoing studies explore a similar use for patients with aggressive lymphoma. Studies are comparing the use of 90Y-IT consolidation with the anti-CD20 antibody rituximab maintenance, which is also gaining acceptance. In conclusion, the documented benefit of radioimmunotherapy should be viewed in the context of the goals of treatment and the changing standards of care for lymphoma. Keywords: radioimmunotherapy, 90Y-ibritumomab tiuxetan, follicular lymphoma, consolidation

  20. Experimental radioimmunotherapy of a xenografted human glioma using 131I-labeled monoclonal antibody to epidermal growth factor receptor

    International Nuclear Information System (INIS)

    131I-labeled F (ab')2 fragments of murine monoclonal antibodies (MAb) 425 specific to the epidermal growth factor receptor expressed on human gliomas were used in experimental human malignant glioma immunotherapy. Two injections of 150 μCi 131I-labeled 425 F(ab')2 achieved growth inhibition of U-87MG human malignant glioma xenografts in nude mice. This radiolabeled specific MAb F(ab')2 was significantly superior to radiolabeled fragments of an anti-hepatitis virus control MAb A5C3 in influencing tumor growth. However, similar treatment of established human malignant glioma xenografts did not inhibit progressive tumor growth significantly. No clear tumor inhibition was produced by unlabeled MAb 425F(ab')2. These studies suggest that 131I-labeled MAbs have a significant antitumor effect where unmodified antibody is ineffective. Multiple doses of antibody may achieve an increase in labeled MAb concentration in tumors. (author)

  1. Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab

    OpenAIRE

    Gigi, E; GEORGIOU T; Mougiou, D; Boura, P; Raptopoulou-Gigi, M

    2013-01-01

    Hepatitis B virus (HBV) can still be found within the hepatocytes after its clearance and the control of viral replication depends on the immune response. However during immunosuppression, seroconversion of HBsAg has been described followed by disease reactivation. Hepatitis B virus reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents and in particular, by the use of rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profou...

  2. Alpha-radioimmunotherapy: a review of recent developments

    International Nuclear Information System (INIS)

    The use of heavy particles in the treatment of cancer is increasing remarkably, whether with external radiation or using a vector such as an antibody in radioimmunotherapy. Recent pre-clinical and clinical developments of alpha-radioimmunotherapy have provided more interesting information in parallel of the use of high Linear Energy Transfer (Let) external irradiation. This review aims at presenting recent advances of this therapeutic approach, and at detailing the biological specificities of this kind of radiation. (authors)

  3. Radio-immunotherapy

    International Nuclear Information System (INIS)

    Radioimmunotherapy (R.I.T.) is a new modality of targeted therapy in which irradiation from radionuclides is delivered to tumor targets using monoclonal antibodies (MAb) directed to tumor-associated antigen. R.I.T. has been developed for more than 20 years. Today, R.I.T. can be used in clinical practice using non-ablative activity of murine anti-CD20 90Y-ibritumomab tiuxetan (Zevalin) for treatment of patients with relapsed or refractory follicular lymphomas (F.L.), with overall response rate of 70 to 80% and 20 to 30% of complete response. Different approaches are explored to improve efficacy of R.I.T. in N.H.L.: myelo-ablative R.I.T. or HD treatment, R.I.T. as consolidation after chemotherapy to target M.R.D., R.I.T. in first-line treatment, fractionated R.I.T., R.I.T. using other Ag targets. For solid tumors, interesting results have been obtained using anti-CEA R.I.T. delivered as consolidation treatment or using pre-targeting system. (authors)

  4. Radioimmunotherapy of malignant gliomas

    International Nuclear Information System (INIS)

    Despite all technical advances (intraoperative resection control, fluorescence guided resection, advances in external beam radiation techniques) and new consolidated findings on systemic chemotherapy treatment of malignant gliomas with conventional therapeutic modalities (surgery, radiation therapy and chemotherapy) is still highly unfavourable. Total tumor erradication is impossible due to tumor infiltrations into the normal brain and the limitations given by the limited tolerance of surrounding brain tissue. New treatment strategies, therefore, aim for a more selective destruction of tumor cells. Malignant glioma cells selectively express several antigens or receptors which are not or only to a minor extent present in normal brain tissue. Administration of radiolabelled monoclonal antibodies, especially when given locoregionally, targeting these tumor-specific antigens offers an innovative therapeutic strategy that has recently demonstrated encouraging antitumor effects and acceptable toxicity in many phase I/II clinical trials. This review offers a comprehensive summary of own experiences and results of clinical trials reported in the literature dealing with radioimmunotherapy of malignant glioma and highlights future plans to further develop this therapeutic strategy. (orig.)

  5. B cell depletion with rituximab in patients with rheumatoid arthritis: Multiplex bead array reveals the kinetics of IgG and IgA antibodies to citrullinated antigens.

    Science.gov (United States)

    Cambridge, Geraldine; Leandro, Maria J; Lahey, Lauren J; Fairhead, Thomas; Robinson, William H; Sokolove, Jeremy

    2016-06-01

    The serology of patients with Rheumatoid arthritis (RA) is characterized by persistently raised levels of autoantibodies: Rheumatoid Factors (RhF) against Fc of IgG, and to citrullinated (Cit) protein/peptide sequences: ACPA, recognizing multiple Cit-sequences. B cell depletion therapy based on rituximab delivers good clinical responses in RA patients, particularly in the seropositive group, with responses sometimes lasting beyond the phase of B cell reconstitution. In general, ACPA levels fall following rituximab, but fluctuations with respect to predicting relapse have proved disappointing. In order to identify possible immunodominant specificities within either IgG- or IgA-ACPA we used a Multiplex bead-based array consisting of 30 Cit-peptides/proteins and 22 corresponding native sequences. The kinetics of the serum ACPA response to individual specificities was measured at key points (Baseline, B cell depletion phase, Relapse) within an initial cycle of rituximab therapy in 16 consecutive patients with severe, active RA. All had achieved significant decreases in Disease Activity Scores-28 and maintained B cell depletion in the peripheral blood (<5 CD19+cells/μl) for at least 3 months. At Baseline, mean fluorescence intensity shown by individual IgG- and IgA-ACPA were strongly correlated (R(2) = 0.75; p < 0.0001) but IgA-ACPA were approximately 10-fold lower. Data were Z-normalised in order to compare serial results and antibody classes. At Baseline, a total of 68 IgG- and 51 IgA-ACPA had Z-scores ≥ 1 (above population mean) were identified, with at least one Cit-antigen identified in each serum. ACPA to individual specificities subsequently fluctuated with 3 different patterns. Most 51/68 (75%) IgG- and 48/51 IgA-ACPA (94%) fell between Baseline and Depletion, of which 57% IgG- and 65% IgA-ACPA rebounded pre-Relapse. Interestingly, 17/68 IgG-ACPA (25%) and some IgA-ACPA (3/51; 6%) transiently increased from Baseline, subsequently falling pre

  6. Improved radioimmunotherapy of hematologic malignancies

    International Nuclear Information System (INIS)

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides (131Iodine, 111Indium, 90Yttrium, 99mTechnetium, 186Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer

  7. Improved radioimmunotherapy of hematologic malignancies

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  8. Rituximab done

    DEFF Research Database (Denmark)

    Walker, Ulrich A; Jaeger, Veronika K; Chatzidionysiou, Katerina;

    2016-01-01

    OBJECTIVE: To compare the effectiveness of biologics after rituximab (RTX) treatment in RA. METHODS: The effectiveness of TNF-α inhibitors (TNFi), abatacept (ABA) or tocilizumab (TCZ) was examined in patients previously treated with RTX using clinical data collected in the Collaborative Registries...... for the Evaluation of Rituximab in RA Collaborative registry. Patients had stopped RTX 6 months or less prior to the new biologic and had a baseline visit within 21 days of starting the new biologic. RESULTS: Two hundred and sixty-five patients were analysed after 6 months of treatment. Patients on...... TCZ (n = 86) had a greater decline of DAS28-ESR and clinical disease activity index than patients on TNFi (n = 89) or ABA (n = 90). This effect was also seen after adjusting for baseline prednisone use and the number of previous biologics. The mean DAS28-ESR scores in patients on TCZ were 1.0 (95% CI...

  9. High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a 177Lu-based CD22-specific radioimmunoconjugate and rituximab

    International Nuclear Information System (INIS)

    Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter 177Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A''-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of 177Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1null) interleukin-2 receptor common gamma chain (IL2r γ null) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. 177Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A''-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the 177Lu-labelled anti-CD22 IgG than of 177Lu-labelled rituximab. Treatment with 177Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with 177Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with 177Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL. (orig.)

  10. High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a {sup 177}Lu-based CD22-specific radioimmunoconjugate and rituximab

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Tobias; Boetticher, Benedikt; Keller, Armin; Schlegelmilch, Anne; Jaeger, Dirk; Krauss, Juergen [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); Mier, Walter; Kraemer, Susanne; Leotta, Karin [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); Sauter, Max; Haberkorn, Uwe [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); Grosse-Hovest, Ludger [University of Tuebingen, Department of Immunology, Tuebingen (Germany); Arndt, Michaela A.E. [Heidelberg University Hospital, Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg (Germany); German Cancer Research Center (DKFZ), Immunotherapy Program, National Center for Tumor Diseases, Heidelberg (Germany)

    2016-03-15

    Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter {sup 177}Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A''-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of {sup 177}Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1{sup null}) interleukin-2 receptor common gamma chain (IL2r γ {sup null}) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. {sup 177}Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A''-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the {sup 177}Lu-labelled anti-CD22 IgG than of {sup 177}Lu-labelled rituximab. Treatment with {sup 177}Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with {sup 177}Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with {sup 177}Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for

  11. Improved radioimmunotherapy of hematologic malignancies. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1996-08-15

    Experiments were performed to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells. An attempt was made to examine in vivo the effects of lysosomotropic amines and thioamides on the retention of radiolabeled monoclonal antibodies by tumor cells. Experiments also examined the impact of newer radioiodination techniques on the metabolic degradation of radioiodinated antibodies, and on the radioimmunoscintigraphy and radioimmunotherapy of neoplasms. The endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with I-131, In-111, and Y-90 were compared. The utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer was investigated.

  12. Improved radioimmunotherapy of hematologic malignancies. Final technical report

    International Nuclear Information System (INIS)

    Experiments were performed to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells. An attempt was made to examine in vivo the effects of lysosomotropic amines and thioamides on the retention of radiolabeled monoclonal antibodies by tumor cells. Experiments also examined the impact of newer radioiodination techniques on the metabolic degradation of radioiodinated antibodies, and on the radioimmunoscintigraphy and radioimmunotherapy of neoplasms. The endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with I-131, In-111, and Y-90 were compared. The utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer was investigated

  13. Evaluation of Efficacy of Radioimmunotherapy with 90Y-Labeled Fully Human Anti-Transferrin Receptor Monoclonal Antibody in Pancreatic Cancer Mouse Models.

    Directory of Open Access Journals (Sweden)

    Aya Sugyo

    Full Text Available Pancreatic cancer is an aggressive tumor and the prognosis remains poor. Therefore, development of more effective therapy is needed. We previously reported that 89Zr-labeled TSP-A01, an antibody against transferrin receptor (TfR, is highly accumulated in a pancreatic cancer xenograft, but not in major normal organs. In the present study, we evaluated the efficacy of radioimmunotherapy (RIT with 90Y-TSP-A01 in pancreatic cancer mouse models.TfR expression in pancreatic cancer cell lines (AsPC-1, BxPC-3, MIAPaCa-2 was evaluated by immunofluorescence staining. 111In-labeled anti-TfR antibodies (TSP-A01, TSP-A02 were evaluated in vitro by cell binding assay with the three cell lines and by competitive inhibition assay with MIAPaCa-2. In vivo biodistribution was evaluated in mice bearing BxPC-3 and MIAPaCa-2 xenografts. Tumor volumes of BxPC-3 and MIAPaCa-2 were sequentially measured after 90Y-TSP-A01 injection and histological analysis of tumors was conducted.MIAPaCa-2 cells showed the highest TfR expression, followed by AsPC-1 and BxPC-3 cells. 111In-TSP-A01 and 111In-TSP-A02 bound specifically to the three cell lines according to TfR expression. The dissociation constants for TSP-A01, DOTA-TSP-A01, TSP-A02, and DOTA-TSP-A02 were 0.22, 0.28, 0.17, and 0.22 nM, respectively. 111In-TSP-A01 was highly accumulated in tumors, especially in MIAPaCa-2, but this was not true of 111In-TSP-A02. The absorbed dose for 90Y-TSP-A01 was estimated to be 8.3 Gy/MBq to BxPC-3 and 12.4 Gy/MBq to MIAPaCa-2. MIAPaCa-2 tumors treated with 3.7 MBq of 90Y-TSP-A01 had almost completely disappeared around 3 weeks after injection and regrowth was not observed. Growth of BxPC-3 tumors was inhibited by 3.7 MBq of 90Y-TSP-A01, but the tumor size was not reduced.90Y-TSP-A01 treatment achieved an almost complete response in MIAPaCa-2 tumors, whereas it merely inhibited the growth of BxPC-3 tumors. 90Y-TSP-A01 is a promising RIT agent for pancreatic cancer, although further

  14. Development and validation of the 57Co assay for determining the ligand to antibody ratio in bifunctional chelate/antibody conjugates for use in radioimmunotherapy

    International Nuclear Information System (INIS)

    Introduction: The ligand to antibody ratio is an important characteristic of a chelate/antibody conjugate. It has been widely reported that if the ratio is too high, there will be detrimental effects on immunoreactivity and biodistribution; conversely, if the ratio is too low, the radionuclide may not bind efficiently, and the stability and the specific activity will be reduced. There are little published data on the accuracy or precision of the 57Co assay. The UK Clinical Trials Regulations state that “systems with procedures that assure the quality of every aspect of the trial should be implemented”. The aims of this study were to assess the reliability and accuracy of the 57Co binding assay and validate it against defined criteria. Method: Thirty-two serial assays were assessed for reliability. Two batches of conjugated antibody were also analysed by matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) mass spectrometry (MS) to allow the comparison of the functional test with a physical method. Results: Reliability: The coefficient of variation was 0.13. Accuracy: There was 9% variation between the 57Co binding assay and MALDI-TOF MS results. Conclusion: A detailed method for the 57Co ligand to antibody test is described that allows a discrete value to be obtained. The assay was validated as fit for purpose against target values of coefficient of variation <0.20, accuracy±10%, over a permissive range of 0.5–3.0 ligand to antibody ratio.

  15. Alpha-emitting radioisotopes production for radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Chun, Kwon Soo [Korea Institutet of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2007-02-15

    This review discusses the production of alpha-particle-emitting radionuclides in radioimmunotherapy. Radioimmunotherapy labeled with alpha-particle is expected to be very useful for the treatment of monocellular cancer (e.g. leukemia) and micrometastasis at an early stage, residual tumor remained in tissues after chemotherapy and tumor resection, due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha particle. Despite of the expected effectiveness of alpha-particle in radioimmunotherapy, its clinical research has not been activated by the several reasons, shortage of a suitable a-particle development and a reliable radionuclide production and supply system, appropriate antibody and chelator development. Among them, the establishment of radionuclide development and supply system is a key factor to make an alpha-immunotherapy more popular in clinical trial. Alpha-emitter can be produced by several methods, natural radionuclides, reactor irradiation, cyclotron irradiation, generator system and elution. Due to the sharply increasing demand of {sup 213}Bi, which is a most promising radionuclide in radioimmunotherapy and now has been produced with reactor, the cyclotron production system should be developed urgently to meet the demand.

  16. Research about the radioimmunotherapy of fungal infection

    International Nuclear Information System (INIS)

    The wide use of the broad-spectrum antibiotics, corticosteroids and immunosuppressant may lead to lower immunity which can increases the chance of fungi infection. Searching a better antifungal therapy is one of the direction of medical research. Ionizing radiation can quickly and effectively kill the microorganisms, and also can be the antifungal. The research suggests that the method of targeting radioimmunotherapy labeled specific antibody may become an effective antifungal treatment channels. (authors)

  17. Clinical scale preparation and evaluation of {sup 131}I-Rituximab for Non-Hodgkin's lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Kameswaran, Mythili; Vimalnath, K. Viswanathan; Rajeswari, Ardhi; Joshi, Prahlad Vasudeo; Samuel, Grace [Bhabha Atomic Research Centre, Mumbai (India). Radiopharmaceuticals Div.; Sarma, H.D. [Bhabha Atomic Research Centre, Mumbai (India). Radiation Biology and Health Sciences Div.

    2014-09-01

    Radioimmunotherapy (RIT) with anti CD20 MoAb conjugated to a β{sup -} emitting radioisotope like {sup 131}I or {sup 90}Y has the added advantage of delivering radiation not only to tumor cells that bind the antibody but also due to a crossfire effect, to neighboring tumor cells inaccessible to the antibody. In order to make available an indigenous radioimmunotherapeutic agent for Non Hodgkin's Lymphoma (NHL), radioiodinated Rituximab has been prepared and evaluated at a clinical scale. Radioiodination of Rituximab was performed by the conventional Chloramine T method using 7.4 GBq Na{sup 131}I in a lead shielded plant. Six batches of radioiodination were prepared and characterized by electrophoresis and HPLC to evaluate the reproducibility of the product. The product remained stable retaining the radiochemical purity > 95% upto 5 days after radioiodination. In vitro cell binding studies and biodistribution studies in normal Swiss mice have indicated the potential of this molecule as a radioimmunotherapeutic agent for NHL. (orig.)

  18. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using {sup 149}Tb-rituximab

    Energy Technology Data Exchange (ETDEWEB)

    Beyer, G.J.; Soloviev, D.; Buchegger, F. [Division of Nuclear Medicine, University Hospital of Geneva, 24 Rue Micheli du Crest, 1211, Geneva 14 (Switzerland); Miederer, M. [Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York (United States); Vranjes-Duric, S. [Laboratory of Radioisotopes, Vinca Institute of Nuclear Sciences, Belgrade (Czechoslovakia); Comor, J.J. [Laboratory of Physics, Vinca Institute of Nuclear Sciences, Belgrade (Czechoslovakia); Kuenzi, G.; Hartley, O. [Department of Medical Biochemistry, University Medical Center, Geneva (Switzerland); Senekowitsch-Schmidtke, R. [Clinic of Nuclear Medicine, Technical University of Munich, Munich (Germany)

    2004-04-01

    This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10{sup 6} Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 {mu}g unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%{+-}4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%{+-}2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with {sup 149}Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach. (orig.)

  19. Choice of radionuclides for radioimmunotherapy

    International Nuclear Information System (INIS)

    Innumerable questions need to be answered and obstacles overcome before radioimmunotherapy can be generally successful in cancer patients. Major developments have greatly enhanced the likelihood of success. The important development of appropriate radionuclides and radiochemistry for this therapy must be intimately linked with the biological and biochemical realities. All aspects must be considered, such as the specific nature of the antigenic target, the pharmacokinetics of the antibody fragment carrier, the capability of in vivo quantitation of tumor uptake and turnover time, as well as total body kinetics. With this knowledge, then, practical radiochemistry methods can be integrated with the suitable radionuclide choices, and production methods can be developed which will deliver effective and dependable products for patient therapy

  20. Country report: Germany. Preclinical evaluation of Y-90 labelled Rituximab and ERIC-1, two antibodies for tumor therapy

    International Nuclear Information System (INIS)

    This project focuses on harnessing the great potential of radionuclide therapy, using various different vehicles to transport radionuclides into tumor tissues. A central aim of the project will be to manufacture specific vehicle molecules whose tumor affinity and suitability for radioactive coupling have already been proven through laboratory trials on animals and cell cultures at the Department of Nuclear Medicine, University of Cologne and to label it with Y- 90. The vectors to be used to transport radionuclides into tumor tissue for treatment are antibodies against lymphomas and neuroblastomas. The technology applied for coupling Y-90 to various antibodies has been developed to a high level in Cologne and is now ready to be transferred and adapted to GMP (Good Manufacturing Practice) conditions. The antibody against NHL can be acquired commercially and must then be modified for binding to the therapeutically active nuclide Y-90. Similarly, the antibody against neuroblastoma must also be modified to bind to Y-90 but is produced in Cologne. To improve the therapeutic value of antibodies we tried to introduce the pretargeting method

  1. Radioimmunotherapy and Autologous Stem-Cell Transplantation in the Treatment of B-Cell Non-Hodgkin Lymphoma.

    Science.gov (United States)

    Shimoni, Avichai; Zwas, Shifra Tzila

    2016-03-01

    High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is the standard therapy for patients with chemosensitive-relapsed or chemosensitive-refractory aggressive lymphoma. The use of rituximab, an anti-CD20 monoclonal antibody, has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates. However, despite this progress a significant proportion of patients are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches. Novel approaches are needed for these high-risk patients, especially in the rituximab era. Radioimmunotherapy (RIT) is a form of targeted therapy using the parent monoclonal antibody to deliver radiation emitted by a conjugated radioisotope, to the vicinity of antigen-positive tissues. Two radioimmunoconjugates--yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) have been in clinical use. There are multiple studies demonstrating the safety and efficacy of both agents in both indolent and aggressive lymphoma. Radiolabeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. RIT targets radiation to disease sites while limiting exposure of uninvolved critical organs, thus it can safely replace total-body irradiation during conditioning for ASCT. The major toxicity and limiting factor in RIT is myelotoxicity that is easily reversed by stem-cell rescue. RIT can be combined at standard doses with high-dose chemotherapy or can be given in escalated doses either alone or with high-dose chemotherapy before ASCT. Several phase II studies have shown the safety and potential efficacy of both agents using these approaches. A small randomized study comparing standard-dose Zevalin with combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) high-dose chemotherapy and BEAM alone suggested a

  2. Review of 90Y-ibritumomab tiuxetan as first-line consolidation radio-immunotherapy for B-cell follicular non-Hodgkin’s lymphoma

    International Nuclear Information System (INIS)

    Several studies have indicated that radioimmunotherapy is an effective and clinically relevant complementary therapeutic approach for patients with B-cell non-Hodgkin’s lymphoma (NHL) and may convert partial to complete response when given as consolidation after induction chemotherapy. Yttrium-90(90Y)-ibritumomab tiuxetan (90Y-IT, Zevalin®, Y2B8) has documented efficacy for both indolent and aggressive NHL. Patients considered eligible for 90Y-IT treatment should satisfy several screening criteria. A recently completed randomized study for patients with follicular lymphoma has demonstrated that 90Y-ibritumomab consolidation also produced a marked prolongation of the median time to progression from 13.5 to 37 months, while partial responders seem to derive relatively more benefit. Other published and ongoing studies explore a similar use for patients with aggressive lymphoma. Studies are comparing the use of 90Y-IT consolidation with the anti-CD20 antibody rituximab maintenance, which is also gaining acceptance. In conclusion, the documented benefit of radioimmunotherapy should be viewed in the context of the goals of treatment and the changing standards of care for lymphoma

  3. The Effect of Combination Therapy with Rituximab and Intravenous Immunoglobulin on the Progression of Chronic Antibody Mediated Rejection in Renal Transplant Recipients

    Science.gov (United States)

    Yun, Jintak; Khvan, Marina; Park, Cheol Whee; Choi, Yeong Jin; Kim, Yong-Soo; Yang, Chul Woo

    2014-01-01

    The treatment for chronic active antibody-mediated rejection (CAMR) remains controversial. We investigated the efficacy of rituximab (RTX) and intravenous immunoglobulin (IVIg) for CAMR. Eighteen patients with CAMR were treated with RTX (375 mg/m2) and IVIg (0.4 g/kg) for 4 days. The efficacy of RTX/IVIg combination therapy (RIT) was assessed by decline in estimated glomerular filtration rate per month (ΔeGFR) before and after RIT. Patients were divided into responder and nonresponder groups based on decrease and no decrease in ΔeGFR, respectively, and their clinical and histological characteristics were compared. Response rate to RIT was 66.7% (12/18), and overall ΔeGFR decreased significantly to 0.4 ± 1.7 mL·min−1·1.73 m−2 per month 6 months after RIT compared to that observed 6 months before RIT (1.8 ± 1.0, P < 0.05). Clinical and histological features between the 12 responders and the 6 nonresponders were not significantly different, but nonresponders had a significantly higher proteinuria levels at the time of RIT (2.5 ± 2.5 versus 7.0 ± 3.5 protein/creatinine (g/g), P < 0.001). The effect of the RIT on ΔeGFR had dissipated in all patients by 1 year post-RIT. Thus, RIT delayed CAMR progression, and baseline proteinuria level was a prognostic factor for response to RIT. PMID:24741626

  4. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma.

    Science.gov (United States)

    Montraveta, Arnau; Xargay-Torrent, Sílvia; López-Guerra, Mónica; Rosich, Laia; Pérez-Galán, Patricia; Salaverria, Itziar; Beà, Silvia; Kalko, Susana G; de Frias, Mercè; Campàs, Clara; Roué, Gaël; Colomer, Dolors

    2014-02-15

    Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients. PMID:24519895

  5. Successful Desensitization of a Patient with Rituximab Hypersensitivity

    Directory of Open Access Journals (Sweden)

    Pinar Ataca

    2015-01-01

    Full Text Available Rituximab is a monoclonal antibody which targets CD20 in B cells that is used for the treatment of CD20 positive oncologic and hematologic malignancies. Rituximab causes hypersensitivity reactions during infusions. The delay of treatment or loss of a highly efficient drug can be prevented by rapid drug desensitization method in patients who are allergic to rituximab. We report a low grade B cell non-Hodgkin lymphoma patient with rituximab hypersensitivity successfully treated with rapid drug desensitization. In experienced centers, drug desensitization is a novel modality to break through in case of hypersensitivity that should be considered.

  6. Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation.

    Science.gov (United States)

    Chen, Yun; Kornblit, Brian; Hamlin, Donald K; Sale, George E; Santos, Erlinda B; Wilbur, D Scott; Storer, Barry E; Storb, Rainer; Sandmaier, Brenda M

    2012-02-01

    To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 ((211)At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with (211)At doses less than or equal to 405 μCi/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest (211)At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with (211)At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning. PMID:22134165

  7. Radioimmunotherapy: Opportunities, obstacles and challenges, with special reference to developing countries

    International Nuclear Information System (INIS)

    The targeting characteristics of, combined with the ease of radionuclide conjugation to, monoclonal antibodies makes them ideally suited for the selective delivery of potentially cytotoxic radioactivity to tumour. While early murine monoclonal antibodies were immunogenic, precluding repeat administration, genetic engineering has made possible the development of less immunogenic molecules, including fragments that can be grown in bacterial systems at relatively low cost. It is therefore currently feasible to produce relatively non-immunogenic tumour targeting antibody molecules at a reasonable cost, permitting their application in developing countries. As with chemotherapy, the utility of radioimmunotherapy has been most evident in lymphoma and leukemia. Progress in solid tumours has been exciting but slow. As with thyroid cancer therapy, the most utilized radionuclide in radioimmunotherapy has been iodine-131. The use of radioimmunotherapy as first- or second-line therapy in lymphoma and leukemia is being studied, and it appears likely that radioimmunotherapy could be a suitable, lower-cost alternative to chemotherapy in the treatment of these disorders, especially in developing countries. The cost-benefit of radioimmunotherapy compared to chemotherapy is especially stark when the cost of treating complications of chemotherapy is taken into account. Radioimmunotherapy as cost-effective therapy in developing countries is therefore feasible and has tremendous potential. This review will highlight milestones and pitfalls; suggest guidelines for future development; and outline potential clinical utility for radioimmunotherapy in developing countries. (author)

  8. Intraperitoneal alpha-radioimmunotherapy in mice using different specific activities

    DEFF Research Database (Denmark)

    Elgqvist, Jörgen; Andersson, Håkan; Haglund, Elin; Jensen, Holger; Kahu, Helena; Lindegren, Sture; Warnhammar, Elisabet; Hultborn, Ragnar

    2009-01-01

    The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At....

  9. Repeated Intraperitoneal alpha-Radioimmunotherapy of Ovarian Cancer in Mice

    DEFF Research Database (Denmark)

    Elgqvist, Jörgen; Andersson, Håkan; Jensen, Holger; Kahu, Helena; Lindegren, Sture; Warnhammar, Elisabet; Hultborn, Ragnar

    2010-01-01

    The aim of this study was to investigate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice using different fractionated treatment regimens. The study was performed using the monoclonal antibody MX35 F(ab')(2) labeled with the alpha-particle emitter (211)At. Methods...

  10. Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

    Energy Technology Data Exchange (ETDEWEB)

    Orozco, Johnnie J.; Back, Tom; Kenoyer, Aimee L.; Balkin, Ethan R.; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Frayo, Shani; Hylarides, Mark; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2013-05-15

    Anti-CD45 Radioimmunotherapy using an Alpha-Emitting Radionuclide 211At Combined with Bone Marrow Transplantation Prolongs Survival in a Disseminated Murine Leukemia Model ABSTRACT Despite aggressive chemotherapy combined with hematopoietic cell transplant (HCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using antibodies (Ab) labeled primarily with beta-emitting radionuclides has been explored to reduce relapse.

  11. Improvement of radioimmunotherapy using pretargeting

    Directory of Open Access Journals (Sweden)

    Eric eFrampas

    2013-06-01

    Full Text Available During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabelled monoclonal antibodies and receptor binding agents. Conventional Radioimmunotherapy (RIT is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics.Pretargeting techniques (pRIT are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA and bispecific antibody-hapten bindings. PRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta and Auger emitters with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT.

  12. B Cell Depletion: Rituximab in Glomerular Disease and Transplantation

    Directory of Open Access Journals (Sweden)

    S. Marinaki

    2013-12-01

    Full Text Available B cells play a central role in the pathogenesis of many autoimmune diseases. Selective targeting can be achieved with the use of the monoclonal antibody rituximab. In addition to being a drug for non-Hodgkin's lymphoma, rituximab is also an FDA-approved treatment for refractory rheumatoid arthritis and, since recently, ANCA vasculitis. It has shown efficacy in many autoimmune diseases. This review will discuss current evidence and the rationale of the use of rituximab in glomerular diseases, including randomized controlled trials. The focus will be on the use of rituximab in idiopathic membranous nephropathy, systemic lupus erythematosus and ANCA-associated vasculitis. The emerging role of rituximab in renal transplantation, where it seems to be important for the desensitization protocols for highly sensitized patients as well as for the preconditioning of ABO-incompatible recipients and the treatment of antibody-mediated rejection, will also be addressed.

  13. Improved radioimmunotherapy of hematologic malignancies. [Final report

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1992-03-24

    This research project proposes to develop novel new approaches of improving the radioimmunodetection and radioimmunotherapy of malignancies by augmenting retention of radioimmunoconjugates by tumor cells. The approaches shown to be effective in these laboratory experiments will subsequently be incorporated into out ongoing clinical trials in patients. Specific project objectives include: to study the rates of endocytosis, intracellular routing, and metabolic degradation of radiolabeled monoclonal antibodies targeting tumor-associated antigens on human leukemia and lymphoma cells; To examine the effects of lysosomotropic amines (e.g. chloroquine, amantadine), carboxylic ionophores (monensin, nigericin), and thioamides (propylthiouracil), on the retention of radiolabeled MoAbs by tumor cells; to examine the impact of newer radioiodination techniques (tyramine cellobiose, paraiodobenzoyl) on the metabolic degradation of radioiodinated antibodies; to compare the endocytosis, intracellular routing, and degradation of radioimmunoconjugates prepared with different radionuclides ({sup 131}Iodine, {sup 111}Indium, {sup 90}Yttrium, {sup 99m}Technetium, {sup 186}Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer.

  14. Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors.

    Directory of Open Access Journals (Sweden)

    Fares Al-Ejeh

    Full Text Available BACKGROUND: To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 ((90Y-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment. METHODOLOGY/PRINCIPAL FINDINGS: Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, and then radiolabeled with (90Y. Mice bearing established subcutaneous tumors were treated with (90Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2 model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of (90Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants. CONCLUSIONS/SIGNIFICANCE: We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4

  15. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial

    OpenAIRE

    Récher, Christian; Coiffier, Bertrand; Haioun, Corinne; Molina, Thierry Jo; Fermé, Christophe; Casasnovas, Olivier; Thièblement, Catherine; Bosly, André; LAURENT, GUY; Morschhauser, Franck; Ghesquières, Hervé; Jardin, Fabrice; Bologna, Serge; Fruchart, Christophe; Corront, Bernadette

    2011-01-01

    Background The outcome of diff use large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18–59 years, the potential survival benefi t provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. Methods We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclo phosphamide, ...

  16. Efficacy of Rituximab in Refractory Inflammatory Myopathies Associated with Anti- Synthetase Auto-Antibodies: An Open-Label, Phase II Trial.

    Directory of Open Access Journals (Sweden)

    Yves Allenbach

    Full Text Available Anti-synthetase syndrome (anti-SS is frequently associated with myositis and interstitial lung disease (ILD. We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy of rituximab on muscle and lung outcomes.Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants. They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles at M12. Secondary endpoints were normalization of creatine kinase (CK level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants.Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point. Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718 to 74.5 IU/L (range, 40-47,857. Corticosteroid doses decreased from 52.5 mg/d (range, 10-70 to 9 mg/d (range, 7-65 and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1.This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients.Clinicaltrials.gov NCT00774462.

  17. Acquired Hemophilia A successfully treated with rituximab

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2015-02-01

    Full Text Available Acquired hemophilia A (AHA is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in  obtaining a long-term suppression of inhibitors of AHA,  besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with  a normalization of clotting  parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm. , but after stopping rituximab, an initial worsening of coagulation  parameters  induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days.  This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs remains to be established and warrants further investigation.

  18. Rituximab Desensitization in Pediatric Patients: Results of a Case Series

    Science.gov (United States)

    Lee, Joyce P.; Platt, Craig D.

    2016-01-01

    Rituximab is a monoclonal antibody (mAb) primarily used to treat oncologic and autoinflammatory conditions. Although hypersensitivity reactions (HSRs) and desensitization protocols to mAbs have been well described in adults, the experience in the pediatric population is very limited. We sought to determine the safety and efficacy of desensitization to rituximab in the pediatric population at our institution. We retrospectively reviewed the experience with HSRs and desensitization to rituximab during a 5-year period in our tertiary care pediatric center, including reaction evaluation, premedication regimens, and desensitization procedures and protocols. A total of 17 desensitizations to rituximab were performed in three patients. A 14-year-old patient underwent successful desensitization to rituximab using a published adult protocol without incident. Two younger patients (ages 7 years and 23 months) experienced significant reactions during initial desensitization attempts. Therefore, we designed a modified desensitization protocol to rituximab, with particular attention to the rate of infusion as mg/kg/h. This new patient weight-based protocol was successfully used in a total of 13 desensitizations in these two patients. Desensitization to rituximab was a safe and effective procedure in our pediatric population. We present a new patient weight-based desensitization protocol for pediatric patients who develop HSRs to rituximab, with particular usefulness for younger pediatric patients and potential utility in pediatric patients with HSRs to other mAbs.

  19. Radioimmunotherapy for lymphoma - analysis of clinical trials and treatment algorithms

    International Nuclear Information System (INIS)

    Ibritumomab, an 90Yttrium (90Y) labelled radioimmunoconjugate, is registered in Europe to treat follicular lymphomas. Its mode of action combines the selectivity of monoclonal antibodies with the efficiency of radiotherapy, making it a unique and useful therapeutic agent. This paper is for haemato-oncologists with a decent practice in lymphoma therapy, who have not yet used ibritumomab themselves. It summarizes clinical trials with radioimmunotherapy, indicating clinical situations where it may be specifically useful. (author)

  20. Practical considerations on the use of rituximab in autoimmune neurological disorders

    OpenAIRE

    Kosmidis, Mixalis L.; Dalakas, Marinos C

    2010-01-01

    Rituximab (Mabthera, Rituxan) is a chimeric human/murine monoclonal antibody against CD-20 surface antigen expressed on B-cells. Rituximab, by causing B-cell depletion, appears to be effective in several autoimmune disorders; it has been approved for rheumatoid arthritis and is a promising new agent in the treatment of several autoimmune neurological disorders. A controlled study in patients with relapsing remitting multiple sclerosis has shown that rituximab significantly reduces the number ...

  1. Rituximab for Non-Hodgkin’s Lymphoma: A Story of Rapid Success in Translation

    OpenAIRE

    Harrison, Andrew M.; Thalji, Nassir M.; Greenberg, Alexandra J.; Tapia, Carmen J.; Windebank, Anthony J.

    2013-01-01

    Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin’s lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed...

  2. Radioimmunotherapy: Development of an effective approach

    International Nuclear Information System (INIS)

    Goals of this program are to answer the fundamental scientific questions for the development of an effective approach for delivering radiation therapy to cancer on antibody-based radiopharmaceuticals. The following list consists of highlights of developments from our program: documented therapeutic response of lymphoma in patients receiving radioimmunotherapy; development and application of quantitative radionuclide imaging techniques for therapy planning and dosimetry calculations; multicompartmental modeling and analysis of the in vivo MoAb kinetics in patients; a MoAb macrocycle chelate for Cu-67: development, production, in vitro and in vivo testing; NMR analysis of immunoradiotherapeutic effects on the metabolism of lymphoma; analysis of the variable molecular characteristics of the MoAb radiopharmaceutical, and their significance; in vivo studies in mice and patients of the metabolism of radioiodinated MoAb as well as In-111 CITC MoAb; and biodistribution of Cu-67 TETA MoAb in nude mice with human lymphoma

  3. Radioimmunotherapy: Development of an effective approach

    Energy Technology Data Exchange (ETDEWEB)

    1987-01-01

    Goals of this program are to answer the fundamental scientific questions for the development of an effective approach for delivering radiation therapy to cancer on antibody-based radiopharmaceuticals. The following list consists of highlights of developments from our program: documented therapeutic response of lymphoma in patients receiving radioimmunotherapy; development and application of quantitative radionuclide imaging techniques for therapy planning and dosimetry calculations; multicompartmental modeling and analysis of the in vivo MoAb kinetics in patients; a MoAb macrocycle chelate for Cu-67: development, production, in vitro and in vivo testing; NMR analysis of immunoradiotherapeutic effects on the metabolism of lymphoma; analysis of the variable molecular characteristics of the MoAb radiopharmaceutical, and their significance; in vivo studies in mice and patients of the metabolism of radioiodinated MoAb as well as In-111 CITC MoAb; and biodistribution of Cu-67 TETA MoAb in nude mice with human lymphoma.

  4. Association among heterogeneity of intratumoral anti-CD20 antibody distribution, glucose metabolism and therapeutic response in radioimmunotherapy for B-cell lymphoma

    International Nuclear Information System (INIS)

    Full text of publication follows. Aim: in Zevalin therapy for CD20 positive low-grade lymphoma, heterogeneity of intratumoral anti-CD20 antibody distribution as well as status of lesional glucose metabolism prior to therapy may affect tumor response. The aim of this study was to evaluate association of heterogeneity of intratumoral In-111 Zevalin (In-Zevalin), accumulation of F-18 FDG (FDG), and therapeutic response in patients receiving Zevalin therapy. Methods: 16 patients with CD20 positive B-cell non-Hodgkin's lymphoma who underwent Y-90 Zevalin therapy after imaging with In-Zevalin SPECT/CT and FDG PET/CT were enrolled. Patients received In-Zevalin, followed by SPECT/CT scanning at 48 hours after administration. SUVmax of FDG of lesions was measured on PET/CT while lesion accumulation of In-Zevalin as %ID/g and SUVmax of In-Zevalin (In-Zevalin SUVmax) was measured on SPECT/CT. To evaluate heterogeneity of anti-CD20 antibody distribution, skewness and kurtosis of voxel distribution were calculated by placing there-dimensional volumes of interest (3-D VOIs) on SPECT/CT images. As another intratumoral heterogeneity index, cumulative SUVmax-volume histograms describing percentage of total tumor volume above thresholds of In-Zevalin SUVmax (AUC-CSH) were calculated by placing 3-D VOIs. All lesions (n=42) were classified into responders and non-responders lesion-by-lesion on pre- and post-therapeutic CT images. Results: by lesion-based analysis, a positive correlation was observed between FDG SUVmax and accumulation of In-Zevalin. Accumulation of In-Zevalin was 0.0022 ± 0.0009 and 0.0024 ± 0.0008 %ID/g (n.s.), and 2.74 ± 1.43 and 3.29 ± 1.47 SUVmax (n.s.) for responders and non-responders, respectively. In contrast, voxel distribution of In-Zevalin demonstrated skewness of 0.58 ± 0.16 and 0.73 ± 0.24 (p<0.05), kurtosis of 2.39 ± 0.32 and 2.78 ± 0.53 (p<0.02), and AUC-CSH of 0.37 ± 0.04 and 0.34 ± 0.05 (p<0.05) for responders and non

  5. Radioimmunotherapy with Tenarad, a {sup 131}I-labelled antibody fragment targeting the extra-domain A1 of tenascin-C, in patients with refractory Hodgkin's lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Aloj, Luigi [Istituto Nazionale Tumori ' ' Fondazione G. Pascale' ' - IRCCS, Struttura Complessa di Medicina Nucleare, Napoli (Italy); D' Ambrosio, Laura; Aurilio, Michela; Morisco, Anna; Caraco' , Corradina; Di Gennaro, Francesca; Lastoria, Secondo [Istituto Nazionale Tumori ' ' Fondazione G. Pascale' ' - IRCCS, Struttura Complessa Medicina Nucleare, Napoli (Italy); Frigeri, Ferdinando; Capobianco, Gaetana; Pinto, Antonio [Istituto Nazionale Tumori ' ' Fondazione G. Pascale' ' - IRCCS, Struttura Complessa di Ematologia Oncologica, Napoli (Italy); Giovannoni, Leonardo; Menssen, Hans D. [Philogen, SpA, Siena (Italy); Neri, Dario [Institute of Pharmaceutical Sciences, ETH, Zurich (Switzerland)

    2014-05-15

    The extra-domain A1 of tenascin-C (TC-A1) is highly expressed in the extracellular matrix of tumours and on newly formed blood vessels and is thus a valuable target for radionuclide therapy. Tenarad is a fully human miniantibody or small immunoprotein (SIP, molecular weight 80 kDa) labelled with {sup 131}I that is derived from a TC-A1-binding antibody. Previous phase I/II studies with a similar compound ({sup 131}I-L19SIP) used for radioimmunotherapy (RIT) have shown preliminary efficacy in a variety of cancer types. In this ongoing phase I/II trial, Tenarad was administered to patients with recurrent Hodgkin's lymphoma (HL) refractory to conventional treatments. Eight patients (four men, four women; age range 19 - 41) were enrolled between April 2010 and March 2011. All patients had received a median of three previous lines of chemotherapy (range three to six) and seven had also undergone autologous stem cell transplantation (ASCT) or bone marrow transplantation. In addition, seven patients received external beam radiation. All patients had nodal disease, constitutional B symptoms and some showed extranodal disease in skeletal bone (four patients), lung (three), liver (two) and spleen (one). Baseline assessments included whole-body FDG PET with contrast-enhanced CT and diagnostic Tenarad planar and SPECT studies. Patients were considered eligible to receive a therapeutic dose of Tenarad (2.05 GBq/m{sup 2}) if tumour uptake was more than four times higher than that of muscle. All patients were eligible and received the therapeutic dose of Tenarad. Only one patient developed grade 4 thrombocytopenia and leucocytopenia, requiring hospitalization and therapeutic intervention. All other patients had haematological toxicity of grade 3 or lower, which resolved spontaneously. At the first response assessment (4 - 6 weeks after therapy), one patient showed a complete response, one showed a partial response (PR) and five had disease stabilization (SD). Five patients

  6. Internal radiotherapy. 2. Treatment of non-hodgkin's lymphoma with 90Y-labeled anti-CD20 monoclonal antibody

    International Nuclear Information System (INIS)

    This paper describes recent trends of radioimmunotherapy using specific monoclonal antibodies against tumors, its principle and outcomes, with major emphasis on the title. When the antibodies like rituximab (rit), anti-CD20 antibody against B-cell malignant lymphoma, are labeled by a certain radioisotope, they become more active in specifically killing malignant cells by their immune cytotoxicity following binding plus lethal effect of radiation (beta ray). In Western areas, 90Y-labeled (ibritumomab, ibrit) or 131I-labeled rit is now available for the purpose. The efficacy of the former ibrit in the phase III trial has been reported to be 83%, in contrast to that of rit alone, 56%, with the similar safety to rit, in out-patients with the tumor. The protocol for the therapy is consisted from the first therapy with intravenous rit and imaging by 111In-labeled rit on day 1 and the second with the rit and ibrit (0.4 mCi/kg) on day 8. Patients are excluded from the latter therapy when the image by 111In shows the abnormal distribution in the liver and bone marrow. In Japan, phase I/II clinical trials of ibrit have been conducted to confirm its efficacy and safety and the agent is to be approved within this year. The radioimmunotherapy is thought to become more popular. (T.I.)

  7. Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

    Science.gov (United States)

    DeNardo, Sally J.; Kukis, David L.; Kroger, Linda A.; O’Donnell, Robert T.; Lamborn, Kathleen R.; Miers, Laird A.; DeNardo, David G.; Meares, Claude F.; DeNardo, Gerald L.

    1997-01-01

    Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90Y-labeled DOTA-peptide-ChL6 (90Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N",N‴-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24–72 hours before 90Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy. PMID:9108094

  8. Rituximab: An emerging therapeutic agent for kidney transplantation

    Directory of Open Access Journals (Sweden)

    Joseph Kahwaji

    2009-10-01

    Full Text Available Joseph Kahwaji, Chris Tong, Stanley C Jordan, Ashley A VoComprehensive Transplant Center, Transplant immunology Laboratory, HLA Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, USAAbstract: Rituximab (anti-CD20, anti-B-cell is now emerging as an important drug for modification of B-cell and antibody responses in solid-organ transplant recipients. Its uses are varied and range from facilitating desensitization and ABO blood group-incompatible transplantation to the treatment of antibody-mediated rejection (AMR, post-transplant lymphoproliferative disorder (PTLD, and recurrent glomerular diseases in the renal allograft. Despite these uses, prospective randomized trials are lacking. Only case reports exist in regards to its use in de novo and recurrent diseases in the renal allograft. Recent reports suggests that the addition of rituximab to intravenous immunoglobulin (IVIG may have significant benefits for desensitization and treatment of AMR and chronic rejection. Current dosing recommendations are based on data from United States Food and Drug Administration-approved indications for treatment of B-cell lymphomas and rheumatoid arthritis. From the initial reported experience in solid organ transplant recipients, the drug is well tolerated and not associated with increased infectious risks. However, close monitoring for viral infections is recommended with rituximab use. The occurrence of progressive multifocal leukoencephalopathy (PML has been reported with rituximab use. However, this is rare and not reported in the renal transplant population. Here we will review current information regarding the effectiveness of rituximab as an agent for desensitization of highly human leukocyte antigen-sensitized and ABO-incompatible transplant recipients and its use in treatment of AMR. In addition, the post-transplant use of rituximab for treatment of PTLD and for recurrent and de novo glomerulonephritis in the allograft will be discussed. In

  9. The evaluation and optimal use of rituximab in lymphoid malignancies

    Directory of Open Access Journals (Sweden)

    Smolewski P

    2012-01-01

    Full Text Available Tadeusz Robak1, Pawel Robak2, Piotr Smolewski21Department of Hematology, 2Experimental Hematology, Medical University of Łódź, Łódź, PolandAbstract: Rituximab is an IgG1, chimeric monoclonal antibody (mAb containing murine light- and heavy-chain variable-region sequences and human constant-region sequences. Rituximab targets the CD20 molecule expressed on normal and malignant B-lymphocytes. At present, rituximab is the most important mAb of clinical value in patients with B-cell lymphoid malignancies. Since approval in 1997, rituximab has become widely used in chronic lymphocytic leukemia (CLL, follicular lymphoma (FL, mantle cell lymphoma (MCL, and diffused large B-cell lymphoma (DLBCL when combined with chemotherapy. Currently, rituximab is commonly combined with first-line chemotherapy for FL and should be offered as maintenance therapy to all appropriate patients with this disease. Randomized Phase III trials demonstrated the superiority of rituximab added to CHOP chemotherapy against CHOP chemotherapy alone in patients with DLBCL. Rituximab alone has limited activity in MCL but can be used in MCL in combination with chemotherapy, despite the benefits not being as impressive as when used against other lymphoma entities. In addition, for the less frequent B-cell lymphomas, small series show considerable activity for most of these entities. Fludarabine and rituximab combination therapies in CLL yielded promising results in several studies. Two large Phase III randomized trials demonstrated the superiority of chemoimmunotherapy with rituximab compared with chemotherapy alone in previously untreated and refractory/relapsed patients with CLL. Therefore, it can be concluded that rituximab, with only few exceptions, can generally be accepted as a standard component of anti B-cell non-Hodgkin's lymphoma therapies. In this review, the pharmacology, mode of action, pharmacokinetics, and current place in the therapy of B-cell lymphoid

  10. Dosimetrical considerations in astatine-211 radioimmunotherapy

    International Nuclear Information System (INIS)

    Several dosimetrical quantities have been suggested for use in alpha-particle dosimetry. To evaluate the expected biological effect when using these quantities, a Monte Carlo program was set to register the single-event distribution of both specific energy and alpha-particle track length to a cell nucleus (r=5.6 μm). Distributions were acquired for both 'bound' (simulating the effect of 211At-labelled antibodies bound to antigens on cell surfaces (r=7.0 μm)) as well as 'non-bound' (simulating 211At-labelled antibodies that have not bound to a cell) astatine-211. From these distributions, various theoretical cell survival curves were established for 3 different dosimetrical quantities, i.e. specific energy, number of alpha-particle hits and total track length. The survival curves for all quantities are presented for the corresponding mean absorbed dose in order to facilitate comparisons of the expected effects of using the 3 different quantities for both distributions of 211At decays. The theoretical survival curves presented here could, combined with experiments using 'bound' and 'non-bound' 211At in a single-cell suspension, reveal which dosimetrical quantity is most suitable for 211 At-radioimmunotherapy. (author)

  11. An approach for chemical evaluation of immunoconjugates of “cold” 177lutetium-rituximab

    OpenAIRE

    Gjorgieva Ackova, Darinka; Smilkov, Katarina; Stafilov, Trajče; Kiprijanovska, Sanja; Sukarova Stefanovska, Emilija; Janevik-Ivanovska, Emilija

    2014-01-01

    Various radiolabeled monoclonal antibodies have been developed for the treatment and diagnosis of malignancies. Rituximab is a chimeric mouse-human monoclonal antibody. Rituximab selectively binds with high affinity to the CD20 antigen (human B-lymphocyte restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and on >90% of B cell non-Hodgkin’s lymphomas. These properties make the CD20 receptor a suitable target for radioactive ther...

  12. Rituximab (MabThera) til behandling af aktiv reumatoid artritis

    DEFF Research Database (Denmark)

    El Fassi, Daniel; Nielsen, Claus Henrik; Bendtzen, Klaus

    2006-01-01

    Rituximab (RTX) is a murine/human monoclonal antibody to CD20, a protein expressed almost exclusively on human B-lymphocytes. RTX induces rapid and marked B-cell depletion with beneficial clinical effects in 1/3 to 1/2 of rheumatoid arthritis patients. Treatment is given as two iv. infusions with...

  13. Radioimmunotherapy: Development of an effective approach

    International Nuclear Information System (INIS)

    We plan to extend our success in treating B cell malignancies with 131I labeled Lym-1 by a major effort in therapy with 67Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the 111In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the 111In-BAD(DOTA)-Lym-1 studies. Lymphomas and related diseases represent a special case for radioimmunotherapy because of their documented radiosensitivity and immunodeficiency, and thus offer a unique opportunity to conduct therapeutic feasibility studies in a responsive human model. Using marine and chimeric L6 and other MoAb to breast cancer, we have applied the strategies that were developed in taking Lym-1 antibody from the bench to the patient. We have examined a number of monoclonal antibodies for treatment of breast cancer and chose chimeric L6 for prototype studies because of certain characteristics. The chemistry of attachment of conjugates to antibodies and their impact on immunological targeting biological activities (cytotoxicity), metabolic fate, and therapeutic index will continue to be a major strength and function of this program. This grant has supported the conception, synthesis, and development of the first macrocylic, bifunctional chelating agent TETA (6-p-nitrobenzyl-1,4,8,11-tetraazatetradecane-N,N',N double-prime, N'double-prime-tetraacetic acid and its derivatives, including Lym-1-2IT-BAT), for use in Cu-67-based radioimmunodiagnosis and therapy. This work has led to the further development of several new macrocylic bifunctional chelating agents for copper, indium, yttrium and other metals. In addition, successful Cu-67 labelings of Lym-1-2IT-BAT for human radiopharmaceutical have shown patient pharmacokinetics of 67Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry

  14. Research demystifies the interaction between Rituximab and its target

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ As the first US FDA-approved monclonal antibody drug for the treatment of B-cell lymphomas and later on for the treatment of autoimmune diseases, Rituximab has been widely sold under the trade name of Rituxan ever since 1997 with an average sales volume over US$ 2 billion each year in the US.However, the recognition mechanism between Rituximab and its target CD20, an antigen expressed on the surface of mature B-cells, remained unclear. Now, an important step toward decoding the longstanding problem is achieved by scientists at the CAS Shanghai Institutes for Biological Sciences(SIBS) and their collaborators from the Second Military Medical University.

  15. Rituximab for the treatment of rheumatoid arthritis: an update

    Directory of Open Access Journals (Sweden)

    Mok CC

    2013-12-01

    Full Text Available Chi Chiu MokDepartment of Medicine, Tuen Mun Hospital, Hong Kong, Special Administrative Region of the People's Republic of ChinaAbstract: Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells. It was first used in the treatment of non-Hodgkin's lymphoma and later approved for the treatment of rheumatoid arthritis (RA that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-necrosis-factor (TNF biologics. Sustained efficacy in RA can be achieved by repeated courses of rituximab. However, the optimal dose and retreatment schedule of rituximab in RA remains to be established. Seropositivity, complete B cell depletion shortly after treatment, and previous failure to no more than one anti-TNF agent are three factors associated with greater clinical benefits to rituximab. Infusion reaction to the first dose of rituximab occurs in approximately 25% of RA patients, and the incidence reduces with subsequent exposure. Immunogenicity to the chimeric compound occurs in 11% of RA patients, but this does not correlate with its efficacy in B cell depletion. Extended observation of randomized controlled trials in RA does not reveal a significant increase in the incidence of serious infections related to rituximab compared to placebo groups, and the infection rate remains static over time. Repeated treatment with rituximab is associated with hypogammaglobulinemia, which may increase the risk of serious, but rarely opportunistic, infections. Reactivation of occult hepatitis B infection has been reported in RA patients receiving rituximab, but no increase in the incidence of tuberculosis was observed. Screening for baseline serum immunoglobulin G level and hepatitis B status (including occult infection is important, especially in Asian countries where hepatitis B infection is prevalent. The rare but fatal progressive multifocal leukoencephalopathy linked to the use

  16. Rituximab in the treatment of non-Hodgkin’s lymphoma

    Directory of Open Access Journals (Sweden)

    Beate Hauptrock

    2008-09-01

    Full Text Available Beate Hauptrock, Georg HessHematology/Oncology, Johannes Gutenberg-University, Mainz, GermanyAbstract: Besides traditional cytostatic drugs the introduction of monoclonal antibodies has substantially influenced current treatment concepts of non-Hodgkin’s lymphoma (NHL.  Rituximab, a monoclonal anti-CD20 chimeric antibody, now has been widely evaluated in the various B-cell lymphatic neoplasms. Large phase III studies helped to prove the value of this drug in follicular lymphoma as part of induction or relapse treatment as well as maintenance treatment. The addition of rituximab to the well established CHOP regimens has increased achievable cure rates in diffuse large cell lymphoma, and this combination is now accepted worldwide as standard of care. Although conflicting results are available, rituximab is widely used for the treatment of mantle cell lymphoma. For the less frequent lymphoma entities phase 2 studies show a considerable efficiency for most of these B-NHL variants. Current research focuses on combined chemoimmunotherapy approaches, optimization of dosing regimens, and combination with novel agents.Keywords: non-Hodgkin’s lymphoma, rituximab, monoclonal-antibody, targeted therapy

  17. Rituximab for the treatment of patients with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    M Gentile

    2010-03-01

    Full Text Available M Gentile, E Vigna, C Mazzone, E Lucia, AG Recchia, L Morabito2, MG Bisconte, C Gentile, F Morabito1UOC di Ematologia, Azienda Ospedaliera di Cosenza, Italy; 2Servicio de Hematología y Hemoterapia, Hospital Universitario de Canarias, La Laguna, Tenerife, SpainAbstract: Chronic lymphocytic leukemia (CLL is a lymphoproliferative disorder that originates from antigen-experienced B lymphocytes that do not die and hence accumulate due to external survival signals or undergo apoptosis and are replenished by proliferating precursors. These neoplastic lymphocytes exhibit a characteristic immunophenotype of CD5+/CD19+/CD20+/HLA-DR+/CD23+/sIgdim. Thus, the CD20 antigen has been an appealing target for therapy. The introduction of the monoclonal antibody rituximab (anti-CD20 enabled an outstanding advance in CLL treatment. The introduction of this monoclonal antibody into chemotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both untreated and relapsed CLL. Although only preliminary data from phase III confirmatory trials have been reported, the FCR regimen, which combines fludarabine and cyclophosphamide with rituximab, is currently the most effective treatment regimen for CLL patients, and has also been demonstrated to significantly improve overall survival . The success of rituximab and the identification of other CLL lymphocyte surface antigens have spurred the development of a multitude of monoclonal antibodies targeting distinct proteins and epitopes in an attempt to target CLL cells more effectively.Keywords: rituximab, chronic lymphocytic leukemia, chemotherapy

  18. Radioimmunotherapy for Treatment of Acute Leukemia.

    Science.gov (United States)

    Bodet-Milin, Caroline; Kraeber-Bodéré, Françoise; Eugène, Thomas; Guérard, François; Gaschet, Joëlle; Bailly, Clément; Mougin, Marie; Bourgeois, Mickaël; Faivre-Chauvet, Alain; Chérel, Michel; Chevallier, Patrice

    2016-03-01

    Acute leukemias are characterized by accumulation of immature cells (blasts) and reduced production of healthy hematopoietic elements. According to the lineage origin, two major leukemias can be distinguished: acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Although the survival rate for pediatric ALL is close to 90%, half of the young adults with AML or ALL and approximately 90% of older patients with AML or ALL still die of their disease, raising the need for innovative therapeutic approaches. As almost all leukemic blasts express specific surface antigens, targeted immunotherapy appears to be particularly promising. However, published results of immunotherapy alone are generally modest. Radioimmunotherapy (RIT) brings additional therapeutic mechanisms using radiolabeled monoclonal antibodies (mAbs) directed to tumor antigens, thus adding radiobiological cytotoxicity to immunologic cytotoxicity. Because of the high radiosensitivity of tumor cells and the diffuse widespread nature of the disease, making it rapidly accessible to circulating radiolabeled mAbs, acute leukemias represent relevant indications for RIT. With the development of recombinant and humanized mAbs, innovative radionuclides, and more efficient radiolabeling and pretargeting techniques, RIT has significantly improved over the last 10 years. Different approaches of α and β RIT targeting CD22, CD33, CD45, or CD66 antigens have already been evaluated or are currently being developed in the treatment of acute leukemia. This review summarizes the preclinical and clinical studies demonstrating the potential of RIT in treatment of AML and ALL. PMID:26897718

  19. Dosimetric measurements and radiobiological consequences of radioimmunotherapy in tumor bearing mice

    International Nuclear Information System (INIS)

    With the development of the hybridoma technology, the production of highly specific tumor associated monoclonal antibodies has provided new optimism for the adjuvant delivery of therapeutic radiation doses via radioimmunotherapy. The authors have used a modified form of the well-established TL dosimetry technology to measure the dose resulting from radioimmunotherapy experiments in tumor bearing mice. Their laboratory has designed and tested a miniature CaSO4:D TLD which fits conveniently inside a 20 gauge needle for the direct implantation of the dosimeter in an animal model undergoing radiolabeled antibody therapy. Direct measurement of absorbed dose from beta and gamma radiation in the animals may be obtained upon removal of the dosimeter at animal sacrifice or by surgery. This absorbed dose data may then be related to antibody affinity and localization data obtained by serial biodistribution studies. Using p96.5 melanoma antibody with a Brown Tumor Model in athymic mice, localization indices measured in the range of 2 to 4 and scored 4 to 7 days post antibody injection, yielded a tumor dose/whole body dose ratio of 1.10 +/- 0.04 (no enhancement). The dose to liver showed marker time-dependent enhancement relative to the whole body, however. An outline of suggested control radiobiological experiments to be performed in conjunction with radioimmunotherapy experiments has been included in order to provide comparative dose response data. 11 references, 14 figures, 3 tables

  20. Improving testing for hepatitis B before treatment with rituximab

    Science.gov (United States)

    Jopson, Laura; Ng, Sarah; Lowery, Matthew; Harwood, Jayne; Waugh, Sheila; Valappil, Manoj; McPherson, Stuart

    2016-01-01

    Aims/Objectives/Background Individuals with current or previous infection with the hepatitis B virus (HBV) can experience viral reactivation when treated with immunosuppression. Rituximab, an anti-CD20 antibody used to treat many diseases, has potent immunosuppressant effects with a high risk of causing HBV reactivation. Reactivation can range from elevated liver enzymes to acute severe hepatitis with liver failure and a significant mortality risk. HBV screening and appropriate use of prophylactic antiviral therapy can prevent reactivation. This work describes the introduction of a local policy for HBV testing in patients before rituximab treatment and assesses its impact. Methods and Results A baseline review (before policy introduction) of 90 patients showed that only 21 (23%) had hepatitis B surface antigen (HBsAg) and 17 (19%) had hepatitis B core antibody (anti-HBcAb) tested before receiving rituximab. Following introduction of the policy (on the basis of international guidelines), improved laboratory reporting protocols and targeted education sessions, two further reviews of HBV testing rates among patients being initiated onto rituximab were performed. There was a marked increase in pre-rituximab testing for HBsAg from 23 to 79% and for anti-HBcAb from 19 to 78%. Throughout the study period, a total of one (0.8%) HBsAg-positive and six (4.7%) anti-HBcAb-positive patients were identified. Conclusions This work clearly indicates that simple strategies can markedly improve appropriate HBV screening. In our cohort, 6% (of whom only 43% had recognized HBV risk factors) required antiviral prophylaxis, which emphasizes the importance of universal screening before rituximab. Reinforcement of the guidelines and ongoing education is needed to further increase testing rates. PMID:27388147

  1. Rituximab and biosimilars – equivalence and reciprocity

    Science.gov (United States)

    Qureshi, Zaina P; Magwood, Jametta S; Singh, Sarveshwari; Bennett, Charles L

    2014-01-01

    Cancer is a debilitating disease affecting millions of people daily. Over the years, cancer treatment has advanced in leaps and bounds. Antibodies are important breakthrough therapeutic agents for cancer. These agents, proteins produced by B lymphocytes of the immune system in response to antigens, bind to receptors on cell surfaces so that the antigen–antibody complexes can be recognized and destroyed by phagocytes. While each B cell synthesizes only one kind of antibody, an entire population of different types of B cells and their respective antibodies are produced in response to various antigens to which the organism had been exposed. However, to be useful clinically, substantial amounts of a single antibody must be generated from a single ancestral B cell. These antibodies produced by a specific population of B cells are the monoclonal antibodies that have become the cornerstone of treatment for cancer and many immunologic illnesses. The purpose of this report is to provide an overview of the clinical development of biosimilars in clinical oncology, focusing on rituximab and like biosimilars. PMID:24829884

  2. Study On The Preparation Of 90Y-DTPA-Rituximab For Non-Hodgkin Lymphoma Treatment

    International Nuclear Information System (INIS)

    Yttrium is one of the most useful radionuclides for radioimmunotherapeutic applications, especially labelling with monoclonal antibodies. Rituximab was bound to the DTPA chelating agent using Hnatowich methods. Cyclic anhydride DTPA (cDTPAa, 0.1 mg/ml) was dissolved in chloroform and was degassed under a stream of nitrogen for 30 minutes. Rituximab solution in 0.05 M bicarbonate buffer was immediately added and mixed for one minute at room temperature. The antibody Rituximab at different concentration (5 mg/ml and 10 mg/ml) was coupled with the cDTPAa, at molar ratios (cDTPAa : Rituximab) of 1:1, 3:1, 5:1, 10:1 and 20:1. The conjugation of DTPA-Rituximab mixture was labelled with Y-90, then using Sephadex G25 in order to determine coupling efficiency. Coupling efficiency at a 3:1 mole ratio was 70%. After purification, the conjugation DTPA-Rituximab was labeled with Y-90 in 0.5 M acetate buffer, pH 5, at room temperature. The labeling yield was about 99%. The radiochemical purity of 90Y-DTPA-Rituximab was more than 98 % which determined by ITLC in 0.1 M acetate at pH 6 as mobile phase. The radiopharmaceuticals have been test for sterility, apyrogenicity and biodistribution. This is a potential radiopharmaceutical for clinical application in therapeutic Non Hodgkin Lymphoma treatments. (author)

  3. Criteria for the selection of radionuclides for tumor radioimmunotherapy

    International Nuclear Information System (INIS)

    The potential of utilizing monoclonal antibodies as carriers of radionuclides for the selective destruction of tumors (radioimmunotherapy, RIT) has stimulated much research activity. From dosimetric and other considerations, the choice of radiolabel is an important factor that needs to be optimized for maximum effectiveness of RIT. This paper reviews and assesses a number of present and future radionuclides that are particularly suitable for RIT based on the various physical, chemical, and biological considerations. Intermediate to high-energy beta emitters' (with and without gamma photons in their emission) are emphasized since they possess a number of advantages over alpha and Auger emitters. Factors relating to the production and availability of candidate radiometals as well as their stable chemical attachment to monoclonal antibodies are discussed. 34 refs., 4 tabs

  4. Development and evaluation of copper-67 and samarium-153 labeled conjugates for tumor radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, S.C.; Mausner, L.F.; Mease, R.C.; Meinken, G.E.; Joshi, V.; Kolsky, K.; Sweet, M.; Steplewski, Z.

    1995-02-01

    The potential of utilizing receptor-specific agents such as monoclonal antibodies (MAb), and MAb-derived smaller molecules, as carriers of radionuclides for the selective destruction of tumors has stimulated much research activity. The success of such applications depends on many factors, especially the tumor binding properties of the antibody reagent, the efficiency of labeling and in-vivo stability of the radioconjugate and, on the careful choice of the radionuclide best suited to treat the tumor under consideration. The radiolabeled antibody technique for radioimmunotherapy (RIT), however, has experienced many limitations, and its success has not matched the expectations that were raised more than a decade ago. The problems that have been identified include: (i) degradation of antibody immunoreactivity resulting from chemical manipulations required for labeling; (ii) lack of suitable radioisotopes and methods for stable attachment of the radiolabel; (iii) in-vivo instability of the radioimmunoconjugates; (iv) excessive accumulation of activity in non-target locations; and (v) lack of radioimmunoconjugate accessibility to cells internal to a tumor mass. A careful choice of the radionuclide(s) best suited to treat the tumor under consideration is one of the most important requirements for successful radioimmunotherapy. This study evaluates copper 67 and samarium 153 for tumor radioimmunotherapy.

  5. Labeling an anti-CD20 monoclonal antibody with 90Y

    International Nuclear Information System (INIS)

    implementation of the radioimmunotherapy with this type of 90Y-labeled antibody sustainably nationwide. The main objective of this study was to establish a methodology for stable marking chimeric monoclonal anti-CD20 antibody rituximab with 90Y. (author)

  6. Optimizing lutetium 177-anti-carbonic anhydrase IX radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model

    NARCIS (Netherlands)

    Muselaers, C.H.J.; Oosterwijk, E.; Bos, D.L.; Oyen, W.J.G.; Mulders, P.F.A.; Boerman, O.C.

    2014-01-01

    A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 (177Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT st

  7. Persistence of babesiosis for >2 years in a patient on rituximab for rheumatoid arthritis.

    Science.gov (United States)

    Raffalli, John; Wormser, Gary P

    2016-06-01

    We report a patient who was being treated with rituximab for rheumatoid arthritis who developed Babesia microti infection that persisted for 26 months despite prolonged anti-babesia drug therapy. The explanation for the persistence was likely to have been the long-term immunocompromising effects of rituximab, as evidenced by seronegativity for B. microti antibodies that lasted for more than 1 year after onset of infection. PMID:27036977

  8. Early-Onset Neutropenia Induced by Rituximab in a Patient with Lupus Nephritis and Hemolytic Anemia

    OpenAIRE

    Mariangelí Arroyo-Ávila; Fred-Jiménez, Ruth M.; Vilá, Luis M.

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L) a...

  9. Selective response to rituximab in a young child with MuSK-associated myasthenia gravis.

    Science.gov (United States)

    Govindarajan, Raghav; Iyadurai, Stanley J; Connolly, Anne; Zaidman, Craig

    2015-08-01

    Neuromuscular junction disorders in children are either genetic, such as congenital myasthenic syndrome, or autoimmune with circulating antibodies most commonly against acetylcholine receptors. There is limited experience recognizing and treating children with myasthenia associated with muscle-specific tyrosine kinase antibodies. We report a seven-year-old child with intermittent esotropia since age 3 months, and two years of progressive and severe diplopia, dysarthria, dysphagia, and facial weakness. Acetylcholine receptor antibodies and genetic testing for congenital myasthenic syndrome were negative. Muscle specific tyrosine kinase antibodies were significantly elevated. Ophthalmoplegia and bulbar weakness were refractory to treatment with acetylcholinesterase inhibitors, corticosteroids and IVIg but completely resolved following treatment with rituximab. Her neurologic examination remained normal at the most recent follow-up, 15 months after initiation of rituximab. Children with MuSK myasthenia, like adults, can respond to rituximab despite long standing disease and failure to improve on other immunosuppressant medications. PMID:25998611

  10. Preparation and biological evaluation of 177Lu-labeled rituximab for B-lymphoma treatment

    OpenAIRE

    Edalat Radfar; Azim Arbabi; Dariush Sardari

    2010-01-01

    Introduction: 177Lu is a beta emitter with suitable decay mode [T1/2=6.7 d, Eβmax=497 keV, EΥ=112keV (6.4%) & 208 keV (11%)] for using in radio therapy. Various radiolabeled monoclonal antibodies have been developed in treatment. Rituximab is a chimeric mouse-human monoclonal antibody. Rituximab binds with human B-lymphocate-restricted differentiation antigen: CD20. Rituxsimab was used successfully as an anti-CD20 radiolabeled antibody before. Methods: 177Lu was p...

  11. Radioimmunotherapy with tositumomab and iodine-131 tositumomab for non-Hodgkin’s lymphoma

    OpenAIRE

    Andemariam, Biree; Leonard, John P.

    2007-01-01

    With the success of targeted monoclonal antibody therapy in non-Hodgkin’s lymphoma, attempts were made to further improve efficacy through the addition of a radioisotope. A goal of radioimmunotherapy is to utilize the monoclonal antibody to deliver radiation to a tumor bed with relatively limited toxicity to the surrounding normal tissues. I-131 Tositumomab is an iodine-131 labeled anti-CD20 murine IgG2a monoclonal antibody and is one of two FDA-approved radioimmunotherapeutic drugs for patie...

  12. Radiolabeled bivalent haptens for tumor immunodetection and radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Gruaz-Guyon, A.; Janevik-Ivanovska, E.; Raguin, O. [Hopital Saint-Antoine, Faculte' de Medecine, Paris (France); De Labriolle-Vaylet, C. [Hopital Saint-Antoine, Faculte' de Medecine, Paris (France); Hopital Saint-Antoine, Service de Medecine Nucleaire, Paris (France); Barbet, J. [Universite' de la Mediterranee, Faculte' de Medecine, Marseille (France)

    2001-06-01

    The pre targeting technique referred to as the Affinity Enhancement System (AES) uses bispecific antibodies and radiolabeled bivalent haptens that bind cooperatively to target cells in vivo. Experimental and clinical data demonstrate that DTPA bivalent haptens can deliver large radiation doses to tumor cells with high tumor to normal tissue contrast ratios and long activity residence time in tumors. Preliminary clinical results of radioimmunotherapy of medullary thyroid carcinomas and lung cancers look promising. Very encouraging results in biodistribution and radioimmunotherapy experiments in animals have been obtained with new haptens bearing two histamine-hemisuccinate suitable for {sup 131}I, {sup 99m}Tc and {sup 188}Re labeling. Targeting isotopes to double antigen positive tumor cells provides a binding enhancement that increases specificity for tumor cells as compared to single antigen targeting on normal cells. This approach may be beneficial for targeting isotopes to B type acute lymphoblastic leukemia and Burkitt lymphoma, as well as others tumors co-expressing two markers of low specificity, and might increase tumor irradiation with minimal irradiation of normal cells.

  13. Immunreconstitution and Infectious Complications After Rituximab Treatment in Children and Adolescents: What Do We Know and What Can We Learn from Adults?

    OpenAIRE

    Jennifer Worch; Olga Makarova; Birgit Burkhardt

    2015-01-01

    Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituxima...

  14. Efficacy and safety of rituximab in the treatment of refractory pemfigus vulgaris

    Directory of Open Access Journals (Sweden)

    Aslı Bilgiç Temel

    2015-06-01

    Full Text Available Background and Design: Pemphigus vulgaris (PV is a severe, chronic, potentially life-threatening autoimmune blistering disease that affects the skin and mucous membranes, associated with the loss of cell-cell adhesion and blister formation. Systemic steroids in combination with immunosuppressive agents are the mainstay of therapy in pemphigus. Rituximab is a chimeric monoclonal anti- CD20 antibody, has been tried increasingly for the treatment of PV. Objective: We sought to test the efficacy and safety of rituximab as an adjuvant therapy by retrospective analysis of clinical and immunological data of patients. Method: A retrospective analysis is presented of 13 patients with refractory pemphigus vulgaris who were treated with rituximab at Akdeniz University Hospital, Dermatology and Venereology Department, Bullous Disease Unit. We evaluated clinical and immunological data with last treatments. Results: Patients were treated with one cycle of two biweekly infusions of rituximab at a dose of 1000 mg on days 1 and 15, except one received four doses of 375 mg / m2 intravenously weekly. The mean follow-up time was 18.5 months. All patients had a decrease in antibody titers or antibodies were completely undetected after treatment. Rituximab use resulted in a significant reduction in steroid dosage during follow-up. At the end of the follow-up period, 7 patients achieved complete disease remission without therapy, 1 patient achieved partial disease remission without therapy, 2 patients achieved complete remission on minimal therapy, 1 patient achieved complete remission on therapy, 1 patient achieved partial remission on minimal therapy, and one patient had no follow-up. Rituximab was well tolerated by all patients. Clinical relapse had seen 53.8% by the mean period of 13.8 months. Relapses have been managed with additional infusions of rituximab. Conclusion: Rituximab is beneficial in the management of refractory PV, induces prolonged clinical

  15. Radioimmunotherapy

    Science.gov (United States)

    ... used to treat: non-Hodgkin B-cell lymphoma (NHL), including both new patients and patients who have ... is generally not administered to pregnant women and children. Pre-screening of patients will occur to ensure ...

  16. Rituximab Administration in Third Trimester of Pregnancy Suppresses Neonatal B-Cell Development

    Directory of Open Access Journals (Sweden)

    D. T. Klink

    2008-01-01

    Full Text Available We describe the effect on the neonate of administration of rituximab to a woman with idiopathic thrombocytopenic purpura (ITP. Rituximab, an anti-CD20 antibody, was given weekly for 4 weeks to a woman with ITP in her third trimester of pregnancy. One month after the last rituximab administration a healthy girl was born. She had normal growth and development during the first six months. At birth, B-lymphocytes were not detectable. Rituximab levels in mother and neonate were 24000 and 6700 ng/mL, respectively. Only 7 cases of rituximab administration during pregnancy were described. No adverse events are described for fetus and neonate. We demonstrate that rituximab passes the placenta and inhibits neonatal B-lymphocyte development. However, after 6 months B-lymphocyte levels normalized and vaccination titres after 10 months were adequate. No infection-related complications occurred. Rituximab administration during pregnancy appears to be safe for the child but further studies are warranted.

  17. Rituximab for the treatment of rheumatoid arthritis: an update

    OpenAIRE

    Mok CC

    2013-01-01

    Chi Chiu MokDepartment of Medicine, Tuen Mun Hospital, Hong Kong, Special Administrative Region of the People's Republic of ChinaAbstract: Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells. It was first used in the treatment of non-Hodgkin's lymphoma and later approved for the treatment of rheumatoid arthritis (RA) that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-nec...

  18. Guideline for radioimmunotherapy of CD20+ follicular B-cell non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    This guideline is a prerequisite for the quality management in the treatment of non-Hodgkon-lymphomas in patients with relapsed or refractory follicular lymphoma after rituximab therapy and as consolidation therapy after first remission following CHOP like treatment using radioimmunotherapy. It is based on an interdisciplinary consensus and contains background information and definitions as well as specified indications and detailed contraindications of treatment. Essential topics are the requirements for institutions performing the therapy. For instance, presence of an expert for medical physics, intense cooperation with all colleagues committed to treatment of lymphomas, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with those colleagues (hemato-oncologists) who propose, in general, radioimmuno-therapy under consideration of the development of the disease. (orig.)

  19. Rituximab-Based Treatment, HCV Replication, and Hepatic Flares

    Directory of Open Access Journals (Sweden)

    Evangelista Sagnelli

    2012-01-01

    Full Text Available Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.

  20. Radioimmunotherapy: Development of an effective approach. Progress report, 1987

    Energy Technology Data Exchange (ETDEWEB)

    1987-12-31

    Goals of this program are to answer the fundamental scientific questions for the development of an effective approach for delivering radiation therapy to cancer on antibody-based radiopharmaceuticals. The following list consists of highlights of developments from our program: documented therapeutic response of lymphoma in patients receiving radioimmunotherapy; development and application of quantitative radionuclide imaging techniques for therapy planning and dosimetry calculations; multicompartmental modeling and analysis of the in vivo MoAb kinetics in patients; a MoAb macrocycle chelate for Cu-67: development, production, in vitro and in vivo testing; NMR analysis of immunoradiotherapeutic effects on the metabolism of lymphoma; analysis of the variable molecular characteristics of the MoAb radiopharmaceutical, and their significance; in vivo studies in mice and patients of the metabolism of radioiodinated MoAb as well as In-111 CITC MoAb; and biodistribution of Cu-67 TETA MoAb in nude mice with human lymphoma.

  1. Rituximab therapy reduces organ-specific T cell responses and ameliorates experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Nancy L Monson

    Full Text Available Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS. The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While Rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues.

  2. Antibody

    Science.gov (United States)

    An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples ... microorganisms (bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produced when the immune system mistakenly ...

  3. Rituximab-Induced Splenic Rupture and Cytokine Release

    Science.gov (United States)

    Nair, Ranjit; Gheith, Shereen; Lamparella, Nicholas

    2016-01-01

    Patient: Female, 55 Final Diagnosis: Mantle cell lymphoma Symptoms: Cytokine release syndrome • hypoglycemia • hypotension • splenic rupture • splenomegaly • vision loss Medication: — Clinical Procedure: Case Report Specialty: Oncology Objective: Unusual clinical course Background: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. Case Report: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. Conclusions: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation. PMID:26972227

  4. Post-transplant lymphoproliferative disorder treated with rituximab: case report

    Institute of Scientific and Technical Information of China (English)

    MENG Hai-tao; LI Ying; LIU Jian-hua; XU Gai-xiang; TENG Xiao-dong

    2007-01-01

    @@ Post-transplant lymphoproliferative disorder (PTLD), a rare disease, is characterized by an abnormal proliferation of lymphoid cells after solid organ transplantation.1 This complication is usually caused by the immunosuppressive therapy following transplantation.Though the techniques of early detection and diagnosis of the disease are well established, treatment is not so straightforward and poses a real challenge. At this time,options include anti-viral therapy, cytotoxic chemotherapy, cellular immunotherapy, and reduction of immunosuppression. But the effects of these therapies are not satisfying. Rituximab, a chimeric monoclonal anti-CD20 antibody used for the treatment of B cell lymphoma with a good effect, is rarely, especially in combination with chemotherapy, used for PTLD. In this report, we describe a case of PTLD treated with rituximab and chemotherapy resulting in complete remission.

  5. Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

    International Nuclear Information System (INIS)

    Introduction: In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium(188Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy. Methods: Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi 188Re-6D2 antibody, saline, unlabeled 6D2 antibody or 188Re-labeled non-specific IgM. Results: On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells. Conclusions: These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers

  6. A pretargeting system for tumor PET imaging and radioimmunotherapy

    Directory of Open Access Journals (Sweden)

    Françoise eKraeber-Bodéré

    2015-03-01

    Full Text Available Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

  7. The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations

    International Nuclear Information System (INIS)

    C-terminal mutations of CD20 constitute part of the mechanisms that resist rituximab therapy. Most CD20 having a C-terminal mutation was not recognized by L26 antibody. As the exact epitope of L26 has not been determined, expression and localization of mutated CD20 have not been completely elucidated. In this study, we revealed that the binding site of L26 monoclonal antibody is located in the C-terminal cytoplasmic region of CD20 molecule, which was often lost in mutated CD20 molecules. This indicates that it is difficult to distinguish the mutation of CD20 from under expression of the CD20 protein. To detect comprehensive CD20 molecules including the resistant mutants, we developed a novel monoclonal antibody that recognizes the N-terminal cytoplasm region of CD20 molecule. We screened L26-negative cases with our antibody and found several mutations. A rituximab-binding analysis using the cryopreserved specimen that mutation was identified in CD20 molecules indicated that the C-terminal region of CD20 undertakes a critical role in presentation of the large loop in which the rituximab-binding site locates. Thus, combination of antibodies of two kinds of epitope permits the identification of C-terminal CD20 mutations associated with irreversible resistance to rituximab and may help the decision of the treatment strategy

  8. Combination of cyclophosphamide, rituximab, and intratumoral CpG oligodeoxynucleotide successfully eradicates established B cell lymphoma.

    Science.gov (United States)

    Betting, David J; Hurvitz, Sara A; Steward, Kristopher K; Yamada, Reiko E; Kafi, Kamran; van Rooijen, Nico; Timmerman, John M

    2012-09-01

    Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy. PMID:22892450

  9. Early-onset neutropenia induced by rituximab in a patient with lupus nephritis and hemolytic anemia.

    Science.gov (United States)

    Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M; Vilá, Luis M

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 10(9)/L) after the second weekly rituximab infusion (375 mg/m(2) weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections. PMID:25767732

  10. Early-Onset Neutropenia Induced by Rituximab in a Patient with Lupus Nephritis and Hemolytic Anemia

    Directory of Open Access Journals (Sweden)

    Mariangelí Arroyo-Ávila

    2015-01-01

    Full Text Available Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L after the second weekly rituximab infusion (375 mg/m2 weekly × 4 given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections.

  11. Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus

    Directory of Open Access Journals (Sweden)

    Pradnya J Londhe

    2014-01-01

    Full Text Available Background: Rituximab, a monoclonal anti-CD20 antibody, has been used with encouraging results in pemphigus. We describe herein refractory cases of pemphigus vulgaris (n = 23 and pemphigus foliaceus (n = 1 treated with rituximab in addition to steroids and immunosuppressants. Aims: To assess the response to treatment, the duration of clinical remission, serology of the response and adverse effects of rituximab in pemphigus patients. Methods: We recorded observations of 24 patients with pemphigus having either refractory disease in spite of high dose of steroids and immunosuppressants, corticosteroid-dependent disease, strong contraindications to corticosteroids, or severe disease. The patients were treated with infusions of one injection per week for three consecutive weeks of 375 mg of rituximab per m 2 of body-surface area. One similar infusion was repeated after 3 months of 3 rd dose. We observed the clinical outcome after 6 months of 3 rd dose of rituximab and looked for complete healing of cutaneous and mucosal lesions (complete remission. Observations: After follow-up of 7-24 months, five patients showed only partial improvement while 19 of 24 patients had a complete remission 3 months after rituximab. Of these 19 patients, 12 patients achieved complete remission and are off all systemic therapy, and the rest are continuing with no or low dose of steroids with immunosuppressants. Two patients relapsed after initial improvement; one was given moderate dose of oral steroids and immunosuppressant and the other was given repeat single dose of rituximab to control relapse. Conclusion: Rituximab is able to induce a prolonged clinical remission in pemphigus after a single course of four infusions. The high cost and limited knowledge of long term adverse effects are limitations to the use of this biologic agent.

  12. Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma

    Directory of Open Access Journals (Sweden)

    Aguiar-Bujanda D

    2015-10-01

    Full Text Available David Aguiar-Bujanda, María Jesús Blanco-Sánchez, María Hernández-Sosa, Saray Galván-Ruíz, Samuel Hernández-Sarmiento Department of Medical Oncology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain Abstract: Rituximab is an IgG1, chimeric monoclonal antibody specifically designed to recognize the CD20 antigen expressed on the surface of normal and malignant B-lymphocytes, from the B-cell precursor to the mature B-cells of the germinal center, and by most neoplasms derived from B-cells. After 2 decades of use, rituximab is firmly positioned in the treatment of follicular lymphoma (FL, both in the front line and in the relapsing disease, improving previous results by including it in classical chemotherapy regimens. However, the pharmacology of rituximab continues to generate controversial issues especially regarding the mechanisms of action in vivo. The contribution of rituximab as a maintenance treatment in FL has been significant progress in the management of this disease without an increase in side effects or a decrease in the quality of life of patients. With the widespread use of rituximab, there are new security alerts and side effects not previously detected in the pivotal trials that clinicians should learn to recognize and manage. In this article, we will review the pharmacokinetics and pharmacodynamics of rituximab, the management issues in the treatment of advanced FL focusing on maintenance rituximab, its long-term efficacy and safety profile, and its effect on the quality of life. Keywords: follicular lymphoma, long-term efficacy, maintenance, rituximab, toxicity

  13. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia

    DEFF Research Database (Denmark)

    Birgens, Henrik Sverre; Frederiksen, Henrik; Hasselbalch, Hans C;

    2013-01-01

    The impact of first-line treatment with the anti-CD 20 chimeric monoclonal antibody rituximab in patients with warm-antibody reactive autoimmune haemolytic anaemia (WAIHA) is unknown. We report the first randomized study of 64 patients with newly diagnosed WAIHA who received prednisolone and...

  14. An Open-Label Trial of Rituximab Therapy in Pulmonary Alveolar Proteinosis

    OpenAIRE

    Kavuru, Mani S.; Malur, Anagha; Marshall, Irene; Barbara P. Barna; Meziane, Moulay; Huizar, Isham; Dalrymple, Heidi; Karnekar, Reema; Thomassen, Mary Jane

    2011-01-01

    Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary Alveolar Proteinosis (PAP) is an autoimmune disorder characterized by autoantibodies to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF).

  15. Practical simplifications for radioimmunotherapy dosimetric models

    Energy Technology Data Exchange (ETDEWEB)

    Shen, S.; DeNardo, G.L.; O`Donnell, R.T.; Yuan, A.; DeNardo, D.A.; Macey, D.J.; DeNardo, S.J. [Univ. of California, Sacramento, CA (United States). Davis Medical Center

    1999-01-01

    Radiation dosimetry is potentially useful for assessment and prediction of efficacy and toxicity for radionuclide therapy. The usefulness of these dose estimates relies on the establishment of a dose-response model using accurate pharmacokinetic data and a radiation dosimetric model. Due to the complexity in radiation dose estimation, many practical simplifications have been introduced in the dosimetric modeling for clinical trials of radioimmunotherapy. Although research efforts are generally needed to improve the simplifications used at each stage of model development, practical simplifications are often possible for specific applications without significant consequences to the dose-response model. In the development of dosimetric methods for radioimmunotherapy, practical simplifications in the dosimetric models were introduced. This study evaluated the magnitude of uncertainty associated with practical simplifications for: (1) organ mass of the MIRD phantom; (2) radiation contribution from target alone; (3) interpolation of S value; (4) macroscopic tumor uniformity; and (5) fit of tumor pharmacokinetic data.

  16. Pre-targeted radioimmunotherapy of solid tumors: A multidisciplinary approach; La radio-immunotherapie preciblee des tumeurs solides: une demarche pluridisciplinaire

    Energy Technology Data Exchange (ETDEWEB)

    Barbet, J.; Kraber-Bodere, F.; Faivre-Chauvet, A.; Gestin, J.F.; Bardies, M.; Chatal, J.F. [Institut National de la Sante et de la Recherche Medicale (INSERM), U601, Institut de Biologie, Dept. de Recherche en Cancerologie, 44 - Nantes (France); Nantes Univ., U601, Dept. de Recherche en Cancerologie, 44 (France); Campion, L. [Institut National de la Sante et de la Recherche Medicale (INSERM), U601, Institut de Biologie, Dept. de Recherche en Cancerologie, 44 - Nantes (France); Centre de lutte contre le cancer Rene-Gauducheau, 44 - Saint-Herblain (France)

    2007-09-15

    No effective therapy is currently available for the management of patients with metastases of most solid tumors. Thus, pre targeted radioimmunotherapy approaches have been developed that have shown promises. One of these techniques uses bi specific monoclonal antibody and radiolabeled bivalent haptens injected sequentially. In two clinical trials, 29 patients with advanced, progressive medullary thyroid carcinoma, as documented by short serum calcitonin doubling times, received an anti-carcinoembryonic antigen x anti-diethylenetriamine pentaacetic acid (DTPA)-indium) bi specific monoclonal antibody, followed four to five days later by an {sup 131}I-labeled bivalent hapten. Overall survival was significantly longer in high-risk, treated patients than in high-risk, untreated patients (110 versus 61 months; P < 0.030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in calcitonin doubling time, experienced significantly longer survival than non-responders (159 versus 109 months; P < 0.035) and untreated patients (159 versus 61 months; P < 0.010). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread. Various multidisciplinary aspects of this long-term endeavor that resulted in long-term disease stabilization and a significantly longer survival in high-risk patients are described and discussed with respect to future directions of research on pre targeted radioimmunotherapy. (authors)

  17. Radioimmunotherapy for recurrent childhood hepatoblastoma after liver transplantation

    International Nuclear Information System (INIS)

    Full text: Monoclonal antibody has been developed for targeting secretory anti-fetoprotein in hepatic tissue. This antibody has been labelled with In-111 and Y-90 for clinical diagnostics and therapy, and can be applied for detecting hepatic neoplasms. Here, we use these antibodies for radiotherapy and radioimmunotherapy dose planning of hepatoblastoma, a rare childhood malignancy. Radiopharmacokinetic parameters were calculated after serial quantitative whole body scanning based on geometric mean images and transmission scanning. Biodistribution data and organ level kinetic parameters were calculated and were compared with those of nonclinical studies in mice. A 3-D dose planning programme was used to calculate tumor doses for In-111 and Y-90, the active tumor was delineated on PET/CT images and tumor dose calculation was done on In-111-MoAb SPECT data using dose point kernel approach both for In-111 and Y-90. The results were compared with MIRD doses obtained for organs in SPECT imaging field, i.e. bone marrow, heart, kidneys, liver, spleen, lungs. From quantitative serial imaging based on 8 whole body images at 0-168 hrs using In-111-anti-AFPMoAb, the half-lives of spleen, lungs, kidneys and whole body were 502 hrs, 230 hrs, 193 hrs and 490 hrs, respectively. The measured blood half-life was 132 hrs, after a total MoAb dose of 50 mg and In-111 activity of 105 MBq. The presumed Y-90 dose based on this kinetic behavior was 43 MBq which should had given 2 Gy bone marrow dose. The calculated MIRD Y-90 doses were for cardiac wall 0.75 Gy, liver 0.62 Gy, spleen 0.51Gy and bone marrow 0.053 Gy, and the effective whole body dose was 0.18 Gy, i.e. 4.23 mGy/MBq. The 3-D programme demonstrated the mean doses in normal tissues as follows: heart 0.58 Gy, liver 0.48 Gy, spleen 0.37 Gy and bone marrow 0.34 Gy. No toxicity was observed to the Y-90-anti- AFP radioimmunotherapy. The actual liver tumor dose according to the 3-D calculations was in average 0.51 Gy, range 0

  18. Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid

    Energy Technology Data Exchange (ETDEWEB)

    He, Ping [Johns Hopkins University, Department of Biomedical Engineering, Baltimore, MD (United States); Kramer, Kim; Cheung, Nai-Kong V. [Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, New York, NY (United States); Smith-Jones, Peter; Larson, Steven M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Zanzonico, Pat; Humm, John [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States)

    2011-02-15

    Radioimmunotherapy (RIT) using {sup 131}I-3F8 injected into cerebrospinal fluid (CSF) was a safe modality for the treatment of leptomeningeal metastases (JCO, 25:5465, 2007). A single-compartment pharmacokinetic model described previously (JNM 50:1324, 2009) showed good fitting to the CSF radioactivity data obtained from patients. We now describe a two-compartment model to account for the ventricular reservoir of {sup 131}I-3F8 and to identify limiting factors that may impact therapeutic ratio. Each parameter was examined for its effects on (1) the area under the radioactivity concentration curve of the bound antibody (AUC[C{sub IAR}]), (2) that of the unbound antibody AUC[C{sub IA}], and (3) their therapeutic ratio (AUC[C{sub IAR}]/AUC[C{sub IA}]). Data fitting showed that CSF kBq/ml data fitted well using the two-compartment model (R = 0.95 {+-} 0.03). Correlations were substantially better when compared to the one-compartment model (R = 0.92 {+-} 0.11 versus 0.77 {+-} 0.21, p = 0.005). In addition, we made the following new predictions: (1) Increasing immunoreactivity of {sup 131}I-3F8 from 10% to 90% increased both (AUC[C{sub IAR}]) and therapeutic ratio (AUC[C{sub IAR}]/AUC[C{sub IA}]) by 7.4 fold, (2) When extrapolated to the clinical setting, the model predicted that if {sup 131}I-3F8 could be split into 4 doses of 1.4 mg each and given at {>=}24 hours apart, an antibody affinity of K{sub D} of 4 x 10{sup -9} at 50% immunoreactivity were adequate in order to deliver {>=}100 Gy to tumor cells while keeping normal CSF exposure to <10 Gy. This model predicted that immunoreactivity, affinity and optimal scheduling of antibody injections were crucial in improving therapeutic index. (orig.)

  19. Improving the Efficacy of Radioimmunotherapy for Non-Hodgkin’s Lymphomas

    OpenAIRE

    Palanca-Wessels, M. Corinna A.; Press, Oliver W

    2010-01-01

    Approximately 66,000 Americans develop non-Hodgkin’s lymphomas (NHL) each year. Although the use of unlabeled antibodies such as rituximab has significantly improved survival when combined with standard chemotherapy regimens, two-thirds of lymphoma patients eventually relapse and succumb to their disease. Novel treatments are urgently needed to cure these patients. One strategy involves the use of radiolabeled immunoconjugates that specifically localize radiation delivery to sites of lymphoma...

  20. Recurrent inflammatory pseudotumor of the jaw with perineural intracranial invasion demonstrating sustained response to Rituximab.

    Science.gov (United States)

    Garcia, Bryan A; Tinsley, Sarah; Schellenberger, Thomas; Bobustuc, George C

    2012-12-01

    Corticosteroids are the mainstay of treatment of inflammatory pseudotumor (IPT) of the head and neck; however, involvement of the skull base and mandible can be unresponsive to steroids and require surgical resection. IPT is known to usually contain a CD20+ lymphocyte subgroup. Rituximab, a chimeric anti-CD20 antibody, has been successfully utilized in the treatment of other CD20+ diseases, including the similar idiopathic orbital inflammatory disease. This is the first report to describe successful treatment with Rituximab of a recurrent IPT of the mandible with trigeminal spread and leptomeningeal involvement with clinical and radiologic evidence demonstrating a sustained response to therapy. PMID:22161155

  1. A case of "refractory" lupus erythematosus profundus responsive to rituximab [case report].

    LENUS (Irish Health Repository)

    McArdle, Adrian

    2012-02-01

    Lupus erythematosus profundus is a rare complication of systemic lupus erythematosus characterized by the presence of deep, tender subcutaneous nodules. A 22-year-old African-American female with extensive lupus profundus resistant to conventional therapies was treated with two infusions of the anti-CD20 monoclonal antibody, rituximab, at a dosage of 1,000 mg each. The patient demonstrated a remarkable clinical response as indicated by the disappearance of the nodules. B-cell depletion therapy with rituximab used alone or in combination with other therapies may be a viable option in patients with lupus profundus refractory to current therapies.

  2. Positive experience of the usage of Rituximab in management of refractory myasthenia gravis in Russia

    OpenAIRE

    N. I. Shcherbakova; N. A. Suponeva; V. V. Shvedkov; A. A. Shabalina; M. V. Kostyreva; V. A. Rudnichenko; O. I. Galkina

    2015-01-01

    A subset of patients (15 to 20%) with myasthenia gravis (MG) remains refractory to standard types of treatment. Analysis of efficiency of rituximab, a chimeric monoclonal antibody to surface antigen of B lymphocytes (CD20), in 16 patients suffering from refractory MG was performed. In all cases, the drug was injected weekly and intravenously in the dosage of 375 mg/m2, for 4 weeks. All patients were dependent on intake of corticosteroids and cyclosporin. During rituximab therapy, the gradatio...

  3. Rituximab used in three cases with relapsed non-Hodgkin’s lymphoma

    OpenAIRE

    Elli, Murat; YILMAZ, SEMA; AYDIN, RAMAZAN; MURAT, SADRIYE; Bilgici, Meltem Ceyhan; DAGDEMIR, AYHAN

    2013-01-01

    Relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL) patients have a poor prognosis. New treatment modalities have been used to improve survival rates in children with relapsed or refractory B-NHL. CD20 is expressed in >98% of childhood B-NHL and a chimeric anti-CD20 monoclonal antibody, rituximab, is increasingly being used at relapse. The aim of the present study was to determine the efficacy of rituximab on relapsed B-NHL. Three B-NHL cases were treated successfully with a combinat...

  4. Pretargeted Molecular Imaging and Radioimmunotherapy

    Directory of Open Access Journals (Sweden)

    David M. Goldenberg, Chien-Hsing Chang, Edmund A. Rossi, William J, McBride, Robert M. Sharkey

    2012-01-01

    Full Text Available Pretargeting is a multi-step process that first has an unlabeled bispecific antibody (bsMAb localize within a tumor by virtue of its anti-tumor binding site(s before administering a small, fast-clearing radiolabeled compound that then attaches to the other portion of the bsMAb. The compound's rapid clearance significantly reduces radiation exposure outside of the tumor and its small size permits speedy delivery to the tumor, creating excellent tumor/nontumor ratios in less than 1 hour. Haptens that bind to an anti-hapten antibody, biotin that binds to streptavidin, or an oligonucleotide binding to a complementary oligonucleotide sequence have all been radiolabeled for use by pretargeting. This review will focus on a highly flexible anti-hapten bsMAb platform that has been used to target a variety of radionuclides to image (SPECT and PET as well as treat tumors.

  5. The study of labeling with Iodine-131 of monoclonal antibody anti-CD20 used for the treatment of non-Hodgkin lymphoma

    International Nuclear Information System (INIS)

    Lymphomas are malignancies of the lymphatic system, described by Thomas Hodgkin in 1932. Traditionally, lymphomas are classified in two basic groups: Hodgkin disease and non-Hodgkin lymphoma (NHL). Patients with NHL were earlier treated with radiotherapy alone or in combination with immunotherapy using monoclonal antibody anti-CD20 (ex., Rituximab-Mabthera, Roche). However, Radioimmunotherapy is a new modality of treatment for patients with NHL, in which cytotoxic radiation from therapeutic radioisotopes is delivered to tumors through monoclonal antibodies. This study focused on labeling conditions of monoclonal antibody anti-CD20 (Rituximab-Mabthera, Roche) with iodine-131, by direct radioiodination method using Chloramine-T as oxidizing agent. Labeling parameters investigated were: Radiochemical purity (RP), method of purification, incubation time, antibody mass, oxidative agent mass, stability in vitro, stability in vivo, immunoreactivity and biological distribution performed in normal Swiss mouse. Product of high radiochemical purity was obtained with no notable difference between the methods applied. No clear evidence of direct influence of incubation time on radiochemical purity of the labeled antibody was observed. Whereas, a clear evidence of direct influence of activity on radiochemical purity of the labeled antibody was observed when antibody mass was varied. After purification, the labeled product presented radiochemical purity of approximately 100 %. Product of superior radiochemical yield was observed when standard condition of labeling was used. The labeled product presented variation in radiochemical purity using five different stabilizer conditions. The condition in which gentisic acid was combined with freeze appears more suitable and capable of minimizing autoradiolysis of the antibody labeled with high therapeutic activity of iodine-131. The labeled product presented low immunoreactivity when compared to the literature. Biological distribution in

  6. The study of conjugation of anti-CD20 monoclonal antibody for labeling with metallic or lanthanides radionuclides

    International Nuclear Information System (INIS)

    Lymphomas are malignancies or cancers that start from the malign transformation of a lymphocyte in the lymphatic system. Generally, lymphomas start from the lymph nodes or from the agglomeration of the lymphatic tissues, organs like stomach, intestines, in some cases it can involve the bone marrow and the blood, it can also disseminate to other organs. Lymphomas are divided in two major categories: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Patient with NHL are generally treated with radiotherapy alone or combined with immunotherapy using monoclonal antibody rituximab (MabThera®). Currently, monoclonal antibodies (Acm) conjugated with bifunctional chelate agents and radiolabeled with metallic or lanthanides radionuclides are a treatment reality for patients with NHL by the principle of radioimmunotherapy (RIT). This study focused on the conditions of conjugation of Acm rituximab (MabThera®) with bifunctional chelating agents DOTA and DTPA. Various parameters were studied: method of Acm purification, conditions of Acm conjugation, the method for determination of number of chelate agent coupled to the Acm, method for purification of the conjugated antibody Acm, conditions of labeling of the conjugated antibody with lutetium-177, method of purification of the radiolabeled immuno conjugate, method of radiochemical purity (RP), specific binding in vitro Raji cells (Human Burkitt) and biological distribution performed in normal Balb-c mouse. The three methodologies employed in pre-purification of Acm (dialysis, size exclusion chromatograph and dial filtration) demonstrated to be efficient; they provided sample recovery exceeding 90%. However, the methodology of dial filtration presents minimal sample loss, and gave the final recovery of the sample in micro liters; thereby facilitating sample use in subsequent experiments. Numbers of chelators attached to the Acm molecule was proportional to the molar ratio studied. When we evaluated the influence of different

  7. Single-dose anti-CD138 radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment of multiple myeloma in a preclinical model

    OpenAIRE

    Fichou, Nolwenn; Gouard, Sébastien; Maurel, Catherine; Barbet, Jacques; Ferrer, Ludovic; Morgenstern, Alfred; Bruchertseifer, Frank; Faivre-Chauvet, Alain; Bigot-Corbel, Edith; Davodeau, François; Gaschet, Joëlle; Chérel, Michel

    2015-01-01

    Objectives Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to 213Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic eff...

  8. Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy.

    Science.gov (United States)

    Dixit, Shreya; Selva-Nayagam, Priya; Hamann, Ian; Fischer, Gayle

    2015-01-01

    Rituximab is being used increasingly for the treatment of B-cell malignancies and nonmalignant conditions. Pyoderma gangrenosum is a rare neutrophilic dermatosis, which can be either idiopathic or associated with underlying systemic inflammatory conditions. We present a series of 4 patients who presented with ulcerative pyoderma gangrenosum in the vulvovaginal area after treatment with rituximab. PMID:24769650

  9. Rituximab in Adult –Onset Still’s Disease: Case Report

    Directory of Open Access Journals (Sweden)

    G Mehrpoor

    2009-01-01

    Full Text Available Summary: Adult-onset Still’s disease (AOSD is a rare systemic inflammatory disorder of unknown etiology. It is characterized by high grade fever, skin rash, arthritis, leukocytosis, increased ESR, CRP and liver enzyme levels and high levels of ferritin. The treatment of AOSD includes NSAIDs, steroids, and disease-modifying antirheumatic drugs (DMARDs. Recently biologic agents have been used for treatment of some rheumatologic disorders. Rituximab(MabThera, an anti-CD20 monoclonal antibody is one of the biologic agents which is used by only a few researchers for treatment of refractory AOSD. Herein, we describe a 23 year old woman, who was treated with Rituximab ,three years after diagnosis of AOSD .She did not respond to Metotroxate and Cellcept .After administration of Rituximab, clinical and laboratory remission was achieved .

  10. The study of labeling with iodine-131 of monoclonal antibody anti-CD20 used for the treatment of non-Hodgkin lymphoma

    International Nuclear Information System (INIS)

    Lymphomas are malignancies of the lymphatic system, described by Thomas Hodgkin in 1932. Traditionally, lymphomas are classified in two basic groups: Hodgkin disease and non-Hodgkin lymphoma (NHL). Patients with NHL were earlier treated with radiotherapy alone or in combination with immunotherapy using monoclonal antibody anti-CD20 (ex., Rituximab-Mabthera, Roche). However, Radioimmunotherapy is a new modality of treatment for patients with NHL, in which cytotoxic radiation from therapeutic radioisotopes is delivered to tumors through monoclonal antibodies. This study focused on labeling conditions of monoclonal anti-CD20 (ex., Rituximab-Mabthera, Roche) with iodine-131, by direct radioiodination method using Chloramine-T as oxidizing agent. Labeling parameters investigated were: Radiochemical purity (RP), method of purification, incubation time, antibody mass, oxidative agent mass, stability in vitro, immunoreactivity and biological distribution performed in normal Swiss mouse. Product of high radiochemical purity was obtained with no notable difference between the methods applied. No clear evidence of direct influence of incubation time on radiochemical purity of the labeled antibody was observed. Whereas, a clear evidence of direct influence of activity on radiochemical purity of the labeled antibody was varied. After purification the labeled product presented radiochemical purity of approximately 100 %. Product of superior radiochemical yield was observed when standard condition of labeling was used. The labeled product presented variation in radiochemical purity using five different stabilizer conditions. The condition in which gentisic acid combined with freeze appears more suitable and capable of minimizing autoradiolysis of the antibody labeled with freeze appears more suitable and capable of minimizing autoradiolysis of the antibody labeled with high therapeutic activity of iodine-131. The labeled product presented low immunoreactivity when compared to the

  11. Practical considerations on the use of rituximab in autoimmune neurological disorders

    Science.gov (United States)

    Kosmidis, Mixalis L.; Dalakas, Marinos C.

    2010-01-01

    Rituximab (Mabthera, Rituxan) is a chimeric human/murine monoclonal antibody against CD-20 surface antigen expressed on B-cells. Rituximab, by causing B-cell depletion, appears to be effective in several autoimmune disorders; it has been approved for rheumatoid arthritis and is a promising new agent in the treatment of several autoimmune neurological disorders. A controlled study in patients with relapsing remitting multiple sclerosis has shown that rituximab significantly reduces the number of new MRI lesions and improves clinical outcome; it also showed some promise in a subset of patients with primary progressive MS. The drug is also effective in a number of patients with Devic’s disease, myasthenia gravis, autoimmune neuropathies, and inflammatory myopathies. The apparent effectiveness of rituximab has moved B-cells into the center stage of clinical and laboratory investigation of autoimmune neurological disorders. We review the evidence-based effectiveness of rituximab in neurological disorders based on controlled trials and anecdotal reports, including our own experience, and address the immunobiology of B-cells in autoimmune central nervous system (CNS) and peripheral nervous system (PNS) disorders. In addition, we provide practical guidelines on how best to use this drug in clinical practice and highlight its potential toxicity. PMID:21179602

  12. Dosimetric considerations in radioimmunotherapy of patients with hepatoma

    International Nuclear Information System (INIS)

    Dosimetric studies of I-131 labeled antiferritin have provided the foundation for preparative and administrative aspects of radiolabeled antibody treatment of patients with hepatoma. Tumor response to I-131 labeled antiferritin IgG was encouraging and radioimmunotherapy with Y-90 labeled antiferritin IgG was recently initiated. For these patients, In-111 labeled antiferritin IgG was used as the imaging agent, with administered activities ranging from 0.8 - 7 mCi. Serial gamma camera imaging from 30 minutes to 6 days post injection demonstrated that 5-30% of the administered activity localized in hepatomas (8/12 patients). The mean value of the effective half-life in the tumor and liver was 2.8 d. Disappearance curves for the blood circulation, spleen, and other normal tissues were biphasic such that 50% of the activity disappeared within 24 hours post injection. The eight patients who demonstrated sufficient tumor localization where subsequently treated with Y-90 labeled antiferritin IgG. Administered activities were dependent on tumor volume and uptake of radiolabeled IgG and ranged from 8 - 20 mCi. The remaining patients were treated under other existing protocols. 10 references

  13. Estimates of dose to intraperitoneal micrometastases from alpha and beta emitters in radioimmunotherapy

    International Nuclear Information System (INIS)

    Intraperitoneal metastases from ovarian and other gynecologic tumors are a significant source of treatment failure. In recent years, investigators have used radiolabeled monoclonal antibodies to treat this disease with encouraging results. We have developed a dose calculational technique which generates isodose distributions from intraperitoneally administered alpha and beta particle emitters. In this study we apply the calculations to tissue biopsy samples to determine the adequacy of dose to ovarian micrometastases. Tissue samples from staging biopsies at the time of surgical debulking are scanned to identify small metastases. The patient population studied comprised those with ovarian disease who based on clinical criteria would be considered good candidates for intraperitoneal radioimmunotherapy. The regions of interest (which include the tumor and surface of the peritoneum) are digitized and tumor volumes are contoured. Dose calculations based on the modeling of intraperitoneally administered antibodies radiolabeled with various isotopes is performed and the minimum dose to tumor and normal tissue is assessed. For example, with tumor uptake of 0.1% injected dose per gram of tissue, the surface tumor dose from alpha emitters is up to 45,000 rads. The dose falls to 6000 rads at approximately 40 microns from the peritoneal surface. The surface dose from 20 mCi 90Y administered in 1500 ml saline is up to 10,000 rads, and at a 2-mm depth, approximately 2000 rads. From our calculation dose distribution from radioimmunotherapy varies as a function of physical characteristics of the isotope, absorption of activity, and amount of disease being treated

  14. Combined radioimmunotherapy and external irradiation for solid tumors in the mouse

    International Nuclear Information System (INIS)

    Objective: To evaluate the optimal external irradiation dose and potential benefits with different treatment timing strategies and sequence of combined external irradiation and radioimmunotherapy for solid tumors in the mouse. Methods: TS1, a monoclonal antibody directed against anticytokeratin 8, can specifically combined with anticytokeratin in the necrotic parts of tumors. Mab TS1 was iodinated with 131I. Among sixty nude mice with tumor cells xenografts (human cervical squamous carcinoma) used in this study, twenty-four were used in a pilot experiment to determine the appropriate level of external irradiation dose by observing the tumor growth inhibition while thirty-six were used in the experiment proper which were divided into 6 groups and given different treatment protocols. Total accumulated dose, percentage of injected activity per gram of tumor tissue and accumulated dose per injected activity were compared between these different groups. Results: In the pilot experiment, the tumor growth was inhibited markedly by 20 Gy of external irradiation, but the response did not significantly increase when the dose was increased to 26 Gy. In the experiment proper, the highest yields in terms of total accumulated dose, percentage of injected activity per gram of tumor tissue and accumulated dose per injected activity were seen in the group which received external irradiation prior to Mab injection. Conclusions: Enhanced effects can be achieved by combined external irradiation with radioimmunotherapy using the monoclonal anticytokeratin antibody 131I-TS1. 20 Gy of external irradiation should be given prior to Mab injection

  15. Physicochemical and Functional Comparability Between the Proposed Biosimilar Rituximab GP2013 and Originator Rituximab

    OpenAIRE

    Visser, Jan; Feuerstein, Isabel; Stangler, Thomas; Schmiederer, Timo; Fritsch, Cornelius; Schiestl, Martin

    2013-01-01

    Background Regulatory approval for a biosimilar product is provided on the basis of its comparability to an originator product. A thorough physicochemical and functional comparability exercise is a key element in demonstrating biosimilarity. Here we report the characterization of a proposed biosimilar rituximab (GP2013) and originator rituximab. Objective To compare GP2013 with originator rituximab using an extensive array of routine analytical and extended characterization methods. Methods P...

  16. Rituximab-Induced Bronchiolitis Obliterans Organizing Pneumonia

    Directory of Open Access Journals (Sweden)

    Ahmet B. Ergin

    2012-01-01

    Full Text Available Rituximab-induced lung disease (R-ILD is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough, but no clear evidence of infection. A variety of pathologic findings have been described in this setting. Bronchiolitis obliterans organizing pneumonia (BOOP is the most common clinicopathologic diagnosis, followed by interstitial pneumonitis, acute respiratory distress syndrome (ARDS, and hypersensitivity pneumonitis. Prompt diagnosis and treatment with corticosteroids are essential as discussed by Wagner et al. (2007. Here we present a case of an 82-year-old man who was treated with rituximab for recurrent marginal zone lymphoma. After the first infusion of rituximab, he reported fever, chills, and dyspnea. On computed tomography imaging, he was found to have bilateral patchy infiltrates, consistent with BOOP on biopsy. In our patient, BOOP was caused by single-agent rituximab, in the first week after the first infusion of rituximab. We reviewed the relevant literature to clarify the different presentations and characteristics of R-ILD and raise awareness of this relatively overlooked entity.

  17. False Positive B-Cells Crossmatch after Prior Rituximab Exposure of the Kidney Donor

    Directory of Open Access Journals (Sweden)

    Judith Desoutter

    2016-01-01

    Full Text Available Crossmatching is essential prior to kidney transplantation to confirm compatibility between the donor and the recipient, particularly to prevent acute antibody-mediated rejection. An unexpected positive crossmatch may be obtained in recipients with an autoimmune disease or preexisting antibodies not detected by single-antigen bead array due to complement interference or who have been previously treated by desensitization protocols such as rituximab, antithymocyte globulin, or intravenous immunoglobulins. We report donor and recipient investigations that revealed unexpected positive B-cells crossmatch, probably due to donor cells, as the donor had received rituximab therapy shortly before organ harvesting, in a context of severe idiopathic thrombocytopenic purpura. We consequently detected unexpected Class II IgG complement-dependent cytotoxicity for all sera tested. Other laboratory investigations failed to elucidate the reasons for this recipient-related positivity.

  18. Immunreconstitution and infectious complications after rituximab treatment in children and adolescents: what do we know and what can we learn from adults?

    Science.gov (United States)

    Worch, Jennifer; Makarova, Olga; Burkhardt, Birgit

    2015-01-01

    Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials. PMID:25643241

  19. Immunreconstitution and Infectious Complications After Rituximab Treatment in Children and Adolescents: What Do We Know and What Can We Learn from Adults?

    Directory of Open Access Journals (Sweden)

    Jennifer Worch

    2015-01-01

    Full Text Available Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials.

  20. Fatal haemoptysis in a case of lymphomatoid granulomatosis treated with rituximab.

    Science.gov (United States)

    Jaffre, S; Jardin, F; Dominique, S; Duet, E; Hubscher, Ph; Genevois, A; Corne, F; Bota, S; Nouvet, G; Thiberville, L

    2006-03-01

    Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive disease, which commonly involves the lungs but also the brain, kidneys, liver and skin. This report describes the case of a 33-yr-old female with an aggressive form of lymphoid granulomatosis treated with an anti-CD20 antibody. Dramatic radiological improvement was seen at the fourth week. However, the patient died at home 1 month after the last rituximab administration from a massive haemoptysis. PMID:16507866

  1. Lymphoma in a patient with rheumatoid arthritis receiving methotrexate treatment: successful treatment with rituximab

    OpenAIRE

    Stewart, M; Malkovska, V; Krishnan, J.; Lessin, L; Barth, W.

    2001-01-01

    A 55 year old man with chronic lymphocytic leukaemia (CLL) and rheumatoid arthritis (RA), treated for four years with methotrexate (MTX), who developed a B cell non-Hodgkin's lymphoma (B-NHL), is described. The tumour was localised to the shoulder and axillary lymph nodes, and positive for Epstein-Barr viral antigens. After failure of radiation and chemotherapy, a complete remission was achieved with a combination of antibody treatment (rituximab) and EPOCH. The development of a second malign...

  2. Rituximab-induced subacute interstitial pneumonitis: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Subramanian Murali

    2010-01-01

    Full Text Available Rituximab is a chimeric anti-CD20 monoclonal antibody used to treat CD20+ non-Hodgkin′s lymphoma (NHL. Some pulmonary adverse reactions such as cough, rhinitis, bronchospasm and dyspnea are relatively common. Severe respiratory conditions like cryptogenic organizing pneumonia, interstitial pneumonitis have rarely been reported. We present a case of interstitial pneumonitis in a patient who was treated with R-CHOP for extranodal NHL. He responded to the steroids.

  3. Rituximab-induced subacute interstitial pneumonitis: A case report and review of literature

    OpenAIRE

    Subramanian Murali; Manjunath R; Kilara Nalini; Mohan Rao K

    2010-01-01

    Rituximab is a chimeric anti-CD20 monoclonal antibody used to treat CD20+ non-Hodgkin′s lymphoma (NHL). Some pulmonary adverse reactions such as cough, rhinitis, bronchospasm and dyspnea are relatively common. Severe respiratory conditions like cryptogenic organizing pneumonia, interstitial pneumonitis have rarely been reported. We present a case of interstitial pneumonitis in a patient who was treated with R-CHOP for extranodal NHL. He responded to the steroids.

  4. Successful therapy with rituximab of refractory acute humoral renal transplant rejection: a case report.

    Science.gov (United States)

    Celik, A; Saglam, F; Cavdar, C; Sifil, A; Atila, K; Sarioglu, S; Bora, S; Gulay, H; Camsari, T

    2008-01-01

    Acute humoral rejection (AHR) is generally less responsive to conventional anti-rejection treatment with consequent allograft losses. Therapeutic options include antilymphocyte antibody (ATG), intravenous immunglobulin (IVIG), plasmapheresis, or immunoadsorption with protein A together with intensification of immunsuppression with a tacrolimus/mycophenolate mofetil combination. This report describes a transplant recipient who responded to rituximab therapy as treatment for steroid-, ATG-, IVIG-, and plasmapheresis-resistant AHR. PMID:18261611

  5. Successful corticosteroid-sparing effect of rituximab in the treatment of refractory idiopathic orbital inflammatory disease.

    OpenAIRE

    Shao, EH; Karydis, A; Gemenetzi, M; Taylor, SR

    2013-01-01

    Idiopathic orbital inflammatory disease (IOID) is an idiopathic inflammatory process within the orbit that can result in permanent visual impairment. Although high-dose oral corticosteroids are currently the mainstay of therapy, their long-term usage can cause significant toxicity. We present a case of IOID that was successfully treated with the anti-CD20 monoclonal antibody rituximab following failed steroid sparing with conventional second-line immunosuppressive agents.

  6. Positive experience of the usage of Rituximab in management of refractory myasthenia gravis in Russia

    Directory of Open Access Journals (Sweden)

    N. I. Shcherbakova

    2015-09-01

    Full Text Available A subset of patients (15 to 20% with myasthenia gravis (MG remains refractory to standard types of treatment. Analysis of efficiency of rituximab, a chimeric monoclonal antibody to surface antigen of B lymphocytes (CD20, in 16 patients suffering from refractory MG was performed. In all cases, the drug was injected weekly and intravenously in the dosage of 375 mg/m2, for 4 weeks. All patients were dependent on intake of corticosteroids and cyclosporin. During rituximab therapy, the gradation of MG has significantly changed, being transformed from severe forms (IV and V MGFA class into moderate and mild forms (III, II, and I MGFA class. Improvement of the clinical state included cease of myasthenic exacerbation, increased respiratory muscle strength; significant reduction of dosages (and even canceling of basic pathogenetic and symptomatic treatment. Complete remission with cancellation of basic therapy was recorded in 4 (25 % of patients within 2-year period. However, 2 of them manifested with aggravation of MG after the first course of rituximab, in 9 and 24 months, correspondingly, which required resumption of corticosteroid therapy and repeating of courses of rituximab, with positive result. In 9 (56.25 % cases, pharmacological remission was recorded; in 3 (18.75 % cases, there was a significant improvement of initially severe forms. In all patients rituximab therapy lead to the clinical improvement: prior to completion of the course, after the 1st and the 2nd infusion - in 12 (75 % patients; 1 to 3 weeks after completion of the course – in 4 (25 % patients. Maximal improvement was registered in 1 to 12 month after completion of the course of rituximab intake (at the terms of 4. ± 2.0 months. There were the following stages of basic therapy cancellation: during first 1 to 3 months of rituximab treatment, pyridostigmine and cyclosporine were cancelled; corticosteroids were dropped off gradually, according to the clinical status of

  7. Update on the rational use of tositumomab and iodine-131 tositumomab radioimmunotherapy for the treatment of non-Hodgkin’s lymphoma

    OpenAIRE

    Burdick, Michael J; Macklis, Roger M.

    2009-01-01

    Michael J Burdick, Roger M MacklisDepartment of Radiation Oncology, Taussig Cancer Center and Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USAAbstract: Targeted radioimmunotherapy in non-Hodgkin’s B-cell lymphoma (NHL) offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131 tositumomab (131I-TST) is a murine monoclonal antibody against the CD20 cell surface protein and is directly covalently conjugated to 131I, a radioactiv...

  8. Update on the rational use of tositumomab and iodine-131 tositumomab radioimmunotherapy for the treatment of non-Hodgkin’s lymphoma

    OpenAIRE

    Burdick, Michael J; Macklis, Roger M.

    2009-01-01

    Targeted radioimmunotherapy in non-Hodgkin’s B-cell lymphoma (NHL) offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131 tositumomab (131I-TST) is a murine monoclonal antibody against the CD20 cell surface protein and is directly covalently conjugated to 131I, a radioactive β and γ emitter. While initially approved for use in relapsed, refractory, or transformed low grade B-cell NHL, investigational uses with promising results include autologous ...

  9. Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model

    OpenAIRE

    Orozco, Johnnie J.; Ethan R. Balkin; Gooley, Ted A.; Kenoyer, Aimee; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Hylarides, Mark D.; Shadman, Mazyar; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD4...

  10. EANM procedure guideline for radio-immunotherapy for B-cell lymphoma with {sup 90}Y-radiolabelled ibritumomab tiuxetan (Zevalin)

    Energy Technology Data Exchange (ETDEWEB)

    Tennvall, Jan [Lund University Hospital, Department of Oncology, Lund (Sweden); Fischer, Manfred; Brans, Boudewijn [University Medical Centre, Department of Nuclear Medicine, Maastricht (Netherlands); Bischof Delaloye, Angelika [Centre Hospitalier Universitaire Vaudois, Service Medecine Nucleaire, Lausanne (Switzerland); Bombardieri, Emilio [Direzione Medicina Nucleare-Centro PET, Istituto Nazionale per la Cura e lo Studio dei Tumori, Milan (Italy); Bodei, Lisa [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Giammarile, Francesco [Centre Leon Berard, Service Medecine Nucleaire, Lyon (France); Lassmann, Michael [Universitaet Wuerzburg, Klinik und Poliklinik fuer Nuklearmedizin, Wuerzburg (Germany); Oyen, Wim [Radboud University, Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands)

    2007-04-15

    In January 2004, EMEA approved {sup 90}Y-radiolabelled ibritumomab tiuxetan, Zevalin, in Europe for the treatment of adult patients with rituximab-relapsed or -refractory CD20+ follicular B-cell non-Hodgkin's lymphoma. The number of European nuclear medicine departments using Zevalin is continuously increasing, since the therapy is often considered successful. The Therapy, Oncology and Dosimetry Committees have worked together in order to define some EANM guidelines on the use of Zevalin, paying particular attention to the problems related to nuclear medicine. The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients who may be candidates for radio-immunotherapy. The guideline also stresses the need for close collaboration with the physician(s) treating the patient for the underlying disease. (orig.)

  11. The study of labeling with Iodine-131 of monoclonal antibody anti-CD20 used for the treatment of non-Hodgkin lymphoma; Estudo de marcacao com Iodo-131 de anticorpo monoclonal anti-CD20 na terapia de linfoma nao-Hodgkin

    Energy Technology Data Exchange (ETDEWEB)

    Akanji, Akinkunmi Ganiyu

    2006-07-01

    Lymphomas are malignancies of the lymphatic system, described by Thomas Hodgkin in 1932. Traditionally, lymphomas are classified in two basic groups: Hodgkin disease and non-Hodgkin lymphoma (NHL). Patients with NHL were earlier treated with radiotherapy alone or in combination with immunotherapy using monoclonal antibody anti-CD20 (ex., Rituximab-Mabthera, Roche). However, Radioimmunotherapy is a new modality of treatment for patients with NHL, in which cytotoxic radiation from therapeutic radioisotopes is delivered to tumors through monoclonal antibodies. This study focused on labeling conditions of monoclonal antibody anti-CD20 (Rituximab-Mabthera, Roche) with iodine-131, by direct radioiodination method using Chloramine-T as oxidizing agent. Labeling parameters investigated were: Radiochemical purity (RP), method of purification, incubation time, antibody mass, oxidative agent mass, stability in vitro, stability in vivo, immunoreactivity and biological distribution performed in normal Swiss mouse. Product of high radiochemical purity was obtained with no notable difference between the methods applied. No clear evidence of direct influence of incubation time on radiochemical purity of the labeled antibody was observed. Whereas, a clear evidence of direct influence of activity on radiochemical purity of the labeled antibody was observed when antibody mass was varied. After purification, the labeled product presented radiochemical purity of approximately 100 %. Product of superior radiochemical yield was observed when standard condition of labeling was used. The labeled product presented variation in radiochemical purity using five different stabilizer conditions. The condition in which gentisic acid was combined with freeze appears more suitable and capable of minimizing autoradiolysis of the antibody labeled with high therapeutic activity of iodine-131. The labeled product presented low immunoreactivity when compared to the literature. Biological distribution in

  12. The study of conjugation of anti-CD20 monoclonal antibody for labeling with metallic or lanthanides radionuclides; Estudo de conjugacao do anticorpo anti-CD20 para marcacao com radionuclideos metalicos ou lantanideos

    Energy Technology Data Exchange (ETDEWEB)

    Akanji, Akinkunmi Ganiyu

    2012-07-01

    Lymphomas are malignancies or cancers that start from the malign transformation of a lymphocyte in the lymphatic system. Generally, lymphomas start from the lymph nodes or from the agglomeration of the lymphatic tissues, organs like stomach, intestines, in some cases it can involve the bone marrow and the blood, it can also disseminate to other organs. Lymphomas are divided in two major categories: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Patient with NHL are generally treated with radiotherapy alone or combined with immunotherapy using monoclonal antibody rituximab (MabThera Registered-Sign ). Currently, monoclonal antibodies (Acm) conjugated with bifunctional chelate agents and radiolabeled with metallic or lanthanides radionuclides are a treatment reality for patients with NHL by the principle of radioimmunotherapy (RIT). This study focused on the conditions of conjugation of Acm rituximab (MabThera Registered-Sign ) with bifunctional chelating agents DOTA and DTPA. Various parameters were studied: method of Acm purification, conditions of Acm conjugation, the method for determination of number of chelate agent coupled to the Acm, method for purification of the conjugated antibody Acm, conditions of labeling of the conjugated antibody with lutetium-177, method of purification of the radiolabeled immuno conjugate, method of radiochemical purity (RP), specific binding in vitro Raji cells (Human Burkitt) and biological distribution performed in normal Balb-c mouse. The three methodologies employed in pre-purification of Acm (dialysis, size exclusion chromatograph and dial filtration) demonstrated to be efficient; they provided sample recovery exceeding 90%. However, the methodology of dial filtration presents minimal sample loss, and gave the final recovery of the sample in micro liters; thereby facilitating sample use in subsequent experiments. Numbers of chelators attached to the Acm molecule was proportional to the molar ratio studied. When we evaluated

  13. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin.

    Science.gov (United States)

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20⁺ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  14. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin

    Directory of Open Access Journals (Sweden)

    Massimo Bortolotti

    2016-06-01

    Full Text Available The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20+ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric and LMW-IT (monomeric maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates.

  15. Early plasmapheresis and rituximab for acute humoral rejection after ABO-compatible liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Nassim Kamar; Laurence Lavayssière; Fabrice Muscari; Janick Selves; Céline Guilbeau-Frugier; Isabelle Cardeau; Laure Esposito; Olivier Cointault; Marie Béatrice Nogier; Jean Marie Peron; Philippe Otal; Marylise Fort; Lionel Rostaing

    2009-01-01

    Acute humoral rejection (AHR) is uncommon after ABOcompatible liver transplantation. Herein, we report two cases of AHR treated with plasmapheresis and rituximab in two ABO-compatible liver-transplant patients with preformed anti-human leukocyte antigen donor-specific antibodies. Patient 1 experienced a biopsy-proven AHR at day 10 post-transplant. She was treated by steroid pulses, and OKT3. Because of persisting signs of biopsy-proven AHR at day 26, she was treated by plasmapheresis and rituximab. Liver enzyme levels did not improve, and she died on day 41. Patient 2 experienced a biopsy-proven AHR on day 10 post-transplant. She was treated by steroid pulses, plasmapheresis, and rituximab.Liver enzymes returned to within normal range 18 dafter diagnosis. Liver biopsies, at 3 and 9 mo post-transplant,showed complete resolution of AHR. We conclude that plasmapheresis should be started as soon as AHR is diagnosed, and be associated with a B-cell depleting agent. Rituximab may be considered as a first-line therapy.

  16. External beam and radioimmunotherapy dosimetry comparison of colorectal xenografts

    International Nuclear Information System (INIS)

    It is of little surprise to most experts in radiation dosimetry that the largest uncertainties associated with calculation of absorbed doses to tumor normal tissues after IV administration of radiolabeled antibodies, does not lie in the calculation methods but rather in the acquisition of time-dependent activity data. In comparison to external beam radiation dosimetry, the problems of temporal and spatial macroscopic and microscopic heterogeneities continue to confound one's best efforts. In fact in some clinical settings, only a radiobiological end-point such as hematopoietic depression is used exclusively with no reference made to absorbed dose quantitation at all. Hence in these cases, it is most practical to simply relate administered activity directly with radiobiological response. To help provide a correlation between activity, absorbed dose and radiobiological response, animal radioimmunotherapy (RIT) experiments were performed here in which the above parameters were measured and compared with multiple dose levels of external beam irradiation. Using the LS174T colorectal xenograft model in nude mice, administered activities of up to 18.5 MBq of I-131 labeled B72.3 delivered an average measured absorbed dose to tumor of 3.2 ± 0.5 cGy/3.7 x 104 Bq. This absorbed dose (1,440 cGy from a nominal 17 MBq administered activity) produced tumor growth delay values that were comparable to a dose of 2,250 cGy on average delivered by single fraction external beam radiation therapy. An average dose enhancement ratio was calculated at 1.6 for RIT as compared with external beam therapy. This enhancement ratio ranged from 1.0-2.4 for several experimental repetitions under a variety of initial conditions

  17. Rituximab induced hypoglycemia in non-Hodgkin's lymphoma

    OpenAIRE

    Lali V; Geetha N.; Hussain Badrudeen M; Pandey Manoj

    2006-01-01

    Abstract Background Hypoglycemia is a vary rare toxicity of rituximab. The exact mechanism of rituximab induced hypoglycemia is not clear. Case presentation A 50 year old female presented with a left tonsillar non Hodgkin's lymphoma and was started on R-CHOP chemotherapy. Twenty four hours after the first rituximab infusion, she developed hypoglycemia which was managed by IV glucose infusion. Conclusion Hypoglycemia following rituximab administration is rare. Possibilities of hypoglycemia sho...

  18. Freeze-dried kit formulations for preparation of Lu-177 conjugated rituximab for treatment of non-Hodgkin’s lymphoma

    OpenAIRE

    Smilkov, Katarina; Gjorgieva, Darinka; Gjorgoski, Icko; Carollo, Angela; Chinol, Marco; Papi, Stefano; Signore, Alberto; Janevik-Ivanovska, Emilija

    2014-01-01

    Two radiolabelled monoclonal antibodies are approved for the treatment of non-Hodgkin’s lymphoma, Yttrium-90-ibritumomab tiuxetan, (Zevalin®) and Iodine-131-tositumomab (Bexxar®). In the current clinical practice, rituximab, a chimeric monoclonal antibody is approved for the treatment of low-grade or follicular, CD-20 positive non-Hodgkin’s lymphoma, as a single agent or in combination with chemotherapy. The radioisotope Lu-177, has a potential to be used in a radiopharmaceutical preparation ...

  19. Treatment of limited stage follicular lymphoma with Rituximab immunotherapy and involved field radiotherapy in a prospective multicenter Phase II trial-MIR trial

    International Nuclear Information System (INIS)

    The optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy. The MIR (Mabthera® and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combination's efficacy and safety with an accrual of 85 patients. Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life. The trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only). ClinicalTrials (NCT): http://www.clinicaltrials.gov/ct2/show/NCT00509184

  20. Aptamer-based radioimmunotherapy. The feasibility and prospect in cancer therapy

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) has emerged as an attractive and promising strategy for the management of malignant diseases. It has been proven to be quite effective in the treatment of numerous tumors, such as non-Hodgkin lymphoma, metastatic prostate cancer, melanoma, thyroid cancer, colon cancer and so on. The RIT currently used is mainly based on monoclonal antibodies to recognize target antigens. As antibodies are large molecules, this method of RIT has some limitations in in vivo use, such as the immunogenicity, the high costs and low efficiency of production. Aptamer is discovered and selected by SELEX technology. As specific recognizers and binders, aptamers and antibodies have such a close similarity as to be interchangeable to some extent. But, aptamers have many advantages over antibodies: higher affinity and specificity, smaller molecular weight, more easily synthesized and modified, more rapidly penetrating into tumors, higher tumor-to-blood distribution ratio and more easily to be cleared. In addition, since aptamer has almost no immunogenicity in vivo, it can be repeatedly administered. Thus, we believe that aptamer-based RIT will be a feasible and promising way to treat human cancers, and it might display better results in cancer treatment than antibody-based RIT. In conclusion, aptamer-based RIT is hopeful to become a key therapeutics in cancer radiotherapy in the near future. (author)

  1. Fractionated 131I anti-CEA radioimmunotherapy: effects on xenograft tumour growth and haematological toxicity in mice

    OpenAIRE

    Violet, J A; Dearling, J L J; Green, A. J.; Begent, R H J; Pedley, R B

    2008-01-01

    Dose fractionation has been proposed as a method to improve the therapeutic ratio of radioimmunotherapy (RIT). This study compared a single administration of 7.4 MBq 131I-anti-CEA antibody given on day 1 with the same total activity given as fractionated treatment: 3.7 MBq (days 1 and 3), 2.4 MBq (days 1, 3, and 5) or 1.8 MBq (days 1, 3, 5, and 8). Studies in nude mice, bearing the human colorectal xenograft LS174T, showed that increasing the fractionation significantly reduced the efficacy o...

  2. Rituximab induction therapy in highly sensitized kidney transplant recipients

    Institute of Scientific and Technical Information of China (English)

    YIN Hang; WAN Hao; HU Xiao-peng; LI Xiao-bei; WANG Wei; LIU Hang; REN Liang; ZHANG Xiao-dong

    2011-01-01

    Background The number of highly sensitized patients is rising, and sensitization can lead to renal transplant failure.The present study aimed to investigate the safety and efficacy of renal transplantation following induction therapy with rituximab in highly sensitized kidney transplant recipients.Methods Seven highly sensitized kidney transplant recipients who underwent rituximab therapy from December 2008 to December 2009 were retrospectively analyzed. There were 3 men and 4 women, with a mean age of 38.5 years (range, 21-47 years). The duration of hemodialysis was 3-12 months, with a mean duration of 11 months. For 4 patients,this was the second transplant; the previous graft survival time was 2-11 years, with a mean survival time of 5.8 years. All the female recipients had history of multiple pregnancies, and all patients had previously received blood transfusions. All donors were men, with a mean age of 32.5 years (range, 25-37 years). In 2 of the 7 patients, both class I and class II of panel reactive antibody were high; the remaining 5 patients showed either high in class I or in class II of panel reactive antibody. The mean panel reactive antibody value was 31% for class I and 51% for class II respectively. The donors and the recipients had the same blood type, with low lymphocyte cytotoxicity ranging from 2% to 5%. The human leukocyte antigen (HLA) mismatch numbers were from 2 to 4. All patients received tacrolimus (0.1 mg·kg-1·d-1) and mycophenolate mofetil (750 mg twice per day) orally 3 days prior to surgery. All patients received a single dose of 600 mg rituximab (375 mg/m2) infusion on the day before surgery and polyclonal antibody (antithymocyte globulin) on the day of surgery.Postoperative creatinine, creatinine clearance rate, and occurrence of rejection by pathological biopsy confirmation were monitored.Results No patient had delayed graft function after surgery. Two patients had acute rejection, one on day 7 and the other on day 13 post

  3. Monoclonal Antibody Therapy does not Abrogate Rejection Risk in Renal Transplant Recipients

    OpenAIRE

    Sanjeev Goswami

    2013-01-01

    Monoclonal antibodies are being increasingly used as therapeutic agents in medicine. Rituximab (anti-CD20) and Daclizumab (anti-IL2Rα) are two such monoclonal antibodies used to prevent organ rejection, but are not fail-safe. We have analyzed the pre and post-transplant antibody profile in serum of renal transplant recipients receiving Rituximab and /or Daclizumab. Study Group: Kidney recipients with acute rejection and having PRA > 10% pre-transplant were selected for the study (n=11). Those...

  4. In vitro evaluation of {sup 213}Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage

    Energy Technology Data Exchange (ETDEWEB)

    Vandenbulcke, Katia; Lahorte, Christophe; Slegers, Guido [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Gent (Belgium); De Vos, Filip; Dierckx, Rudi A. [Division of Nuclear Medicine, Ghent University Hospital (Belgium); Offner, Fritz [Department of Hematology, Ghent University Hospital (Belgium); Philippe, Jan [Department of Clinical Chemistry, Ghent University Hospital (Belgium); Apostolidis, Christos; Molinet, Roger; Nikula, Tuomo K. [European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe (Germany); Bacher, Klaus; De Gelder, Virginie; Vral, Anne; Thierens, Hubert [Department of Anatomy, Embryology, Histology and Medical Physics, Ghent University (Belgium)

    2003-10-01

    External source radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. {sup 213}Bi was eluted from a {sup 225}Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A''-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to {sup 213}Bi conjugated to CD20 antibody or after external {sup 60}Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated {sup 213}Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by {sup 213}Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, {sup 213}Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high

  5. In vitro evaluation of 213Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage

    International Nuclear Information System (INIS)

    External source radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. 213Bi was eluted from a 225Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A''-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to 213Bi conjugated to CD20 antibody or after external 60Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated 213Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by 213Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, 213Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high-LET targeted alpha particle exposure killed B-CLL cells

  6. Rituximab induced hypoglycemia in non-Hodgkin's lymphoma

    Directory of Open Access Journals (Sweden)

    Lali V

    2006-12-01

    Full Text Available Abstract Background Hypoglycemia is a vary rare toxicity of rituximab. The exact mechanism of rituximab induced hypoglycemia is not clear. Case presentation A 50 year old female presented with a left tonsillar non Hodgkin's lymphoma and was started on R-CHOP chemotherapy. Twenty four hours after the first rituximab infusion, she developed hypoglycemia which was managed by IV glucose infusion. Conclusion Hypoglycemia following rituximab administration is rare. Possibilities of hypoglycemia should be kept in mind in patients developing symptoms like fatigue, restlessness, and sweating while on rituximab therapy.

  7. RITUXIMAB DANS LA POLYARTHRITE RHUMATOÏDE

    OpenAIRE

    ABABOU, Hadjer; DAFFI, SOUMIA

    2012-01-01

    La polyarthrite rhumatoïde est un rhumatisme inflammatoire chronique. Les biothérapies mises au point ont révolutionné la prise en charge du patient, parmi ceux-ci, on peut citer le Rituximab: est un anticorps monoclonal inhibant spécifiquement le récepteur CD20 des lymphocytes B. Notre travail a pour buts d'évaluer l'efficacité de Rituximab dans le traitement de polyarthrite rhumatoïde chez les patients suivis dans le service de rééducation CHU Tlemcen. Il s'agit d'une étud...

  8. Placebo-controlled trial of rituximab in IgM anti-myelin–associated glycoprotein neuropathy

    Science.gov (United States)

    Viala, Karine; Nicolas, Guillaume; Créange, Alain; Vallat, Jean-Michel; Pouget, Jean; Clavelou, Pierre; Vial, Christophe; Steck, Andreas; Musset, Lucile; Marin, Benoit

    2013-01-01

    Objective: To determine whether rituximab 375 mg/m2 was efficacious in patients with immunoglobulin M (IgM) anti-myelin–associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) ≥4 and visual analog pain scale >4 or ataxia score ≥2. The primary outcome was mean change in ISS at 12 months. Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form–36 questionnaire. Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. Level of evidence: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy. PMID:23667063

  9. Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer

    Science.gov (United States)

    Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.

    2014-01-01

    BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at

  10. Assessment of Physicochemical Properties of Rituximab Related to Its Immunomodulatory Activity

    Directory of Open Access Journals (Sweden)

    Mariana P. Miranda-Hernández

    2015-01-01

    Full Text Available Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity.

  11. Response to rituximab in a refractory case of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Niaz Faraz

    2010-01-01

    Full Text Available Thrombotic thrombocytopenic purpura (TTP is a serious disorder with a significant morbidity and mortality. Majority of cases of TTP are idiopathic, but some cases may be secon-dary to connective tissue diseases. TTP has been rarely associated with systemic lupus erythe-matosus (SLE and may be refractory to treatment with plasma exchange, requiring immuno-suppressive therapy. We describe a patient with TTP and SLE who was refractory to plasma exchange and corticosteroids but responded to anti-CD20 antibody rituximab with continued re-mission after eight months of follow-up. Rituximab appears to be an effective treatment in re-fractory cases of TTP associated with SLE.

  12. Rituximab-induced neutropenia in a patient with inflammatory myopathy and systemic sclerosis overlap disease

    Science.gov (United States)

    Roberts, Mark; Oddis, Chester; Herrick, Arianne; Chinoy, Hector

    2016-01-01

    Rituximab (RTX) is a monoclonal chimeric antibody directed against the CD20 antigen of B lymphocytes. Late onset neutropenia (LON) is a recognised complication of rituximab usually occurring 4 weeks after the last dose and is reported in both haematological and rheumatological conditions. However, it has never been described in a patient with myositis and systemic sclerosis overlap disease. We describe a case of LON in a 54-year-old man who was diagnosed with myositis and then systemic sclerosis overlap disease. It resolved within 7 days, and the patient did not suffer neutropenic sepsis or any other complications. We propose similar mechanisms for LON as described in other conditions and routine blood monitoring in such patients. PMID:27407275

  13. Update on the rational use of tositumomab and iodine-131 tositumomab radioimmunotherapy for the treatment of non-Hodgkin’s lymphoma

    Directory of Open Access Journals (Sweden)

    Michael J Burdick

    2009-08-01

    Full Text Available Michael J Burdick, Roger M MacklisDepartment of Radiation Oncology, Taussig Cancer Center and Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USAAbstract: Targeted radioimmunotherapy in non-Hodgkin’s B-cell lymphoma (NHL offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131 tositumomab (131I-TST is a murine monoclonal antibody against the CD20 cell surface protein and is directly covalently conjugated to 131I, a radioactive β and γ emitter. While initially approved for use in relapsed, refractory, or transformed low grade B-cell NHL, investigational uses with promising results include autologous stem cell transplant, intermediate grade NHL, and the frontline management of indolent NHL. This review summarizes the 131I-TST literature on mechanism of action, treatment indications, treatment delivery, efficacy, investigational uses, and future prospects.Keywords: tositumomab, radioimmunotherapy, non-Hodgkin’s lymphoma, Bexxar

  14. Treatment of leukemia with radiolabeled monoclonal antibodies.

    Science.gov (United States)

    Sgouros, G; Scheinberg, D A

    1993-01-01

    In contrast to radioimmunotherapy of solid disease, wherein the primary obstacle to success is access of radiolabeled antibody to antigen-positive cells, in the treatment of leukemia delivering a lethal absorbed dose to the isolated cell appears to be the primary obstacle. The isolated cell is defined as one that is exposed only to self-irradiation (from internalized or surface-bound radiolabeled antibody) and to irradiation from free antibody in the blood. It is isolated in the sense that the particulate (beta, electron, alpha) emissions from its nearest neighboring antigen-positive cell do not contribute to its absorbed dose. Disease in the bone marrow and other tissues, since it is confined to a smaller volume, is more easily eradicated because the absorbed dose to a given cell nucleus is enhanced by emissions from adjacent cells (a smaller fraction of the emission energy is 'wasted'). The optimization simulations presented above for the M195 antibody suggest that the optimum dose of antibody that should be administered is that required to yield a concentration within the distribution volume of the antibody that is approximately equal to the concentration of antigen sites as determined by the tumor burden. Although not specifically considered in the modeling example presented above, antibody internalization and catabolism may be expected to play an important role in radioimmunotherapy treatment planning of leukemia. Depending upon the kinetics of internalization and catabolism, the absorbed dose to the red marrow and to antigen-positive cells may be reduced considerably, since catabolism, assuming that it is followed by rapid extrusion of the radioactive label, would decrease the cells' exposure time considerably. The recently demonstrated effectiveness of radioimmunotherapy in certain cases of B-cell lymphoma and in reducing tumor burden in acute myelogenous leukemia suggests that radioimmunotherapy is beginning to fulfill the promise held when it was initially

  15. Successful Treatment of Life-Threatening Interstitial Lung Disease Secondary to Antisynthetase Syndrome Using Rituximab: A Case Report and Review of the Literature.

    Science.gov (United States)

    Dasa, Osama; Ruzieh, Mohammed; Oraibi, Omar

    2016-01-01

    We are presenting a case of antisynthetase syndrome (ASS) that manifested with severe interstitial pneumonitis in the presence of anti-Jo-1 and Ro (SSA) antibodies. Our patient developed respiratory failure with high oxygen requirements despite treatment by high-dose steroids. The patient was then treated with rituximab. This treatment led to significant improvement in the patient condition, with resolution of the ground glass opacities on high-resolution computerized tomography and near normalization of pulmonary function tests. In this communication, we performed a literature review and summarized previous reports pertinent to using of rituximab to treat interstitial lung disease (ILD) secondary to ASS by searching the PubMed database from 1980 to 2014. We were able to find 14 reports that included total of 45 patients with ILD secondary to ASS. A significant improvement in ILD was reported in the majority of reported patients who received rituximab, while there was only 1 mortality-related to Pneumocystis jirovecii pneumonia. Rituximab treatment was tolerated well in the majority of cases. It is our conclusion that rituximab can be considered a therapeutic option in ILD secondary to ASS based on our experience with this case and the currently available evidence in the literature. Nevertheless, there is a need for additional controlled studies to assess the efficacy and safety of rituximab in ILD secondary to ASS compared with other immunosuppressive regimens. PMID:25830868

  16. Rituximab in combination with platinum-containing chemotherapy in patients with relapsed or primary refractory diffuse large B-cell lymphoma.

    Science.gov (United States)

    Bieker, Ralf; Kessler, Torsten; Berdel, Wolfgang E; Mesters, Rolf M

    2003-01-01

    The aim of the study was to evaluate the efficacy of a regimen consisting of rituximab and a platinum-containing chemotherapy with either Ifosfamide, Carboplatin and Etoposide (ICE) or Cisplatin, high-dose Ara-C and Dexamethasone (DHAP) in patients with relapsed or primary refractory diffuse large B-cell lymphoma. Ten patients with relapsed or primary refractory diffuse large B-cell lymphoma were treated from June 2000 until May 2001 with a platinum-containing chemotherapy regimen according to the ICE- or DHAP-protocol in combination with rituximab at the University of Muenster. Two cycles of ICE or DHAP and rituximab were given. In case of at least a minor response after 2 cycles, 2 additional cycles of the same combination were applied. Response rate, remission duration and duration of survival were evaluated. All 10 patients could be analysed with respect to these endpoints. No treatment related mortality was observed. The response rate (CR/PR) was 60% (10/50%). Twenty percent of the patients had progressive disease. The median duration of remission and survival was 3 and 3.5 months, respectively (range: 1-6 and 1-7 months, respectively), the survival rate was 10%. Eight of 10 patients died because of their underlying disease with short remission duration, 1 patient died of complications of allogeneic transplantation in CR. In conclusion, the combination of platinum-containing chemotherapy (ICE or DHAP) with rituximab demonstrates significant activity in intensively pretreated patients with relapsed or primary refractory diffuse large B-cell lymphoma. Considering the short duration of remission and survival, respectively, other experimental therapeutic approaches (e.g. allogeneic stem cell transplantation, radioimmunotherapy) should be pursued following this treatment in order to induce long-term remission. PMID:14534718

  17. Study of in vivo generators Pb-212/Bi--212 and U-230/Th-226 for alpha radioimmunotherapy

    International Nuclear Information System (INIS)

    Alpha-radioimmunotherapy is a promising cancer therapy that uses a-particles vectorized by monoclonal antibody to break down cancerous tumors. The notion of in vivo generator was introduced in 1989 by Leonard Mausner. The concept involves labeling of various molecular carriers (antibodies, peptides, etc) with intermediate half-life generator parents, which after accumulation in the desired tissue generate much shorter half-life daughter radionuclide. This thesis focuses on the study of two in vivo generators potentially interesting for alpha-radioimmunotherapy: Pb-212 / Bi-212 generator and U-230 / Th-226 generator. The first part of this work presents the Pb-212 / Bi-212 generator, two approaches allowing the vectorization. Chelation approach on a protein and an approach by encapsulation in liposomes have been proposed. This last approach appears to be the most interesting. In vitro stability studies have been performed on these labeling. The second part of this work presents the U-230 / Th-226 generator. Studies have first been made to achieve a theoretical model to describe the speciation of Th(IV) in human serum. The efficacy of DTPA as chelating agent for complexation of Th(IV) in human serum could thus be estimated. (author)

  18. Rituximab is more effective than second anti-TNF therapy in rheumatoid arthritis patients and previous TNFα blocker failure

    Directory of Open Access Journals (Sweden)

    Kekow J

    2012-07-01

    Full Text Available Joern Kekow,1 Ulf Mueller-Ladner,2 Hendrik Schulze-Koops31Clinic of Rheumatology and Orthopedics, Otto-von-Guericke University of Magdeburg, Vogelsang-Gommern; 2Department of Rheumatology and Clinical Immunology, Kerckhoff Clinic, Bad Nauheim; 3Division of Rheumatology, University of Munich, Munich, GermanyPurpose: To assess the efficacy of one course of rituximab (two 1-g doses compared to an alternative tumor necrosis factor-α (TNFα blocker in rheumatoid arthritis patients who had experienced one previous TNFα blocker failure (eg, etanercept, adalimumab, or infliximab.Patients and methods: The efficacy of both treatments was studied in this retrospective, multicenter, noninterventional cohort study with 196 patients. All patients had active rheumatoid arthritis defined by a Disease Activity Score-28 of ≥3.2 despite having TNFα blocker therapy, and were followed over 6.6 months on average after switching to rituximab versus a second TNFα blocker (ie, switching to etanercept, adalimumab, or infliximab at baseline.Results: At baseline, both cohorts showed similar demographic and disease-related characteristics (including Disease Activity Score-28. At the end of observation, mean Disease Activity Score-28 was significantly lower after treatment with rituximab than with a second TNFα blocker (-1.64 [95% confidence interval: -1.92; -1.36] versus -1.19 [95% confidence interval: -1.42; -0.96], P = 0.013. This difference between the two groups was even more pronounced when patients were seropositive for rheumatoid factor (-1.66 versus -1.17, P = 0.018 and anti-cyclic citrullinated peptide antibodies (-1.75 versus -1.06, P = 0.002. More rituximab-treated patients achieved good European League Against Rheumatism response than TNFα blocker-treated patients (30% versus 15%, and less patients were nonresponders (22% versus 35% according to European League Against Rheumatism criteria (P = 0.022, chi-squared test.Conclusion: Treatment with rituximab

  19. Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation

    International Nuclear Information System (INIS)

    Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. 90Y, 188Re and 131I are the most frequently used β--particles. Of these, 90Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate 90Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The 90Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow 90Y-anti-CD45-mAb YAML568 are 6.4 ± 1.2 (bone marrow), 3.9 ± 1.4 (liver) and 1.1 ± 0.4 (kidneys). CD45 is expressed also on the extramedullar clonogenic myeloma progenitor cell that circulates in the peripheral blood. Thus, the conditioning of patients with

  20. Rituximab in treatment of idiopathic glomerulopathy

    Directory of Open Access Journals (Sweden)

    Kamel El-Reshaid

    2012-01-01

    Full Text Available The aim of our study was to assess the role of rituximab (Mabthera in the treatment of patients with corticosteroid-resistant and calcineurin-inhibitors ± cellcept refractory idiopathic nephrotic syndrome (INS. A total of 83 patients who had required the previous treatment for a minimum of two years were included in the study. Our protocol included the use of rituximab in four-weekly slow infusions. Five patients were excluded as they could not tolerate rituximab infusion for allergic reaction. As expected, none of the patients had a decline in the total circulating lymphocyte counts yet all had achieved decline of their initially normal CD20 to < 0.5% one month after infusion. The decline persisted for eight to ten months later. In the minimal change disease (MCD group, 31 of the 32 patients had complete remission (CR and were off any immunosuppressive therapy and one of the previous non-responders (NR did not respond. Excluding two patients who had required retreatment, the others remained in CR (17 up to 28 months and six up to 36 months. Treatment with rituximab resulted in amelioration of NS in 17 of the 18 patients with focal segmental glomerulosclerosis (FSGS, while only one patient remained NR. Although renal function remained stable, proteinuria reappeared by eight to 12 months. Retreatment with rituximab resulted in a similar response with stable kidney function. In the 28 patients with membranous glomerulopathy (MG, 24 had achieved CR. Two patients failed to respond and two had partial remission. By 12 months, all patients relapsed. The response was within one month following treatment in patient with MCD, but was gradual within three months in FSGS and MG. Relapsers in all groups responded in a similar pattern to repeat dosing with the drug subsequently. Our prospective study represents an adequate number of patients with biopsy-proven subgroups of INS in both children and adults with long-term follow-up of treatment with rituximab

  1. 188Re-labelled anti-CD20 monoclonal antibody: Labelling and quality control studies

    International Nuclear Information System (INIS)

    Immunotherapy with human chimeric antibody rituximab (Rituxan, IDEC pharmaceuticals) has been a major advance in treatments of patients with CD20-positive B-cell non Hodgkin's lymphoma (NHL). Radioimmunotherapy (RIT) uses the targeting features of monoclonal antibody to deliver radiation from an attached readionuclide and it is an appeling concept that has received widespread attention. Here, we report our experience using rhenium-188 (188Re)- radiolabeled chimeric anti-CD20 antibody (rituximab). A stable antibody-labeling technique had been developed for 188Re. The 188Re-direct labeling of anti-CD20 monoclonal antibody, the methods for quality control: paper chromatography, instant thin layer chromatographysilica gel (ITLC-SG) and HPLC technique, the immunoreactivity and biological recognition of the target antigen assessment of the radiolabeled molecule, in vitro stability and the assessment of in vivo stability through biodistribution studies in normal WISTAR rats are described. For the direct radiolabeling, the reduction of monoclonal antibody (mAb) was performed with 2-mercaptoethanol (2-ME), based on Schwarz's method at a molar ratio 2000:1 (2- ME:mAb). By means of this method some of the disulfide bonds of the antibody are reduced to sulfhydryl groups (we obtained 4-5 groups) and these groups provide sites for the formation of very strong bond between the reduced rhenium and the antibody. The methodology used in this work has been tested in a phase I radioimmunotherapy clinical trial using the humanized mAb hR3 for loco-regional treatment of brain tumours. The labeling efficiency (> 95 %) of this method showed that the final product needs no further purification for clinical purposes (low level formation of colloidal species). In vitro stability studies of the labeled anti-CD20 were performed at room temperature at 4 h, 24 h and 48 h in cysteine, human serum and saline. In the presence of normal human serum, during the first 4h, transchelation of about 15

  2. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Robak, Tadeusz; Dmoszynska, Anna; Solal-Céligny, Philippe;

    2010-01-01

    Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized...

  3. Preparation and quality control and biodistribution studies of [90Y]-DOTA-cetuximab for radioimmunotherapy

    International Nuclear Information System (INIS)

    Yttrium-90 is a useful radionuclide for radioimmunotherapy (RIT) and the anti-epidermal growth factor receptor (anti-EGFR) antibody cetuximab is clinicsally approved for the treatment of EGFR-expressing metastatic colorectal cancer and advanced head and neck cancer. Thus in this work radiolabeling of monoclonal anti-EGFR with 90Y for radioimmunotherapy (RIT) is targeted. Cetuximab was successively labeled with [90Y] chloride (74 MBq) 2 mCi after conjugation with macrocyclics bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid mono-(N-hydroxysuccinimidyl) ester (DOTA-NHS), purified and concentrated by centrifugation using an Amicon Ultra-15 filter (Millipore, MWCo, 30000). 90Y chloride was obtained by 90Sr/90Y generator. Radiolabeling was completed in 2 h by the addition of DOTA-cetuximab conjugate at 42 °C. The stability of radiolabeled was studied in human serum. Biodistribution studies in normal rats were carried out to determine the radioimmunoconjugate distribution up to 96 h. Radiochemical purity of 92 % (using ITLC) was obtained for final radioimmunoconjugate (Specific activity = 0.55 GBq/mg). Stability of radiolabeled protein in presence of human serum was tested at 37 °C for up to 24 h. Biodistribution studies demonstrated the highest ID/g % in the blood (2.62 ± 0.005 at 24 h) and the liver (2.19 ± 0.001). This study demonstrated that 90Y-DOTA-cetuximab is a potential compound for the treatment of EGFR-expressing cancers. (author)

  4. Enhancing target/nontarget ratios in radioimmunotherapy: nonspecific human gammaglobulin versus other modalities

    International Nuclear Information System (INIS)

    Full text: The central problem in using radiobioconjugates in therapy is maximising the target/nontarget ratios. Unlike radioimmunoscintigraphy where temporal subtraction of early and late images or clinical context interpretation can be used, radioimmunotherapy and dosimetry demand the highest ratios for the safe use of such radiobioconjugates: frying the tumour without frying the patient. Simultaneously efforts to obtain greater biological specificity are underway in solid tumour therapy comparable to targeting the idiotypes of B cell tumours, and both peptides and newer antibodies are being explored. For increasing tumour localization pre-targetting using either the avidin/biotin approach or bispecific antibodies looking at a chelate in addition to a tumour antigen is being extensively researched. An alternative approach is to reduce nonspecific uptake particularly in the reticuloendothelial system especially the large mass of the liver. Degalactosylation of the antibodies to reduce affinity of the Fc fragment to galactosyl receptors in the liver, or using designer antibody constructs devoid of the Fc fragment: Fab, Fab 2, Fab 3, Fab n or scFv based constructs has been attempted. An inexpensive approach that we have conceived and used is the use of nonspecific human gammaglobulin prior to radioimmunoconjugate administration. This has been done utilizing commercially available inexpensive 16.5 gms% human immunoglobulin preparations(BHARGLOB)rather than the highly expensive IVIG such as Sandoglobulin used in autoimmune disease therapy Aims: To devise optimal schedules for using nonspecific human gammaglobulin for reducing nontarget uptake. Methods: Prior to clinical studies several different large molecular weight agents were evaluated in experimental animals bearing human tumour xenografts, including dextran,hetastarch and gammaglobulin.Gammaglobulin was chosen as the most convenient to administer. In clinical studies various schedules were tried giving Bharglob

  5. Lack of in Vivo Antibody Dependent Cellular Cytotoxicity with Antibody Containing Gold Nanoparticles

    OpenAIRE

    Ahmed, Marya; Pan, Dorothy W.; Davis, Mark E.

    2015-01-01

    Antibody-dependent cellular cytotoxicity (ADCC) is a cytolytic mechanism that can elicit in vivo antitumor effects and can play a significant role in the efficacy of antibody treatments for cancer. Here, we prepared cetuximab, panitumumab, and rituximab containing gold nanoparticles and investigated their ability to produce an ADCC effect in vivo. Cetuximab treatment of EGFR-expressing H1975 tumor xenografts showed significant tumor regression due to the ADCC activity of the antibody in vivo,...

  6. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis

    Directory of Open Access Journals (Sweden)

    Malur Anagha

    2012-06-01

    Full Text Available Abstract Rationale Pulmonary Alveolar Proteinosis (PAP patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ and the PPARγ-regulated ATP binding cassette (ABC lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation. Objectives This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages. Methods BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes. Results Mean PPARγ and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p ≤ 0.05 after treatment. Lysosomal phospholipase A2 (LPLA2 (a key enzyme in surfactant degradation mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPARγ KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy. Conclusions Reduction in GM

  7. Regulation of serum matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 following rituximab therapy in patients with rheumatoid arthritis refractory to anti-tumor necrosis factor blockers

    OpenAIRE

    Klimiuk, Piotr Adrian; Domysławska, Izabela; Sierakowski, Stanisław; Chwiećko, Justyna

    2014-01-01

    In our article, we evaluated the regulatory effects of the infusions of rituximab, a monoclonal antibody directed against CD20+ B cells, on the serum matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in patients with active rheumatoid arthritis (RA) not responding to anti-tumor necrosis factor (anti-TNF) therapy. Twelve RA patients were planned to receive four infusions of 1,000 mg of rituximab at weeks 0, 2, 24 and 26. The therapy was combined with...

  8. Effect of cetuximab in combination with alpha-radioimmunotherapy in cultured squamous cell carcinomas

    International Nuclear Information System (INIS)

    Aim: The monoclonal antibody cetuximab, targeting the epidermal growth factor receptor (EGFR), is a promising molecular targeting agent to be used in combination with radiation for anticancer therapy. In this study, effects of cetuximab in combination with alpha-emitting radioimmunotherapy (RIT) in a panel of cultured human squamous cell carcinomas (SCCs) were assessed. Methods: SCC cell lines were characterized and treated with cetuximab in combination with anti-CD44v6 RIT using the astatinated chimeric monoclonal antibody U36 (211At-cMAb U36). Effects on 211At-cMAb U36 uptake, internalization and cell proliferation were then assessed in SCC cells. Results: Cetuximab in combination with 211At-cMAb U36 mediated increased growth inhibition compared to RIT or cetuximab alone in two cell lines. However, cetuximab also mediated radioprotective effects compared to RIT alone in two cell lines. The radioprotective effects occurred in the cell lines in which cetuximab clearly inhibited cell growth during radiation exposure. Cetuximab treatment also influenced 211At-cMAb-U36 uptake and internalization, suggesting interactions between CD44v6 and EGFR. Conclusions: Results from this study demonstrate the vast importance of further clarifying the mechanisms of cetuximab and radiation response, and the relationship between EGFR and suitable RIT targets. This is important not only in order to avoid potential radioprotective effects, but also in order to find and utilize potential synergistic effects from these combinations.

  9. Radiolabeling of trastuzumab with 177Lu via DOTA, a new radiopharmaceutical for radioimmunotherapy of breast cancer

    International Nuclear Information System (INIS)

    Aim: Trastuzumab is a monoclonal antibody that is used in treating breast cancer. We labeled this monoclonal antibody with lutetium-177 and performed in vitro quality control tests as a first step in the production of a new radiopharmaceutical. Material and Methods: Trastuzumab was labeled with lutetium-177 using DOTA as chelator. Radiochemical purity and stability in buffer and human blood serum were determined using thin layer chromatography. Immunoreactivity and toxicity of the complex were tested on MCF7 breast cancer cell line. Results: The radiochemical purity of the complex was 96±0.9%. The stabilities in phosphate buffer and in human blood serum at 96 h postpreparation were 93±1.2% and 85±3.5%, respectively. The immunoreactivity of the complex was 89±1.4%. At a concentration of 1 nM, the complex killed 70±3% of MCF7 cells. At 1.9 nM, 90±5% of the cells were killed. Conclusions: The results showed that the new complex could be considered for further evaluation in animals and possibly in humans as a new radiopharmaceutical for use in radioimmunotherapy against breast cancer.

  10. Effect of cetuximab in combination with alpha-radioimmunotherapy in cultured squamous cell carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Nestor, Marika, E-mail: marika.nestor@bms.uu.s [Unit of Otolaryngology and Head and Neck Surgery, Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala (Sweden); Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, S-751 85 Uppsala (Sweden); Sundstroem, Magnus [Unit of Molecular Pathology, Department of Genetics and Pathology, Uppsala University (Sweden); Anniko, Matti [Unit of Otolaryngology and Head and Neck Surgery, Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala (Sweden); Tolmachev, Vladimir [Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, S-751 85 Uppsala (Sweden)

    2011-01-15

    Aim: The monoclonal antibody cetuximab, targeting the epidermal growth factor receptor (EGFR), is a promising molecular targeting agent to be used in combination with radiation for anticancer therapy. In this study, effects of cetuximab in combination with alpha-emitting radioimmunotherapy (RIT) in a panel of cultured human squamous cell carcinomas (SCCs) were assessed. Methods: SCC cell lines were characterized and treated with cetuximab in combination with anti-CD44v6 RIT using the astatinated chimeric monoclonal antibody U36 ({sup 211}At-cMAb U36). Effects on {sup 211}At-cMAb U36 uptake, internalization and cell proliferation were then assessed in SCC cells. Results: Cetuximab in combination with {sup 211}At-cMAb U36 mediated increased growth inhibition compared to RIT or cetuximab alone in two cell lines. However, cetuximab also mediated radioprotective effects compared to RIT alone in two cell lines. The radioprotective effects occurred in the cell lines in which cetuximab clearly inhibited cell growth during radiation exposure. Cetuximab treatment also influenced {sup 211}At-cMAb-U36 uptake and internalization, suggesting interactions between CD44v6 and EGFR. Conclusions: Results from this study demonstrate the vast importance of further clarifying the mechanisms of cetuximab and radiation response, and the relationship between EGFR and suitable RIT targets. This is important not only in order to avoid potential radioprotective effects, but also in order to find and utilize potential synergistic effects from these combinations.

  11. Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate 227Th-rituximab

    International Nuclear Information System (INIS)

    The anti-CD20 antibody rituximab labelled with the α-particle-emitting radionuclide 227Th is of interest as a radiotherapeutic agent for treatment of lymphoma. Complete regression of human lymphoma Raji xenografts in 60% of mice treated with 200 kBq/kg 227Th-rituximab has been observed. To evaluate possible late side effects of 227Th-rituximab, the long-term radiotoxicity of this potential radiopharmaceutical was investigated. BALB/c mice were injected with saline, cold rituximab or 50, 200 or 1,000 kBq/kg 227Th-rituximab and followed for up to 1 year. In addition, nude mice with Raji xenografts treated with various doses of 227Th-rituximab were also included in the study. Toxicity was evaluated by measurements of mouse body weight, white blood cell (WBC) and platelet counts, serum clinical chemistry parameters and histological examination of tissues. Only the 1,000 kBq/kg dosage resulted in decreased body weight of the BALB/c mice. There was a significant but temporary decrease in WBC and platelet count in mice treated with 400 and 1,000 kBq/kg 227Th-rituximab. Therefore, the no-observed-adverse-effect level (NOAEL) was 200 kBq/kg. The maximum tolerated activity was between 600 and 1,000 kBq/kg. No significant signs of toxicity were observed in histological sections in any examined tissue. There were significantly (p 227Th-rituximab or non-labelled antibody when compared with control mice. The maximum tolerated dose to bone marrow was between 2.1 and 3.5 Gy. Therapeutically relevant dose levels of 227Th-rituximab were well tolerated in mice. Bone marrow suppression, as indicated by decrease in WBC count, was the dose-limiting radiotoxicity. These toxicity data together with anti-tumour activity data in a CD20-positive xenograft mouse model indicate that therapeutic effects could be obtained with relatively safe dosage levels of the radioimmunoconjugate. (orig.)

  12. Optimising the therapeutic ratio of radioimmunotherapy; an investigation of the roles of chimerisation, fractionation and radiation dosimetry

    Science.gov (United States)

    Violet, John Albert

    2007-12-01

    Radioimmunotherapy (RIT) is a targeted form of treatment for cancer which uses tumour-associated antibodies to selectively deliver a therapeutic radionuclide to sites of disease. In lymphoma, radioimmunotherapy has proved a remarkably effective agent due to the high radiosensitivity of the tumour and its propensity to undergo apoptosis following irradiation. However, success in the treatment of the more radioresistant common solid tumours has been less successful, and for these patients RIT remains investigative. The effectiveness of RIT is limited by non-specific irradiation of normal tissues whilst antibody remains in the circulation, in particular bone marrow, and also by immunogenicity of antibody which does not allow for repeated therapy. In the first chapter I have hypothesised that lymphomas expressing the interleukin-2 receptor might be effectively treated using a radiolabeled antibody to this receptor. In a phase I/II clinical study, 131I labelled CHT-25, a chimeric antibody against the IL-2Ra chain, has shown encouraging evidence of efficacy in the 9 patients with multiply- relapsed lymphomas treated so far. In addition, use of this antibody has been associated with low immunogenicity allowing for repeated therapies to be given. In the second chapter I have hypothesised that dosimetry led, individual patient therapy, might further optimise 1311 CHT-25 treatment. To investigate this I have used marrow toxicity as a biological assay of absorbed dose and shown that simple, but individual, patient biodistribution indices correlate better with observed toxicity than the population-based dose estimates currently employed. I have proposed that adoption of individual patient dosimetry using tracer studies is worthy of further investigation for the future development of 131I- CHT-25. In the third chapter I have hypothesised that dose fractionation might improve the therapeutic ratio of RIT. This has been investigated in a pre-clinical human colorectal xenograft

  13. Ibrutinib and rituximab induced rapid response in refractory Richter syndrome

    OpenAIRE

    Lamar, Zanetta; Kennedy, LeAnne; Kennedy, Brooke; Lynch, Mary; Goad, Amanda; Hurd, David; McIver, Zachariah

    2015-01-01

    Key Clinical Message We report a 53-year-old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter’s syndrome.

  14. Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.

    Science.gov (United States)

    Burkhardt, Birgit; Yavuz, Deniz; Zimmermann, Martin; Schieferstein, Jutta; Kabickova, Edita; Attarbaschi, Andishe; Lisfeld, Jasmin; Reiter, Alfred; Makarova, Olga; Worch, Jennifer; Bonn, Bettina R; Damm-Welk, Christine

    2016-09-01

    Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab. PMID:27376362

  15. Cyclophosphamide-refractory scleroderma-associated interstitial lung disease: remarkable clinical and radiological response to a single course of rituximab combined with high-dose corticosteroids.

    LENUS (Irish Health Repository)

    Haroon, Muhammad

    2011-10-01

    We would like to report our experience of using rituximab in cyclophosphamide refractory, rapidly progressive interstitial lung disease (ILD) in a patient with limited scleroderma. A 40-year-old man presented with 10-week history of inflammatory polyarthritis, which responded to a short course of oral corticosteroids. However, 3 weeks later, he developed new onset of exertional dyspnoea. High-resolution CT of the thorax was suggestive of early ILD. Surgical lung biopsy showed features of fibrotic non-specific interstitial pneumonia. He was diagnosed with scleroderma on the basis of: presence of anticentromere antibodies, Raynaud\\'s phenomenon, pulmonary fibrosis, digital oedema and hypomotility along with a dilated oesophagus. He was treated aggressively with pulse doses of corticosteroids and cyclophosphamide; however, his ILD continued to deteriorate. At this stage, he received rituximab (two pulses of 1 g each), which led to a gradual clinical improvement. Now, 12 months since his rituximab infusion, he walks 2 miles daily without any exertional dyspnoea.

  16. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Maury, Sébastien; Chevret, Sylvie; Thomas, Xavier; Heim, Dominik; Leguay, Thibaut; Huguet, Françoise; Chevallier, Patrice; Hunault, Mathilde; Boissel, Nicolas; Escoffre-Barbe, Martine; Hess, Urs; Vey, Norbert; Pignon, Jean-Michel; Braun, Thorsten; Marolleau, Jean-Pierre; Cahn, Jean-Yves; Chalandon, Yves; Lhéritier, Véronique; Beldjord, Kheira; Béné, Marie C; Ifrah, Norbert; Dombret, Hervé

    2016-09-15

    Background Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. Methods We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. Results From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. Conclusions Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .). PMID:27626518

  17. Bone marrow infiltration of CD20-negative follicular lymphoma after rituximab therapy: a histological mimicker of hematogones and B-cell acute lymphoblastic leukemia/lymphoma

    Science.gov (United States)

    Matsuda, Ikuo; Hirota, Seiichi

    2015-01-01

    Rituximab is a monoclonal antibody against CD20. Rituximab combined with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, termed R-CHOP, have improved the overall survival of patients with B-cell lymphoma in comparison with that of CHOP therapy. However, as with other molecularly-targeted therapies, resistance to rituximab could emerge sooner or later after rituximab administration. A number of mechanisms for rituximab resistance have been proposed, including downregulation of CD20 protein expression. Differential diagnosis of B-cell proliferation with reduced or lost CD20 expression includes not only B-cell lymphomas with CD20 downregulation, but also other tumorous and non-tumorous lesions. These include precursor B-cell neoplasms such as B acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL) and hematogones, a normal precursor B-cell proliferation during regeneration of hematopoiesis, typically observed following bone marrow suppression by chemotherapy. It is important to distinguish these possibilities because distinct therapies are required for each. In this paper, we report a case where bone marrow infiltration of follicular lymphoma histopathologically mimicked hematogones or B-ALL/LBL when CD20 expression was downregulated in follicular lymphoma after R-CHOP therapy. PMID:26464748

  18. Multi-step radioimmunotherapy of ovarian carcinomatosis

    International Nuclear Information System (INIS)

    Ovarian cancer is the leading cause of mortality among gynecological malignancies. Some 70 - 80% of patients fail conventional therapy, eventually succumbing to ovarian carcinomatosis. We are exploring a multi-step targeting approach as an adjuvant therapy to surgical debulking of the tumour. The prospective intraperitoneal treatment involves administration of a bispecific antibody to target CA-125 on the surface of ovarian cancer cells and biotin; followed by administration of biotinylated, radiolabeled liposomes to effect selective tumour cell killing within the peritoneal cavity. The goal of the study is to provide efficacious control of peritoneal metastatic disease, with improved quality and duration of the life of the patient. Bispecific antibodies to the human ovarian tumour-associated antigen, CA-125, were engineered and their selective targeting of human NIH:OVCAR-3 ovarian cancer cells was demonstrated by confocal laser scanning microscopy. Co-localisation of biotinylated, long-circulating liposomes was demonstrated, using the same technique. Kinetics analysis of internalisation and shedding of the antigen/antibody complex demonstrates an effective residency on the cell surface for at least four hours in vitro. Biodistribution studies in immunodeficient Balb/c mice demonstrate selective tumour association of radiolabeled, targeted liposomes. Tumour growth delay/control studies are imminently planned. Our current results warrant further development of this approach as a potential therapy for human ovarian carcinomatosis

  19. Hepatitis C-Induced Hepatitis Flare in a Patient with Non-Hodgkin B-Cell Lymphoma Treated by Rituximab Including Chemotherapy (Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin - Vincristine, Prednisolone Regimen

    Directory of Open Access Journals (Sweden)

    Asim Ulcay

    2014-06-01

    Full Text Available Hepatitis virus infections can lead to more critical outcomes such as severe hepatic dysfunction, failure and fulminancy in immunosuppressive patients compared to immunocompetent individuals. It is globally accepted that reactivation of both Hepatitis B virus [HBV ] and Hepatitis C virus [HCV] occurs after chemotherapy and antibody treatments of malignant diseases or solid organ/ bone marrow transplant in recipient patients. Especially among B-cell Non Hodgkin Lymphoma [NHL] patients, according to various studies, the seroprevelance of HCV is higher than that of the general population. On the other hand the role of HCV in the pathogenesis and etiology of NHL has been suggested. Today, cytotoxic drugs, corticosteroids, rituximab and hepatotoxic regimens are administered to NHL patients. Specifically, it has been emphasized that the utilization of rituximab [Anti CD20 antibody ] regiments for B-cell NHL patients may result with flares in HCV patients conspicuously. Here, we report the case of an acute flare up due to HCV infection in a patient who underwent a 4 month course of rituximab containing chemotherapy against a B cell NHL [CD20+ ] disease and a dramatic recovery from HCV infection at the end. [Dis Mol Med 2014; 2(3.000: 51-54

  20. Binding Affinity, Specificity and Comparative Biodistribution of the Parental Murine Monoclonal Antibody MX35 (Anti-NaPi2b) and Its Humanized Version Rebmab200

    DEFF Research Database (Denmark)

    Lindegren, Sture; Andrade, Luciana N S; Bäck, Tom;

    2015-01-01

    The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovar...

  1. Relationship of T regulatory cells content, activity and serum autoantibodies level in patients with systemic lupus erythematosus receiving rituximab

    Directory of Open Access Journals (Sweden)

    A V Torgashina

    2009-04-01

    Full Text Available Objective. To reveal changes of CD+CD25+FoxP3+ T-regulatory cells (T-reg number in pts with systemic lupus erythematosus (SLE receiving rituximab and to assess relationship T reg content with changes of disease activity and serum autoantibodies level during treatment. Material and methods. 12 pts with definite SLE were included. Pts were examined before treatment, after 1, 3 and 6 months. Besides routine laboratory tests anti-double-stranded DNA antibodies, B lymphocytes and T reg cells number was evaluated with flow-cytometry. SLE activity was assessed with SLEDAI 2K scale. Rituximab 500 mg was administered every week iv during 4 weeks. 4 pts received combined treatment with cyclophosphan. Results. Mean age of pts was 30,5±9,8 years (Me 31 years, varied from 18 to 49 years, disease duration varied from 7 to 148 months. T reg number before treatment was not decreased and did not correlated with anti-DNA antibodies level. T reg markers (Foxp3+, CD25+, CD4+CD25+ changes and values of SLE activity on SLEDAI 2K after the end of treatment correlated with presence of clinical response to treatment with rituximab in 3 months. Binary logistic regression model including 4 above mentioned predictors in total allows predicting correctly clinical response to therapy in 83% of cases. Conclusion. Changes of CD25+, CD4+CD25+, CD4+CD25+FoxP3+ T-cells number immediately after the end of treatment with rituximab correlated with clinical effect of the treatment and determined subsequent response to anti-B cell therapy.

  2. Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy

    International Nuclear Information System (INIS)

    Peritoneal spread is one of major causes of mortality in colorectal cancer patients. In the current investigation, the efficacy of radio-immunotherapy (RIT) with intraperitoneal (i.p.) administration of an anti-colorectal cancer IgG1, 131I-A7, was compared to that with intravenous (i.v.) administration in BALB/c female mice bearing peritoneal nodules of LS180 human colon cancer cells, at the same toxicity level. Distribution of either i.p. or i.v. administered 131I-A7 and i.p. administered irrelevant 131I -HPMS-1 was assessed. Based on the results of toxicity determination at increments of 2 MBq and estimated dosimetry, an i.p. dose of 11 MBq and an i.v. dose of 9 MBq were chosen for treatment. Mice were monitored for long-term survival: untreated mice (n=11), mice undergoing i.p. RIT with 131I-A7 (n=11), mice undergoing i.v. RIT with 131I-A7 (n=11) and mice undergoing non-specific i.p. RIT with 131I-HPMS-1 (n=5). Intraperitoneal injection of 131I-A7 produced faster and greater tumor accumulation than i.v. injection: 34.2±16.5% of the injected dose per g (% ID/g) and 11.1±3.6% ID/g at 2 h, respectively (P131I-HPMS-1 did not show specific accumulation. Non-specific RIT with 131I-HPMS-1 (mean survival, 26.0±2.5 days) did not affect the survival as compared to no treatment (26.7±1.9 days). Intravenous RIT with 131I-A7 prolonged the survival of mice to 32.8±1.8 days (P131I-A7 improved the survival more significantly and attained cure in 2 of 11 mice (P<0.05 vs. i.v. RIT). In conclusion, i.p. RIT is more beneficial in treating peritoneal carcinomatosis of colon cancer than i.v. RIT in a murine model. (author)

  3. Radioimmunotherapy in a radiation oncology environment: Building a multi-specialty team

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) is a new branch of radiation medicine in which antibodies specific for tumor-associated antigens are linked to radioactive atoms to provide biologically targeted short-range molecular radiotherapy. Two such biologically targeted radiopharmaceuticals have been approved for commercial use in the last few years. Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar) both recognize the CD-20 surface antigen found on normal and malignant B cells. Both of these compounds produce impressive clinical results when used in the management of indolent, refractory, and transformed CD-20+ B-cell non-Hodgkin's lymphoma, but the unsealed sources involved in this class of compounds also require new types of patient care coordination and patient/environmental safety procedures. Because these multifunctional compounds are ideally administered through a multi-departmental team approach, the planning process to initiate and direct such a team is quite important. This article reviews some of the key processes that may be necessary to establish a successful clinical RIT team. The manuscript highlights the important roles that Radiation oncology team members may play in this multi-department enterprise

  4. Experimental study of 188Re-BAC5 radioimmunotherapy on nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    The feasibility of radioimmunotherapy for NPC with 188Re-BAC5, a kind of monoclonal antibody to NPC, was investigated. The 188Re-BAC5 was prepared by direct labeling method and its biological activity was determined. The MTT method was used to determine the inhibition effect of the 188Re-BAC5 on CNE-2 cell line culture, and the destruction effect on CNE-2 multicellular spheroids model was also observed. The control group were 188Re-BSA and 188ReO4-. The biological activity of BAC5 was 1:780000 after purification. The labeling yield of 188Re-BAC5 was above 80%. The immuno-activity of 188Re-BAC5 was 61% ± 15%. The results of MTT showed that the inhibition effect of 188Re-BAC5 group was much stronger than the control group (P188Re-BAC5 had a obvious destruction effect on spheroids, and there was a significant difference between 188Re-BAC5 and the control group. In conclusion, 188Re-BAC5 may serve a possible way in the treatment of NPC in the near future

  5. Treatment of orbital inflammation with rituximab in Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Baslund, Bo; Wiencke, Anne Katrine; Rasmussen, Niels;

    2012-01-01

    OBJECTIVES: To study the efficacy of rituximab therapy for the treatment of orbital inflammation in patients with Wegener's granulomatosis (WG). METHODS: Ten WG patients with orbital inflammation were included in this case-series. None had symptoms suggestive of extra-orbital disease activity...... inflammation. All patients were treated with 1000 mg of rituximab administered twice with an interval of 14 days between the infusions. Six months after therapy, a physical examination and a control computerised tomography (CT) scan was performed. RESULTS: All patients had orbital inflammation demonstrated by...... size of the orbital mass was unchanged in eight patients. CONCLUSIONS: Rituximab therapy has positive effects on symptoms, visual acuity and/or granuloma size in some WG patients with orbital inflammation. Treatment with rituximab should be considered in WG patients with this serious manifestation of...

  6. Protein A immunoadsorption combined with rituximab in renal transplant recipients positive for panel reactive antibody(Report of 7 cases)%蛋白A免疫吸附联合利妥昔单抗在PRA阳性肾移植受者中的应用七例报告

    Institute of Scientific and Technical Information of China (English)

    胡小鹏; 尹航; 刘航; 李晓北; 王玮; 任亮; 杨晓勇; 万昊; 张小东

    2009-01-01

    目的 探讨术前群体反应性抗体(PRA)阳性的肾移植受者应用蛋白A免疫吸附联合利妥昔单抗(RTX)治疗的效果及安全性.方法 7例中,行二次肾移植者5例,有多次妊娠史者2例.7例均行亲属活体供肾移植,供者均为男性.供、受者ABO血型相同,补体依赖细胞毒试验阴性,HLA抗原错配数2~5个.术前单纯PRAⅠ类抗体增高者2例,单纯PRAⅡ类抗体增高者2例,PRA Ⅰ、Ⅱ类抗体均增高者3例;IgG平均为13.4 g/L,IgA平均为1.78 g/L,IgM平均为1.47 g/L.术前行免疫吸附2~10次,平均为5次.当患者PRA或免疫球蛋白水平降至正常值及以下时进行移植,并于手术当天单次静脉输注RTX 600 mg,同时给予抗淋巴细胞球蛋白或抗胸腺细胞球蛋白.术后采用他克莫司(或环孢素A)、霉酚酸酯及泼尼松预防排斥反应.监测患者血肌酐及内生肌酐清除率(Ccr);临床上考虑患者发生排斥反应时,行移植肾穿刺活检;分别于术前及术后1周测定患者外周血中CD19+和CD20+细胞百分比(仅检测3例).结果 免疫吸附及RTX治疗期间,患者均未出现不良反应.行免疫吸附后,7例患者的PRA Ⅰ、Ⅱ类抗体均有所下降,IgG、IgA和IgM的平均值也有所下降.术后患者移植肾功能恢复良好,未发生移植肾功能恢复延迟,其中3例分别在术后8、10和14 d出现急性排斥反应,治疗后均逆转.术前患者外周血中CD19+细胞分别为1.98%、4.64%和4.45%,CD20+细胞分别为15.15%、2.01%和1.15%;术后1周时,其外周血中CD19+细胞分别为0.39%、0.98%和0.11%,CD20+细胞分别为0.34%、0.15%和0.01%.术后1例发生肺部巨细胞病毒感染,治疗后好转,1例因肺部烟曲霉感染而死亡,死亡时肾功能正常.结论 对于术前PRA阳性者应用蛋白A免疫吸附及RTX治疗有一定效果,经处理后患者可接受肾移植.%Objective To investigate the safety and efficacy of combined use of protein A immunoadsorption and rituximab(RTX)in kidney

  7. Modern trends in radioimmunotherapy of cancer. Pre targeting strategies for the treatment of ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mcquarrie, S.A.; Xiao, Z.; Mercer, J. R.; Suresh, M. R. [Edmonton Univ. of Alberta, Edmonton, AL (Canada). Faculty of Pharmacy and Pharmaceutical Sciences; Miller, G. G. [University of Alberta, Noujaim Institute for Pharmaceutical Oncology Research, Edmonton, AL (Canada)

    2001-06-01

    A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA 125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA 125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using {sup 125}I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. It has been demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells.

  8. Radioimmunotherapy for Lymphoma%淋巴瘤的放射免疫治疗

    Institute of Scientific and Technical Information of China (English)

    卢霞; 王荣福

    2009-01-01

    恶性淋巴瘤是欧美国家常见的造血系统恶性肿瘤,其发病率逐年上升.大多数滤泡型非霍奇金淋巴瘤多为慢性、难治性恶性肿瘤,易复发,治疗困难.现有的治疗方案包括化疗、放疗、单克隆抗体介导的免疫治疗、放射免疫治疗及造血干细胞移植治疗.放射性核素131I和90 Y标记的单克隆抗体的放射免疫治疗的疗效有待于进一步研究.%Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in the United States with a rapidly increasing incidence. Most follicular NHL is indolent but incurable, Most patients with follicular NHL who transform to an aggressive NHL are very difficult to treat successfully. Treatment options have included chemotherapy, radiation, immunotherapy with monoclonal antibodies, alone or in combination, and hematopoietic stem cell transplantation. The efficacy of monoclonal antibodies is augmented when they are combined with a radioisotope like iodine-131 or yttrium-90. There have been a number of studies done in recent years studying the efficacy of this form of therapy, i.e., radioimmunotherapy (RIT) in patients with NHL. This review attempts to integrate the information from the various clinical trials done using RIT in patients with relapsed/refractory or newly diagnosed NHL.

  9. Modern trends in radioimmunotherapy of cancer. Pre targeting strategies for the treatment of ovarian cancer

    International Nuclear Information System (INIS)

    A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA 125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA 125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using 125I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. It has been demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells

  10. Avidin chase can reduce myelotoxicity associated with radioimmunotherapy of experimental liver micrometastases in mice

    International Nuclear Information System (INIS)

    Myelotoxicity is the main factor which decides the maximum tolerated dose (MTD) in radioimmunotherapy (RIT). Since bone marrow is mostly irradiated from blood radioactivity, enhancing the clearance of unbound circulating radiolabeled antibody is important to reduce myelotoxicity and to increase the MTD. We applied the avidin chase method, which was devised to obtain high tumor-to-background ratios in tumor-targeting, to RIT of experimental liver micrometastases and evaluated its influence on the side effects and therapeutic outcome. Seven days after intrasplenic injection of human colon cancer LS174T cells, nude mice were intravenously injected with biotinylated 131I-labeled anti-CEA monoclonal antibody (MAb) (24-38 μg, 11.1 MBq). Mice of the chase group then received an intravenous injection of avidin twice (24 and 30 h, 72-115 μg each). Biodistribution, side effects (white blood cell counts and body weight change), and short- and long-term therapeutic effects were determined. Avidin chase markedly accelerated the clearance of radiolabeled MAb from the blood (P<0.0001) and normal tissues, resulting in milder leukocytopenia and body weight loss, both of which recovered earlier than in the non-chase group (P<0.01). The tumor uptake of radiolabeled MAb was also decreased by avidin chase, but the metastases-to-background ratios were increased. Avidin chase gave the therapeutic gain ratio of 1.89. Treated groups with and without avidin chase showed significant therapeutic effects compared to the non-treated group. There was no significant difference in the therapeutic effects between the two treated groups. Avidin chase effectively reduced the side effects of RIT and should increase the MTD. (author)

  11. Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models.

    Directory of Open Access Journals (Sweden)

    Sofia H L Frost

    Full Text Available Pretargeted radioimmunotherapy (PRIT is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y and lutetium-177 (177Lu are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma or Granta (mantle cell lymphoma xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-biotin second step reagent.The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq as for 177Lu (0.6 Gy/MBq. More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes.90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma

  12. Retrospective analysis of a B cell depletion therapy with rituximab in patients with systemic rheumatic autoimmune diseases refractory to standard therapy

    OpenAIRE

    Haasler, Nadja

    2016-01-01

    Objective: To assess the efficacy of rituximab (a chimeric monoclonal anti-CD20 antibody, RTX) in patients with 3 different rheumatic diseases: systemic lupus erythematodes (SLE), granulomatosis with polyangiitis (GPA, Wegener granulomatosis), scleroderma/polymyositis overlap syndrome. Methods: This is a retrospective study of case series of patients and the effects of RTX on clinical, serological and immunological parameters. Therefore we analysed data from 21 patients who had been treate...

  13. Neuromyelitis optica: Contribution of therapeutic responses markers monitoring in patients given rituximab.

    Science.gov (United States)

    Romero, G; Ticchioni, M; Cohen, M; Rosenthal-Allieri, M A; Mondot, L; Lebrun Frenay, C

    2016-03-01

    Neuromyelitis optica (NMO) is a central nervous system inflammatory autoimmune disease characterized by medullary and/or optical nerve damage. It is rare but life-threatening. Concerning the treatment of NMO, many drugs have been used in background therapy. Some studies have shown efficacy of rituximab (an antiCD20 monoclonal anti-body) either on the reduction of the annual number of exacerbation or the mean score EDSS. In 2013, a Korean team reported a new protocol during which they administered rituximab only when memory B lymphocytes CD27+ were detectable in the bloodstream. In our patient, institution of this protocol led to clinical benefit with a major decrease in the EDSS score over time (7 in August 2012 vs. 1 in October 2015), a reduction of the total administered dose (4g in 2013 vs. 1.375g in 2014 vs. 0g in 2015) and side effects. Compared with the rate of theoretical administration, health expenditure savings reached 1700 Euros per month over the 11-month treatment. Monitoring therapeutic response markers with memory B lymphocyte counts appear to be an efficient cost-effective way to measure clinical efficiency, reduce total doses, and limit side effects. PMID:26915311

  14. Pretreatment with rituximab enhances radiosensitivity of non-Hodgkin's lymphoma cells

    International Nuclear Information System (INIS)

    The present study examines the effects of ionizing radiation in combination with rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, on proliferation, cell cycle distribution and apoptosis in B-lymphoma RL and Raji cells. Exposure to ionizing radiation (9 Gy) induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX (10 μg/mL) markedly enhanced apoptosis and cell growth delay in RL and Raji cells. Cooperative antiproliferative and apoptotic effects of RTX and radiation were achieved through the inhibition of c-myc and bcl-XL expression. Furthermore, RTX-modulated expression of cell cycle regulating proteins, such as p53, p21/WAF1, p27/KIP1, contributed to the development of radiation-induced cell killing and growth arrest. Each NHL cell line that underwent apoptosis induced by combination treatment revealed enhanced caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage as compared to only irradiated cells. These findings show that rituximab synergistically enhances radiation-induced apoptosis and cell growth delay through the expression of proteins involved in the programmed cell death and cell cycle regulation pathways. (author)

  15. Lymphomatoid granulomatosis treated successfully with rituximab in a renal transplant patient.

    Science.gov (United States)

    Castrale, Cindy; El Haggan, Wael; Chapon, Françoise; Reman, Oumedaly; Lobbedez, Thierry; Ryckelynck, Jean Philippe; Hurault de Ligny, Bruno

    2011-01-01

    Lymphomatoid granulomatosis (LYG) in renal transplant recipients is rare multisystemic angiocentric lymphoproliferative disorder with significant malignant potential. Here, we describe LYG in a 70-year-old renal allograft recipient who, 4 years after transplantation, on tacrolimus and mycophenolate mofetil and prednisone maintenance immunosuppression, complained of low-grade fever, persistent headache and gait disturbance. The MRI of the brain revealed diffuse periventricular cerebral and cerebellar contrast-enhanced lesions. The CT scan of the thorax showed multiple pulmonary nodular opacities in both lung fields. The patient was diagnosed LYG based on the cerebral biopsy showing perivascular infiltration of CD20-positive B-lymphocytes with granulomatous lesions and immunofluorescence staining with anti-EBV antibodies. With careful reduction of the immunossuppression combined with the use of rituximab, our patient showed a complete disappearance of LYG, and she is clinically well more than 4 years after the diagnosis, with good kidney function. No recurrence has been observed by radiological imaging until now. This is the first report of a durable (>4 years) complete remission of LYG after treatment with rituximab in renal transplantation. PMID:21559262

  16. Lymphomatoid Granulomatosis Treated Successfully with Rituximab in a Renal Transplant Patient

    Directory of Open Access Journals (Sweden)

    Cindy Castrale

    2011-01-01

    Full Text Available Lymphomatoid granulomatosis (LYG in renal transplant recipients is rare multisystemic angiocentric lymphoproliferative disorder with significant malignant potential. Here, we describe LYG in a 70-year-old renal allograft recipient who, 4 years after transplantation, on tacrolimus and mycophenolate mofetil and prednisone maintenance immunosuppression, complained of low-grade fever, persistent headache and gait disturbance. The MRI of the brain revealed diffuse periventricular cerebral and cerebellar contrast-enhanced lesions. The CT scan of the thorax showed multiple pulmonary nodular opacities in both lung fields. The patient was diagnosed LYG based on the cerebral biopsy showing perivascular infiltration of CD20-positive B-lymphocytes with granulomatous lesions and immunofluorescence staining with anti-EBV antibodies. With careful reduction of the immunossuppression combined with the use of rituximab, our patient showed a complete disappearance of LYG, and she is clinically well more than 4 years after the diagnosis, with good kidney function. No recurrence has been observed by radiological imaging until now. This is the first report of a durable (>4 years complete remission of LYG after treatment with rituximab in renal transplantation.

  17. Evaluation of non-radioactive lutetium- and yttrium-labeled immunoconjugates of rituximab - a vibrational spectroscopy study

    OpenAIRE

    Gjorgieva Ackova, Darinka; Smilkov, Katarina; Janevik-Ivanovska, Emilija; Stafilov, Trajče; Arsova-Sarafinovska, Zorica; Makreski, Petre

    2015-01-01

    Fourier Transform Infrared (FT-IR) and Raman Spectroscopy were used to study the molecular structure of the recombinant monoclonal antibody and anti-CD20-conjugates which are intended to be used as anti-cancer therapeutic agents. We characterized the secondary structure of a therapeutic immunoconjugates of rituximab, formulated with three different bifunctional chelating agents (p-SCN-Bn-DOTA, p-SCN-Bn-DTPA, 1B4M-DTPA) and labeled with non-radioactive lutetium and yttrium. The secondary struc...

  18. Rituximab in patients with CIDP: A report of 13 cases and review of the literature

    OpenAIRE

    Benedetti, Luana; Briani, Chiara; Franciotta, Diego; Fazio, Raffaella; Paolasso, Ilaria; Comi, Cristoforo; Luigetti, Marco; Sabatelli, Mario; Giannini, Fabio; Mancardi, Giovanni Luigi; Schenone, Angelo; Nobile-Orazio, Eduardo; Cocito, Dario

    2010-01-01

    Abstract Background: A few case reports have shown controversial results of rituximab efficacy in patients with CIDP. Objective: To analyze the efficacy of rituximab in a large CIDP cohort. Methods: A retrospective, observational and multicenter study on the use of rituximab in CIDP. We treated 13 Italian CIDP patients with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring haematological diseases. Patients ...

  19. Radiolabelling rituximab with (99m)Tc in three steps procedure.

    Science.gov (United States)

    Fontan, Charlotte; Bezombes, Christine; Salabert, Anne Sophie; Costes, Julien; Lopez, Raphael; Fournie, Jean-Jacques; Avet-Loiseau, Hervé; Coulais, Yvon; Payoux, Pierre; Tafani, Mathieu

    2015-06-15

    Lymphomas are the most frequent haematological malignancy. In non-Hodgkin's lymphomas (NHL), more than 90% of tumor cells express the cluster of differentiation (CD) 20 antigen. At the end of frontline therapy, the evaluation of remission is based on computed tomography (CT) and positron emission tomography coupled with computer tomography (PET/CT) with [(18)F]-fluorodeoxyglucose ([(18)F]FDG). Unfortunately, these techniques are not specific and cannot distinguish residual active tumor from inflammation. The aim of this study was to develop a specific radiotracer of NHL CD 20+ cells for clinical applications. The radiolabelling technique presented, based on the use of tricarbonyl compound, does not include an antibody reduction because this step could damage the protein. Actually, rituximab, an anti-CD 20 chimeric antibody used for the treatment of these NHL, was radiolabelled with Isolink® (99m)Tc-tricarbonyl compound in a three-step procedure without using a specific antibody reducer. Radiolabelling yield was greater than 97%. In vitro experiments showed a conservation of antibody integrity. In vivo experiments using Single-photon emission computed tomography/CT showed significant tumor targeting 24 h after injection of the radiotracer. It was consequently possible to develop an immunoradiolabelling method to specifically detect the residual disease. As this procedure is fast, reproducible and gentle, it will be possible to comply with Good Manufacturing Practices. PMID:26017396

  20. Analysing saturable antibody binding based on serum data and pharmacokinetic modelling

    Energy Technology Data Exchange (ETDEWEB)

    Kletting, Peter; Kiryakos, Hady; Reske, Sven N; Glatting, Gerhard, E-mail: gerhard.glatting@uni-ulm.d, E-mail: peter.kletting@uniklinik-ulm.d [Klinik fuer Nuklearmedizin, Universitaet Ulm, D-89070 Ulm (Germany)

    2011-01-07

    In radioimmunotherapy, organ dose calculations are frequently based on pretherapeutic biodistribution measurements, assuming equivalence between pretherapeutic and therapeutic biodistribution. However, when saturation of antibody binding sites is important, this assumption might not be justified. Residual antibody and different amounts of administered antibody may lead to a considerably altered therapeutic biodistribution. In this study we developed a method based on serum activity measurements to investigate this effect in radioimmunotherapy with {sup 90}Y-labelled anti-CD66 antibody. Pretherapeutic and therapeutic serum activity data of ten patients with acute leukaemia were fitted to a set of four parsimonious pharmacokinetic models. All models included the key mechanisms of antibody binding, immunoreactivity and degradation; however, they differed with respect to linear or nonlinear binding and global or individual fitting of the model parameters. The empirically most supported model was chosen according to the corrected Akaike information criterion. The nonlinear models were most supported by the data (sum of probabilities {approx}100%). Using the presented method, we identified relevant saturable binding for radioimmunotherapy with {sup 90}Y-labelled anti-CD66 antibody solely based on serum data. This general method may also be applicable to investigate other systems where saturation of binding sites might be important.

  1. Analysing saturable antibody binding based on serum data and pharmacokinetic modelling

    Science.gov (United States)

    Kletting, Peter; Kiryakos, Hady; Reske, Sven N.; Glatting, Gerhard

    2011-01-01

    In radioimmunotherapy, organ dose calculations are frequently based on pretherapeutic biodistribution measurements, assuming equivalence between pretherapeutic and therapeutic biodistribution. However, when saturation of antibody binding sites is important, this assumption might not be justified. Residual antibody and different amounts of administered antibody may lead to a considerably altered therapeutic biodistribution. In this study we developed a method based on serum activity measurements to investigate this effect in radioimmunotherapy with 90Y-labelled anti-CD66 antibody. Pretherapeutic and therapeutic serum activity data of ten patients with acute leukaemia were fitted to a set of four parsimonious pharmacokinetic models. All models included the key mechanisms of antibody binding, immunoreactivity and degradation; however, they differed with respect to linear or nonlinear binding and global or individual fitting of the model parameters. The empirically most supported model was chosen according to the corrected Akaike information criterion. The nonlinear models were most supported by the data (sum of probabilities ≈100%). Using the presented method, we identified relevant saturable binding for radioimmunotherapy with 90Y-labelled anti-CD66 antibody solely based on serum data. This general method may also be applicable to investigate other systems where saturation of binding sites might be important.

  2. Cytomegalovirus enterocolitis in a patient with diffuse large B-cell lymphoma after chemotherapy with rituximab

    Institute of Scientific and Technical Information of China (English)

    Jason Seewoodhary

    2006-01-01

    Rituximab has been associated with the development of cytomegalovirus enterocolitis in immunosuppressed patients. A 51-year-old patient with diffuse large B-cell lymphoma who received a conditioning chemotherapy regimen (RCVP and RICE) consisting of rituximab before bone marrow transplantation went on to develop cytomegalovirus enterocolitis. This supports evidence from previously described cases that rituximab may be associated with cytomegalovirus enterocolitis.

  3. Fatal Cytomegalovirus Disease after Combination Therapy with Corticosteroids and Rituximab for Granulomatosis with Polyangiitis

    Directory of Open Access Journals (Sweden)

    Talal Hilal

    2015-01-01

    Full Text Available The association of cytomegalovirus (CMV with autoimmune disease is poorly understood with suggested causality and reported viral reactivation coinciding with active inflammation. We report a case of a patient who presented with diffuse alveolar hemorrhage and acute renal failure from rapidly progressive glomerulonephritis ultimately diagnosed with granulomatosis with polyangiitis (GPA. She was acutely managed with plasmapheresis to reduce antibody-mediated end-organ damage, hemodialysis for worsening hyperkalemia and acidosis, and high-dose intravenous methylprednisolone. She was transitioned to oral prednisone and started on weekly rituximab with resultant remission induction over a three-week period at which point she developed reactivation of CMV causing severe fatal lung disease and viremia. The case highlights the multiple factors associated with CMV reactivation in cases of severe systemic inflammatory states and the need for further research to help establish practice guidelines regarding antimicrobial prophylaxis in patients with autoimmune diseases on prolonged courses of corticosteroids and biologic agents.

  4. Alpha radioimmunotherapy of multiple myeloma: study of feasibility of ex vivo medullary purge

    International Nuclear Information System (INIS)

    The efficiency of the radioimmunotherapy (RIT) using beta emitters has been clinically proved in treatments of refractory forms of lymphoma. The alpha-emitting radioelements of short half-life are also good potential candidates for RIT, applicable to tumor targets accessible rapidly to the molecules of the radio-immuno-conjugates of size compatible with the short range of alpha particles (50 to 80 μm). The goal of this study is to demonstrate the feasibility of such an approach on a model of myeloma multiply targeted by specific antibodies (B-B4) coupled to bismuth-213 with a chelating agent (benzyl-DTPA). The efficiency of the alpha RIT was evaluated in vitro by means of different techniques analyzing the cellular mortality (the method of limited dilution), the effects on DNA (the testing of micro-nuclei), the analysis of radio-induced apoptosis (the test with acridine orange) and finally the study of non-specific irradiation on population of cells of hematopoietic system un-recognized by the B-B4 benzyl-DTPA) immuno-conjugate. The first results have shown besides the technical feasibility of the project a strong dose dependent cellular mortality with a survival falling rapidly from 28% to around 1 o/oo for a single doubling of the dose from 14.8 kBq / 105 cells (0.4 μCi) to 29.6 kBq/105 cells (0.8 μCi). The cellular mortality was total at 300 kBq/105 cells (8 μCi). The cells in an apoptosis state were evidenced at rates up to 40% for a dose of 7.4 kBq/105 cells (0.2 μ Ci). New experiments will permit confirming these first results and determining the irradiation range having in view a utilization in protocols of purging of the myeloma cells on pockets obtained after plasmaphereses

  5. Improved response of colon cancer xenografts to radioimmunotherapy with pentoxifylline treatment

    International Nuclear Information System (INIS)

    A methylxanthine, pentoxifylline (PTX), has the potential to improve tumour microcirculation and oxygenation in vivo. We aimed to determine whether this agent would enhance the response of tumours to experimental radioimmunotherapy (RIT). Balb/c nu/nu mice with xenografts of LS180 human colon cancer were treated with 4.63 MBq of 131I-A7 anti-colorectal monoclonal antibody. A dose of 50 mg/kg of PTX was administered i.p. immediately after the 131I-A7 injection and daily thereafter for 7 days. The effect of PTX administration on 131I-A7 targeting in tumours was assessed with biodistribution and radioluminography on day 2. Intratumoural pO2 was measured with microelectrodes. The administration of PTX alone did not suppress tumour growth, but the efficacy of RIT with 131I-A7 was significantly improved by PTX: tumour volumes on day 15, relative to the initial volume, were 16.8±3.60 in the non-treated controls, 13.9±2.17 with PTX, 3.43±0.44 with RIT, and 1.86±0.59 with RIT+PTX (P131I-A7. However, intratumoural pO2 was significantly improved by PTX administration: 16.9±9.75 mmHg in control tumours versus 25.6±11.3 mmHg in PTX-treated tumours (P<0.01). These results indicate that PTX-induced radiosensitisation of tumour cells due to better oxygenation is responsible for the better RIT outcomes, because the net radiation absorbed dose to the tumours did not appear to be changed. (orig.)

  6. Rituximab in combination with multiagent chemotherapy for pediatric follicular lymphoma.

    Science.gov (United States)

    Kumar, Riten; Galardy, Paul J; Dogan, Ahmet; Rodriguez, Vilmarie; Khan, Shakila P

    2011-08-01

    Given the rarity of follicular lymphoma (FL) in children, there is limited data on which to base treatment recommendations. Herein, we report our institutional experience of using rituximab with multiagent chemotherapy for pediatric FL. Six pediatric patients were diagnosed with FL from 2000 to 2009. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for varying durations. Five of the six patients remain in remission with a median follow-up of 31 months. Larger randomized trials are indicated to establish the efficacy of this regimen for pediatric FL patients. PMID:21462303

  7. Rituximab as a possible cause of posterior reversible encephalopathy syndrome

    Directory of Open Access Journals (Sweden)

    Ahmed Imran Siddiqi

    2011-09-01

    Full Text Available A 66-year-old woman presented with new onset generalisedtonic-clonic seizures following her first dose ofchemotherapy comprising Rituximab, Cyclophosphamide,Hydroxydaunorubicin, Oncovin and Prednisolone (R-CHOP10 days earlier for non-Hodgkin’s lymphoma. On admission,computed tomography (CT scan of the cranium showed noabnormality. The CT was repeated within 48 hours as thepatient developed status epilepticus and papilledema; therepeat scan showed characteristics of posterior reversibleencephalopathy syndrome (PRES. Association of rituximabwith this condition was suspected as there was norecurrence of PRES after receiving two more cycles of CHOPwithout rituximab. Contrary to previously published casereports, this patient had a delayed clinical presentation.

  8. RITUXIMAB: NEW POTENTIALITIES OF THERAPY FOR RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    D E Karateev

    2008-01-01

    Full Text Available Some patients with rheumatoid arthritis (RA are unresponsive or intolerant to both synthetic first-line anti-inflammatory drugs (FLAID and tumor necrosis factor (TNF а inhibitors already included into all the treatment standards . Along with the conventional methods for overcoming drug resistance - switching to another FLAID or another TNF а blocker, the use of biologicals with another mechanism of action rather than suppression of TNF а gives a good account of itself. Prominent among these agents is the anti-B-cell drug rituximab. The new possibilities of the therapy, which open up the use of rituximab in patients with RA, are discussed.

  9. Development of [{sup 62}Zn/{sup 62}Cu]-DOTA-rituximab as a possible novel in vivo PET generator for anti-CD20 antigen imaging

    Energy Technology Data Exchange (ETDEWEB)

    Gholipour, Nazila [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Dept. of Radiopharmacy; Jalilian, Amir R.; Fazaeli, Yousef; Moradkhani, Sedigheh; Bolourinovin, Fateme [Nuclear Science and Technology Research Institute (NSTRI), Tehran (Iran, Islamic Republic of); Sabzevari, Omid [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Dept. of Toxicology and Pharmacology; Khalaj, Ali [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Dept. of Medical Chemistry

    2014-07-01

    In this study, zinc-62 was prepared at radiopharmaceutical grade (for {sup 62}Zn/{sup 62}Cu generator production) using {sup nat}Cu(p, xn) reaction with the production yield of 5.9 mCi/μAh at 30 MeV proton energy (radiochemical separation yield >95%, radionuclidic purity >99% and radiochemical purity >99%). In the next step, rituximab was successively labeled with [{sup 62}Zn]-ZnCl{sub 2} after conjugation with p-SCN-Bz-DOTA followed by molecular filtration and determination of the average number of DOTA conjugated per mAb (6:1) by spectrophotometric method. Radiochemical purity (>97%, measured by ITLC and HPLC), integrity of protein after radiolabeling (gel electrophoresis) and stability of [{sup 62}Zn]-DOTA-rituximab (in final formulation, and human serum) were determined 1-8 h as well as biodistribution studies in wild-type rats followed by coincidence imaging for 6 h. However, the accumulation of the radiolabeled antibody was not consistent with the former reported rituximab conjugates. [{sup 62}Zn]-labeled monoclonal antibodies and fragments can be prepared as potential in vivo PET generators for molecular imaging however, the search for application of stable zinc complexes must be continued.

  10. The future of antibody therapeutics: ADCs bi-specifics and RIT

    International Nuclear Information System (INIS)

    Full text of publication follows. Antibodies are widely accepted as remarkably versatile therapeutic agents. As evidence of this, the ∼ 30 antibody products marketed worldwide had total global sales of more than 50 billion dollars in 2012, and the commercial clinical pipeline currently comprises over 350 antibody-based product candidates. In a testament to scientific ingenuity, the investigational molecules (clinical and preclinical) are notably diverse in their composition of matter and include antibodies conjugated to a variety of agents (drugs, radioisotopes), bi-specific antibodies, and fragments or domains of antibodies. The concepts that form the basis of these agents were established decades ago, but advances in technology are now allowing new opportunities for their development. In this presentation, future directions in antibody therapeutics development will be discussed, with a focus on antibody-drug conjugates, bi-specific antibodies and radioimmunotherapy. (author)

  11. Intratumoral but not systemic delivery of CpG oligodeoxynucleotide augments the efficacy of anti-CD20 monoclonal antibody therapy against B cell lymphoma.

    Science.gov (United States)

    Betting, David J; Yamada, Reiko E; Kafi, Kamran; Said, Jonathan; van Rooijen, Nico; Timmerman, John M

    2009-01-01

    The anti-CD20 monoclonal antibody rituximab (Rituxan) has become a mainstay in the treatment of B cell non-Hodgkin lymphomas. The mechanisms of action for rituximab include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction. Combination of anti-CD20 antibodies with immunostimulatory agents may improve their efficacy via enhancement of one or more of these mechanisms. Toll-like receptor 9 agonist CpG oligodeoxynucleotides administered systemically have been studied in clinical trials with and without rituximab. However, recent data suggest that intratumoral (IT) delivery of CpG has advantages in the treatment of tumors. Using a syngeneic murine B cell lymphoma line expressing human CD20, we found that IT, but not systemically administered CpG significantly improved the efficacy of rituximab against 7-day established tumors. Rituximab plus IT CpG could eradicate tumors from 42% of mice, whereas systemically administered CpG, with or without rituximab, did not achieve tumor eradication. Both natural killer cells and complement participated in the cure of tumors by rituximab plus IT CpG, apparently by increasing tumor cell sensitivity to complement and ADCC lysis, and by augmenting the cytotoxicity of ADCC effectors. No role for T cells in mediating tumor eradication was demonstrated in this model. These results suggest that previous clinical trials in B cell lymphoma combining systemic administration of CpG with rituximab may have employed suboptimal routes of CpG delivery. Future trials combining IT CpG with anti-CD20 antibodies or the antibody-mediated targeting of CpG directly to the sites of B cell lymphoma may thus be warranted. PMID:19483647

  12. Rituximab therapy in steroid-resistant severe hypothyroid Grave's ophthalmopathy

    OpenAIRE

    Aditi Pandit; Abhay Gundgurthi; Sandeep Kharb; Karninder S Brar; Garg, M. K.

    2013-01-01

    Association of Grave′s ophthalmopathy with hyperthyroidism is well known, and it has also been reported in euthyroid or hypothyroid autoimmune thyroiditis, which rarely requires treatment. Here, we report a case of bilaterally symmetrical severe corticosteroid-resistant hypothyroid Grave′s ophthalmopathy successfully treated with rituximab.

  13. Ongoing investigations and new uses of radioimmunotherapy in the treatment of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Studies in radiation oncology are focusing on the optimal use of systemic targeted radionuclide therapy (STaRT) in the treatment of patients with cancer. The two approved radioimmunotherapy agents, yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab, are being studied in a range of lymphoid malignancies, from low-grade to aggressive B-cell non-Hodgkin's lymphomas. Studies of standard- and escalated-dose radioimmunotherapy with or without stem cell support are reviewed, as are radioimmunotherapy with other therapeutic modalities in these settings. The results of these trials have important implications for clinical practice, and it is hoped that they will further clarify the optimal timing and dosing of these agents

  14. In vitro characterization of 177Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

    International Nuclear Information System (INIS)

    131I- and 90Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin's lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (177Lu or 90Y. Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 105 times excess of diethylenetriaminepentaacetic acid (DTPA, 37 C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m2 body surface 177Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314 mGy. The administration of 177Lu-DOTA-rituximab was tolerated well. Our results show that DOTA-rituximab (4:1) can be labelled with 177Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL. (orig.)

  15. Lutetium-177-G250 radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model

    International Nuclear Information System (INIS)

    Full text of publication follows. Aim: Despite the good results achieved with agents targeting the VEGF and mTOR pathways, the treatment of advanced clear cell renal cell carcinoma (ccRCC) still poses a great challenge. A new approach in the treatment of ccRCC is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with Lutetium-177 (Lu177) labeled G250, we conducted protein dose escalation study and subsequently a RIT study with Lu177-G250 in an intraperitoneal ccRCC mouse model. Materials and methods: 25 athymic female BALB/c mice were injected intraperitoneally with 3 x 106 SK-RC-52 cells. To determine the optimal G250 protein dose, 3 weeks after inoculation the mice were injected with either 1, 3, 10, 30 or 100 μg G250 radiolabeled with 15 MBq indium-111 (In111). SPECT/CT images were made with the micro SPECT USPECT II camera 48 hours p.i. After imaging, the mice are killed and the biodistribution of In111-G250 was determined. The optimal protein dose was used in a subsequent therapy experiment in 3 groups of mice with i.p. SK-RC-52 tumors. One group (n=10) was injected with 13 MBq Lu177-G250, a control group received nonspecific antibody MOPC21 labeled with 13 MBq Lu177 (n=10) and the second control group received 20 MBq In111-G250 (n=10). Tumor growth was monitored with SPECT/CT imaging before treatment and with 3 week intervals. Primary endpoints were overall survival and toxicity. Results: The optimal G250 protein dose to target ccRCC in this model was 10 μg G250, as determined with SPECT/CT imaging and biodistribution. Treatment with 13 MBq Lu177-G250 was well tolerated. Treatment with Lu177-G250 resulted in significantly prolonged median survival of 139 days, in comparison with 49 days (Lu177-MOPC21) and 53 days In111-G250 (p=0.015). Conclusion: this is the first RIT study with radiolabeled G250 protein in mice with i.p. growing ccRCC. Treatment with Lu177-G250 resulted in significantly

  16. Importance of pre-treatment radiation absorbed dose estimation for radioimmunotherapy of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Non-Hodgkin's lymphoma I-131 radioimmunotherapy data were analyzed to determine whether a predictive relationship exists between radiation absorbed doses calculated from biodistribution studies and doses derived from patient size. Radioactivity treatment administrations scaled to patient size (MBq/kg or MBq/m2) or fixed MBq doses do not produce consistent radiation absorbed dose to critical organs. Treatment trials that do not provide dose estimates for critical normal organs are less likely to succeed in identifying a clinical role for radioimmunotherapy

  17. Bio-effect model applied to {sup 131}I radioimmunotherapy of refractory non-Hodgkin's lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Roberson, Peter L.; Amro, Hanan; Schipper, Matthew J. [University of Michigan, Department of Radiation Oncology, Ann Arbor, MI (United States); Wilderman, Scott J.; Avram, Anca M.; Dewaraja, Yuni K. [University of Michigan Medical Center, Department of Radiology, Ann Arbor, MI (United States); Kaminski, Mark S. [University of Michigan Medical Center, Division of Hematology and Oncology, Department of Internal Medicine, Ann Arbor, MI (United States)

    2011-05-15

    Improved data collection methods have improved absorbed dose estimation by tracking activity distributions and tumor extent at multiple time points, allowing individualized absorbed dose estimation. Treatment with tositumomab and {sup 131}I-tositumomab anti-CD20 radioimmunotherapy (BEXXAR) yields a cold antibody antitumor response (cold protein effect) and a radiation response. Biologically effective contributions, including the cold protein effect, are included in an equivalent biological effect model that was fit to patient data. Fifty-seven tumors in 19 patients were followed using 6 single proton emission computed tomography (SPECT)/CT studies, 3 each post tracer (5 mCi) and therapy ({proportional_to}100 mCi) injections with tositumomab and {sup 131}I-tositumomab. Both injections used identical antibody mass, a flood dose of 450 mg plus 35 mg of {sup 131}I tagged antibody. The SPECT/CT data were used to calculate absorbed dose rate distributions and tumor and whole-body time-activity curves, yielding a space-time dependent absorbed dose rate description for each tumor. Tumor volume outlines on CT were used to derive the time dependence of tumor size for tracer and therapy time points. A combination of an equivalent biological effect model and an inactivated cell clearance model was used to fit absorbed dose sensitivity and cold effect sensitivity parameters to tumor shrinkage data, from which equivalent therapy values were calculated. Patient responses were categorized into three groups: standard radiation sensitivity with no cold effect (7 patients), standard radiation sensitivity with cold effect (11 patients), and high radiation sensitivity with cold effect (1 patient). Fit parameters can be used to categorize patient response, implying a potential predictive capability. (orig.)

  18. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial

    DEFF Research Database (Denmark)

    Salles, Gilles; Seymour, John Francis; Offner, Fritz;

    2011-01-01

    Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab p...

  19. A comparative study of preliminary dosimetry for human based on distribution data in rats with 111In, 90Y, 153Sm, and 177Lu labeled rituximab

    Directory of Open Access Journals (Sweden)

    Radfar Edalat

    2012-01-01

    Full Text Available Radio immunotherapy is one of the most important and effective therapies for B-cell non Hoddgkin’s lymphoma treatment. Today, anti CD-20 antibodies labeled with beta emitter radionuclides are used in radio immunotherapy. Various radionuclides for labeling anti CD-20 antibodies have been studied and developed for the treatment and diagnosis of malignancies. This paper describes the preparation, bio-distribution and absorbed dose rate of 111In, 90Y, 177Lu, and 153Sm labeled anti CD-20 antibodies (rituximab in human organs, after injection to rats. The macro cyclic bifunctional chelating agent, N-succinimidyl-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA-NHS for conjugation to antibody, was used to prepare DOTA-rituximab. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. Radio-labeling was performed at 40 °C for 24 hours. After the quality control studies, the final radioactive solution was injected intravenously into rats through their tail vein. The tissue uptakes of each injection were measured. Then we calculated S values for 177Lu and 153Sm by using specific absorbed fractions and data used in the manner of radio-labeled analysis and dosimetry for humans. The absorbed dose rate of each organ was calculated in the specific time by medical internal radiation dose method with linear approximation in the activity measurements.

  20. Dosimetric evaluation of copper-64 in copper-67-2IT-BAT-Lym-1 for radioimmunotherapy

    International Nuclear Information System (INIS)

    Copper 67 (67Cu) is an attractive radionuclide for radioimmunotherapy because of its favorable physical and biologic characteristics. Current supplies of 67Cu, however, contain as much as 60% of 64Cu at the time of delivery. Scatter photons from 64Cu enter the 67Cu energy window, affecting image resolution and counting accuracy. The radiation dose to tissue is also altered. A line source and a small vial source of 67Cu containing varying amounts of 64Cu were used to evaluate the impact of 64Cu on image resolution and activity quantitation, respectively. Identical pharmacokinetics for 67Cu and 64Cu was assumed, and the radiation dosimetry of 64Cu was assessed using quantitative imaging data for 67Cu because the amount of 64Cu could be calculated for any time after 67Cu production. MIRD formalism was used to estimate the therapeutic index, defined as the ratio of radiation dose to tumor divided by the radiation dose to bone marrow. The shorter physical half-life of 64Cu relative to that of 67Cu and slower uptake and longer retention of antibody by tumor than by marrow result in a lower therapeutic index for 64Cu. The 25% radioimpurity of 64Cu causes less than 10% deviation in activity quantitation and diminution in the therapeutic index. The change in therapeutic index is predictable over time and can be used to determine the optimal time for radiopharmaceutical administration. 34 refs., 4 figs., 2 tabs

  1. 131I-chTNT-mediated radioimmunotherapy for non-uptaking 131I pulmonary metastases from differentiated thyroid carcinoma

    International Nuclear Information System (INIS)

    In this paper, the safety and efficacy of 131I-labeled mouse/human chimeric monoclonal antibody (131I-chTNT)-mediated radioimmunotherapy are evaluated because the patients have non-uptaking 131I pulmonary metastases from differentiated thyroid carcinoma (DTC). The 16 patients were injected intravenously by 29.6±3.7 MBq·kg-1 using 131I-chTNT. The chest computer tomography was performed before treatment, as well as 28 and 70 days after treatment. Responses and safety were assessed during the treatment. The results show that the 131I-chTNT infusion was well tolerated with the 12.5% complete response, 18.8% partial response, 25.0% progressive disease, and the 43.8% stable disease, indicating that most treatment-related adverse effects are mild transient and reversible. The 131I-chTNT is promising for patients with non-uptaking the 131I pulmonary metastases from DTC. (authors)

  2. Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy

    International Nuclear Information System (INIS)

    We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of 131I-A7, an IgG1 anti-colorectal monoclonal antibody, or 131I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation (n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice (n=8) (P131I-A7 RIT displayed a marked therapeutic effect (n=8) (P131I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy (n=10) (P131I-HPMS-1 RIT failed to provide an appreciable benefit (n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases. (orig.)

  3. Rituximab and Other New Anti-CD20 MAbs for Non-Hodgkin’s Lymphoma Treatment

    Directory of Open Access Journals (Sweden)

    Letizia Polito

    2013-10-01

    Full Text Available Non-Hodgkin’s lymphomas (NHLs are a heterogeneous group of different haematological cancers with a wide range of aggressiveness. NHLs represent >80% of lymphomas and the majority of NHLs involve B cells. CD20 represents a good target for NHL immunotherapy because it is largely expressed on B cell NHL and not on B cell precursors and plasma cells. The anti-CD20 monoclonal antibody (mAb rituximab (RTX was the first antibody approved by the FDA for lymphoma therapy and has revolutionised B cell lymphoma treatment. Several clinical trials have demonstrated the high efficacy of RTX, resulting in a significant improvement in overall response rates and in NHL patient survival. However, RTX, both as a single agent and in combination with chemotherapy, induces several side-effects and resistance mechanisms. Remarkable efforts have been made to improve RTX efficacy, including conjugation to an active moiety (radionuclide, toxin, enzyme, or drug and the development of new anti-CD20 mAbs. This review summarises the characteristics of RTX and other anti-CD20 mAbs for NHL treatment; the results of the main clinical trials are reported.

  4. 131I-Tositumomab Myeloablative Radioimmunotherapy for Non-Hodgkin's Lymphoma: Radiation Dose to the Testes

    Energy Technology Data Exchange (ETDEWEB)

    Hattori, Naoya; Gopal, Ajay K.; Shields, Andrew T.; Fisher, Darrell R.; Gooley, Ted; Pagel, John M.; Press, Oliver W.; Rajendran, Joseph G.

    2012-12-01

    To investigate radiation dose to testes delivered by radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. METHODS: We evaluated dosimetry results for 67 male patients (54 ± 11 years old) with non-Hodgkin lymphoma who underwent myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. In a subset of patients, male sex hormones were measured before and one year after the therapy. RESULTS: Absorbed dose to testes showed greater variability (range = 4.4 to 70.2 Gy) than did dose to lungs (9.5 to 28.4 Gy, p < 0.0001) or liver (6.5 to 27.2 Gy, p < 0.0001). Absorbed dose to the testes per 131I administered (1.18 ± 0.59 mGy/MBq) was not significantly different from that to the liver (1.03 ± 0.29 mGy/MBq, p = 0.08), or to the lungs (1.19 ± 0.50 mGy/MBq, p = 0.889). Pre-therapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction (4.6 ± 1.8 nmol/L (pre-RIT) vs. 3.8 ± 2.9 nmol/L (post-RIT), p < 0.05). Patients receiving higher radiation doses to the testes (≥ 25 Gy) showed a greater reduction (4.7 ± 1.6 nmol/L (pre RIT) vs. 3.3 ± 2.7 nmol/L (post-RIT), p < 0.05) than did patients receiving lower doses (< 25 Gy), who showed no significant change in total testosterone levels. CONCLUSION: The testicular radiation absorbed dose varied highly among individual patients. Patients receiving higher doses to testes were more likely to show post-RIT suppression of testosterone levels. Key Words: 131I-tositumomab, follicular lymphoma, radioimmunotherapy, radiation dosimetry, male sex hormones.  

  5. Strategies to improve the efficacy of radioimmunotherapy: Radiobiologic aspects

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate methods of improving the therapeutic index (dose to tumor/dose to normal organs) and, hence, the efficacy of radioimmunotherapy (RIT). One method investigated was to increase the biologic response for a given radiation dose to tumor. To enhance the biologic efficacy of the dose, initial studies focused on first understanding the radiobiology of RIT irradiation and determining what role factors, such as radiation repair, repopulation, and redistribution, play in determining RIT response. In vitro studies using 4 colon carcinoma cell lines have compared the radiobiologic efficacy of low dose-rate irradiation delivered by Yttrium-90 (Y-90) with conventional high dose-rate external beam irradiation (XRT). Results suggested that one factor which determined a cell's sensitivity to Y-90 irradiation was its ability to repair radiation sublethal damage. In vivo studies demonstrated that those cell lines which were more sensitive to Y-90 irradiation in vitro were also more sensitive to RIT in vivo. For a more radioresistant line, WiDr, RIT was approximately two-fold less effective than an equivalent dose of single fraction XRT, while for a more radiosensitive line, LS174T, RIT was approximately as effective as an equivalent dose of single fraction XRT. Therefore, a tumor's response to RIT in vivo appeared to be, in part, dependent on the tumor cell's ability to repair radiation damage. Finally, studies investigated strategies at enhancing the biologic efficacy of RIT irradiation by combining RIT with chemotherapy agents that can potentially inhibit radiation repair. Agents, such as 5-fluorouracil, appeared to be synergistic with RIT irradiation n vitro and may therefore prove promising in improving the therapeutic index of RIT

  6. Rituximab Efficacy during a Refractory Polyarteritis Nodosa Flare

    Directory of Open Access Journals (Sweden)

    Emmanuel Ribeiro

    2009-01-01

    Full Text Available Polyarteritis nodosa (PAN is a systemic vasculitis whose severe forms are treated with glucocorticoids and cyclophosphamide. Refractory patients are exposed to many complications, notably accelerated atherosclerosis. We report a case report of 71-year-old man followed for polyarteritis nodosa refractory to glucocorticoids and cyclosphosphamide. Systemic vasculitis relapses are followed to accelerated atherosclerosis: severe ischemic lesions led to amputation of lower limbs. Remission of refractory PAN is obtained with rituximab. Disappearance of biological inflammatory is allowed to regression of ischemic lesions in upper limbs. In this situation, we recommend a systematic vascular work-up for patients suffered from refractory vasculitis. On the other hand, therapeutic trials are needed to determine the real efficacy and place of rituximab in the treatment of polyarteritis nodosa.

  7. Study on the Radioiodination of Sheep Anti-myeloma Polyclonal Antibodies for the Determination of in-vitro Cytotoxic Effect on Myeloma Cells

    International Nuclear Information System (INIS)

    The present work aims to study the effect of radiolabeled anti-myeloma polyclonal antibodies on the growth and viability of myeloma cells in-vitro. Two Sheep were immunized by myeloma cells (SP2/OR) as antigen. Productions of Sheep anti-myeloma polyclonal antibodies followed by radioiodination using different oxidizing agents were carried out. Labeled and unlabeled antibodies were incubated with myeloma cells. Growth and viability of myeloma cells were investigated before and after addition of antibodies. The results show significant reduction in growth and viability of myeloma cells by using labeled antibodies. This technique of treatment can be used in radio-immunotherapy of myeloma cell

  8. Successful Treatment of Type B Insulin Resistance With Rituximab

    OpenAIRE

    Manikas, Emmanouil-Dimitrios; Isaac, Iona; Semple, Robert K.; Malek, Rana; Führer, Dagmar; Moeller, Lars C.

    2015-01-01

    Context: Type B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone. Case Description: A 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose...

  9. Successful treatment of HIV-associated multicentric Castleman's disease and multiple organ failure with rituximab and supportive care: a case report

    Directory of Open Access Journals (Sweden)

    Isaacson Peter G

    2010-01-01

    Full Text Available Abstract Introduction Multicentric Castleman's Disease (MCD, a lymphoproliferative disorder associated with Human Herpes Virus-8 (HHV-8 infection, is increasing in incidence amongst HIV patients. This condition is associated with lymphadenopathy, polyclonal gammopathy, hepato-splenomegaly and systemic symptoms. A number of small studies have demonstrated the efficacy of the anti-CD20 monoclonal antibody, rituximab, in treating this condition. Case presentation We report the case of a 46 year old Zambian woman who presented with pyrexia, diarrhoea and vomiting, confusion, lymphadenopathy, and renal failure. She rapidly developed multiple organ failure following the initiation of treatment of MCD with rituximab. Following admission to intensive care (ICU, she received prompt multi-organ support. After 21 days on the ICU she returned to the haematology medical ward, and was discharged in remission from her disease after 149 days in hospital. Conclusion Rituximab, the efficacy of which has thus far been examined predominantly in patients outside the ICU, in conjunction with extensive organ support was effective treatment for MCD with associated multiple organ failure. There is, to our knowledge, only one other published report of its successful use in an ICU setting, where it was combined with cyclophosphamide, adriamycin and prednisolone. Reports such as ours support the notion that critically unwell patients with HIV and haematological disease can benefit from intensive care.

  10. DNA damage-centered signaling pathways are effectively activated during low dose-rate Auger radioimmunotherapy

    International Nuclear Information System (INIS)

    Introduction: Low dose-rate radioimmunotherapy (RIT) using 125I-labelled monoclonal antibodies (125I-mAbs) is associated with unexpected high cytotoxicity per Gy. Methods: We investigated whether this hypersensitivity was due to lack of detection of DNA damage by the targeted cells. DNA damage was measured with the alkaline comet assay, gamma-H2AX foci and the micronucleus test in p53−/− and p53+/+ HCT116 cells exposed to increasing activities of internalizing anti-HER1 125I-mAbs or non-internalizing anti-CEA 125I-mAbs. The expression of proteins involved in radiation response and progression of cells through the cycle were determined. Results: Cell hypersensitivity to low absorbed doses of anti-CEA 125I-mAbs was not due to defect in DNA damage detection, since ATM (ataxia telangiectasia mutated gene), gamma-H2AX, p53 and p21 were activated in RIT-treated HCT116 cells and G2/M cell cycle arrest was observed. Moreover, the alkaline comet assay showed that DNA breaks accumulated when cells were placed at 4 °C during exposure but were repaired under standard RIT conditions (37 °C), suggesting that lesions detected under alkaline conditions (mostly DNA single strand breaks and alkali-labile sites) are efficiently repaired in treated cells. The level of gamma-H2AX protein corroborated by the level of foci measured in nuclei of treated cells was shown to accumulate with time thereby suggesting the continuous presence of DNA double strand breaks. This was accompanied by the formation of micronuclei. Conclusion: Hypersensitivity to non-internalizing 125I-mAbs is not due to lack of detection of DNA damage after low absorbed dose-rates. However, DNA double strand breaks accumulate in cells exposed both to internalizing and non-internalizing 125I-mAbs and lead to micronuclei formation. These results suggest impairment in DNA double strand breaks repair after low absorbed doses of 125I-mAbs

  11. Y-90-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    International Nuclear Information System (INIS)

    The goal of this work was to determine an optimal radioimmunotherapy agent for non-Hodgkin's lymphoma. We established the stability profile of yttrium-90-labeled humanized LL2 (hLL2) monoclonal antibody prepared with different chelating agents, and from these data estimated the improvement using the most stable yttrium-90 chelate-hLL2 complex. Methods: The complementary-determining region- (cdr)-grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to derivatives of DTPA and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). The conjugates were labeled with Y-90 and tested against a 10,000-fold molar excess of free DTPA and against human serum. The conjugates were also labeled with Y-88 and compared for biodistribution in normal and lymphoma xenograft-bearing athymic mice. In vivo data were analyzed for uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and dosimetry calculations were made for each. Results: Y-90-DOTA -mAb were stable to either DTPA or serum challenge. DTPA complexes of hLL2 lost 3-4% of Y-90 (days 1-4) and 10-15% thereafter. In vivo, stability differences showed lower Y-90 uptake in bone using DOTA. Absorbed doses per 37 MBq (1 mCi) Y-90-mAb were 3555 and 5405 cGy for bone, and 2664 and 4524 cGy for washed-bone for 90Y-DOTA-hLL2 and 90Y-MxDTPA-hLL2, respectively, amounting to 52% and 69.8% increases in absorbed radiation doses for bone and washed-bone when switching from a DOTA to a Mx-DTPA chelate. Conclusion: Y-90-hLL2 prepared with the DOTA chelate represents a preferred agent for RAIT of non-Hodgkin's lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, as compared to yttrium-90-hLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this will result in a substantial toxicological advantage for a DOTA-based hLL2 conjugate

  12. Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients

    International Nuclear Information System (INIS)

    A three-step avidin-biotin approach has been applied as a pretargeting system in radioimmunotherapy (RIT) as an alternative to conventional RIT with directly labelled monoclonal antibodies (MoAbs). Although dosimetric and toxicity studies following conventional RIT have been reported, these aspects have not previously been evaluated in a three-step RIT protocol. This report presents the results of pharmacokinetic and dosimetric studies performed in 24 patients with different tumours. Special consideration was given to the dose delivered to the red marrow and to the haematological toxicity. The possible additive dose to red marrow due to the release of unbound yttrium-90 was investigated. The protocol consisted in the injection of biotinylated MoAbs (first step) followed 1 day later by the combined administration of avidin and streptavidin (second step). After 24 h, biotin radiolabelled with 1.85-2.97 GBq/m2 of 90Y was injected (third step). Two different chelating agents, DTPA and DOTA, coupled to biotin, were used in these studies. Indium-111 biotin was used as a tracer of 90Y to follow the biodistribution during therapy. Serial blood samples and complete urine collection were obtained over 3 days. Whole-body and single-photon emission tomography images were acquired at 1, 16, 24 and 40 h after injection. The sequence of images was used to extrapolate 90Y-biotin time-activity curves. Numerical fitting and compartmental modelling were used to calculate the residence time values (τ) for critical organs and tumour, and results were compared; the absorbed doses were estimated using the MIRDOSE3.1 software. The residence times obtained by the numerical and compartmental models showed no relevant differences (90Y activities capable of delivering a high dose to the tumour and sparing red marrow and other normal organs. Although 90Y-biotin clears rapidly from circulation, the use of DOTA-biotin conjugate for a stable chelation of 90Y is strongly recommended, considering

  13. Recent developments in monoclonal antibody radiolabeling techniques

    International Nuclear Information System (INIS)

    Monoclonal antibodies (MAbs) have shown the potential to serve as selective carriers of radionuclides to specific in vivo antigens. Accordingly, there has been an intense surge of research activity in an effort to develop and evaluate MAb-based radiopharmaceuticals for tumor imaging (radioimmunoscintigraphy) and therapy (radioimmunotherapy), as well as for diagnosing nonmalignant diseases. A number of problems have recently been identified, related to the MAbs themselves and to radiolabeling techniques, that comprise both the selectivity and the specificity of the in vivo distribution of radiolabeled MAbs. This paper will address some of these issues and primarily discuss recent developments in the techniques for radiolabeling monoclonal antibodies that may help resolve problems related to the poor in vivo stability of the radiolabel and may thus produce improved biodistribution. Even though many issues are identical with therapeutic radionuclides, the discussion will focus mainly on radioimmunoscintigraphic labels. 78 refs., 6 tabs

  14. Eradication of colon cancer cells before tumour formation in the peritoneal cavity of mice treated with intraperitoneal Re-186 radioimmunotherapy

    International Nuclear Information System (INIS)

    A treatment adjuvant to surgical resection of the primary lesion has been proven to be beneficial in improving the prognosis of patients with high risks of peritoneal dissemination of colon cancer. This study was performed to determine the comparative efficacy of intraperitoneal radioimmunotherapy (RIT) using Re-186 or I-131 labeled murine antibodies in the extermination of cancer cells. A murine anti-colorectal IgG1, A7 monoclonal antibody, was radio-labeled either with I-131 (by the chloramine-T method) or Re-186 (by the MAG3 pre-chelated method). A total number of 16 mice were subjected to RIT with Re-186 A7 (N=8) or I-131 A7 (N=8) at equitoxic doses in Balb/c bu/nu mice 10 min after intraperitoneal injection of LS180 human colon cancer cells. A third group of mice were subjected to chemotherapy with 5-fluorouracil at 30 mg/kg for 4 consecutive days following the intraperitoneal injection of the same LS180 human colon cancer cells. There were 19 mice in the control group who were not subjected to any form of therapy. The results revealed that the mean survival of mice in the control (N-19), I-131 A7 RIT (N=8) and Chemotherapy (N=6) groups were 33.8 ± 1.0, 80.1 ± 2.5 and 49.3 ± 5.3 days respectively. The eight mice who were subjected to Re-186 A7 RIT showed much better survival compared to the other groups. Two of the eight mice from this group died at 105 and 111 days following Re-186 A7 RIT. Other six mice were sacrificed at 172 days, and autopsy revealed no macroscopic peritoneal tumor growth. Based on this pilot study we concluded that individual tumor cells in the peritoneal cavity would be effectively exterminated by intraperitoneal RIT with Re-186 A7. (author)

  15. Radiolabeled monoclonal antibodies for imaging and therapy: Potential, problems, and prospects: Scientific highlights

    International Nuclear Information System (INIS)

    This meeting focused on areas of research on radiolabeled monoclonal antibodies. Topics covered included the production, purification, and fragmentation of monoclonal antibodies and immunochemistry of hybridomas; the production and the chemistry of radionuclides; the radiohalogenation and radiometal labeling techniques; the in-vivo pharmacokinetics of radiolabeled antibodies; the considerations of immunoreactivity of radiolabeled preparations; the instrumentation and imaging techniques as applied to radioimmunodetection; the radiation dosimetry in diagnostic and therapeutic use of labeled antibodies; the radioimmunoscintigraphy and radioimmunotherapy studies; and perspectives and directions for future research. Tutorial as well as scientific lectures describing the latest research data on the above topics were presented. Three workshop panels were convened on ''Methods for Determining Immunoreactivity of Radiolabeled Monoclonal Antibodies - Problems and Pitfalls,'' Radiobiological and Dosimetric Considerations for Immunotherapy with Labeled Antibodies,'' and ''The Human Anti-Mouse Antibody Response in Patients.''

  16. Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors

    Directory of Open Access Journals (Sweden)

    Verbrugge Sue Ellen

    2013-01-01

    Full Text Available Abstract Background In clinical and experimental settings, antibody-based anti-CD20/rituximab and small molecule proteasome inhibitor (PI bortezomib (BTZ treatment proved effective modalities for B cell depletion in lymphoproliferative disorders as well as autoimmune diseases. However, the chronic nature of these diseases requires either prolonged or re-treatment, often with acquired resistance as a consequence. Methods Here we studied the molecular basis of acquired resistance to BTZ in JY human B lymphoblastic cells following prolonged exposure to this drug and examined possibilities to overcome resistance by next generation PIs and anti-CD20/rituximab-mediated complement-dependent cytotoxicity (CDC. Results Characterization of BTZ-resistant JY/BTZ cells compared to parental JY/WT cells revealed the following features: (a 10–12 fold resistance to BTZ associated with the acquisition of a mutation in the PSMB5 gene (encoding the constitutive β5 proteasome subunit introducing an amino acid substitution (Met45Ile in the BTZ-binding pocket, (b a significant 2–4 fold increase in the mRNA and protein levels of the constitutive β5 proteasome subunit along with unaltered immunoproteasome expression, (c full sensitivity to the irreversible epoxyketone-based PIs carfilzomib and (to a lesser extent the immunoproteasome inhibitor ONX 0914. Finally, in association with impaired ubiquitination and attenuated breakdown of CD20, JY/BTZ cells harbored a net 3-fold increase in CD20 cell surface expression, which was functionally implicated in conferring a significantly increased anti-CD20/rituximab-mediated CDC. Conclusions These results demonstrate that acquired resistance to BTZ in B cells can be overcome by next generation PIs and by anti-CD20/rituximab-induced CDC, thereby paving the way for salvage therapy in BTZ-resistant disease.

  17. Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

    NARCIS (Netherlands)

    Miloslavsky, E. M.; Specks, U.; Merkel, P. A.; Seo, P.; Spiera, R.; Langford, C. A.; Hoffman, G. S.; Kallenberg, C. G. M.; St Clair, E. W.; Tchao, N. K.; Viviano, L.; Ding, L.; Sejismundo, L. P.; Mieras, K.; Ikle, D.; Jepson, B.; Mueller, M.; Brunetta, P.; Allen, N. B.; Fervenza, F. C.; Geetha, D.; Keogh, K.; Kissin, E. Y.; Monach, P. A.; Peikert, T.; Stegeman, C.; Ytterberg, S. R.; Stone, J. H.

    2013-01-01

    Objective. To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods. The Rit

  18. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis

    DEFF Research Database (Denmark)

    Buch, Maya H; Smolen, Josef S; Betteridge, Neil;

    2011-01-01

    Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in th...

  19. Tc-99m-labeled Rituximab for Imaging B Lymphocyte Infiltration in Inflammatory Autoimmune Disease Patients

    NARCIS (Netherlands)

    Malviya, G.; Anzola, K. L.; Podesta, E.; Lagana, B.; Del Mastro, C.; Dierckx, R. A.; Scopinaro, F.; Signore, A.

    2012-01-01

    The rationale of the present study was to radiolabel rituximab with 99m-technetium and to image B lymphocytes infiltration in the affected tissues of patients with chronic inflammatory autoimmune diseases, in particular, the candidates to be treated with unlabelled rituximab, in order to provide a r

  20. Thyroid Antibodies

    Science.gov (United States)

    ... be limited. Home Visit Global Sites Search Help? Thyroid Antibodies Share this page: Was this page helpful? Also known as: Thyroid Autoantibodies; Antithyroid Antibodies; Antimicrosomal Antibody; Thyroid Microsomal Antibody; ...

  1. Improving the treatment outcome of patients with chronic lymphocytic leukemia through targeted antibody therapy.

    Science.gov (United States)

    Stephens, Deborah M; Byrd, John C

    2013-04-01

    Therapy for chronic lymphocytic leukemia (CLL) has evolved dramatically throughout the years. In 1997, rituximab (Rituxan), a CD20 monoclonal antibody (mAb), became the first mAb approved by the Food and Drug Administration for marketing in the treatment of cancer, specifically targeting B-cell malignancies. Over the last 10 years, rituximab or other mAbs including alemtuzumab and ofatumumab have become an integral part of the standard of care for CLL patients as single agents or in combination with chemotherapy or other immunotherapy. This review discusses the currently approved and novel mAbs for the treatment of CLL. PMID:23561475

  2. Long-term experience of plasmapheresis in antibody-mediated rejection in renal transplantation.

    LENUS (Irish Health Repository)

    Brown, C M

    2009-11-01

    Antibody-mediated rejection (AMR) continues to pose a serious challenge in renal transplantation with potentially devastating consequences. Treatment options for this condition include plasmapheresis, high-dose intravenous immunoglobulin (IVIG), plasmapheresis with low-dose IVIG, and the use of rituximab (anti-CD20 chimeric antibody). We previously reported on the short-term outcome of plasmapheresis as a rescue therapy for AMR in our centre. We now report on the long-term follow up.

  3. Expression and biological characterization of an anti-CD20 biosimilar candidate antibody: A case study

    OpenAIRE

    Dorvignit, Denise; Palacios, Julio L.; Merino, Maylin; Hernández, Tays; Sosa, Katya; Casacó, Angel; López-Requena, Alejandro; Mateo de Acosta, Cristina

    2012-01-01

    The CD20 molecule is a non-glycosylated protein expressed mainly on the surface of B lymphocytes. In some pathogenic B cells, it shows an increased expression, thus becoming an attractive target for diagnosis and therapy. Rituximab is a chimeric antibody that specifically recognizes the human CD20 molecule. This antibody is indicated for the treatment of non-Hodgkin lymphomas and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In this work, we describe the ...

  4. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies

    OpenAIRE

    Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

    2014-01-01

    Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab...

  5. Clinical application of antibody monoclonal humanized anti-EGFrnimotuzumab labeled

    International Nuclear Information System (INIS)

    Most malignant tumors are of epithelial origin. These are characterized by overexpression of the receptor of epidermal growth factor (EGFR), which the neoplastic cells escape the regulatory mechanisms are allowed, so its high concentration of membrane is generally associated with a poor prognosis . By binding an antibody specifically to this receptor, preventing binding of EGF latter and activation mechanism tyrosine kinase inhibiting cell mitosis and apoptosis causing tumor cell. For this reason, the EGFr has been considered as an attractive target for anti-tumor therapy. The humanized monoclonal antibody anti-EGFr nimotuzumab was developed by the Center of Molecular Immunology (Havana, Cuba). Numerous clinical trials have been developed in the Department of Clinical Research Center Isotopes (Cuba), in which it has been applied this antibody, both labeled with 99mTc for immuno gammagraphic detection of tumors, as labeled with 188Re for radioimmunotherapy of gliomas high degree of malignancy. The aim of this paper is to show the experience of the Department of Clinical Research of CENTIS in various clinical trials with marking for both immuno gammagraphics detection of tumors, such as for radioimmunotherapy nimotuzumab. (author)

  6. Refractory thrombotic thrombocytopenic purpura associated with primary Sjogren syndrome treated with rituximab: a case report.

    Science.gov (United States)

    Toumeh, Anis; Josh, Navpreet; Narwal, Rawan; Assaly, Ragheb

    2014-01-01

    Thrombotic thrombocytopenic purpura (TTP) is an uncommon, serious disease that involves multiple organs and is rapidly fatal if left untreated. TTP is associated with multisystem symptoms, such as thrombocytopenia, microangiopathic hemolytic anemia, renal impairment, central nervous system involvement, and fever. TTP is idiopathic in about 37% of the cases and can be associated with autoimmune diseases in 13% of the cases. Autoimmune disease-associated TTP can be refractory to plasma exchange and requires immunosuppressive therapy. We report a case of a previously healthy 55-year-old African American female who presented with shortness of breath, hemolytic anemia, renal impairment, and thrombocytopenia. The diagnosis of TTP was made, and plasmapheresis was initiated. However, recurrence happened 48 hours after plasmapheresis was stopped. Autoimmune workup for refractory TTP revealed positive antinuclear antibodies, Anti-SSA, and Anti-SSB. Lip biopsy revealed findings consistent with Sjogren syndrome. Treatment with Rituximab was started, and significant clinical and laboratory response was achieved. The patient remained asymptomatic thereafter. A high clinical suspicion of autoimmune diseases is important as TTP tends to be refractory to plasma exchange in these cases, and immunosuppressive therapy is a key. PMID:23011161

  7. [Rituximab (MabThera)--a new biological medicine in rheumatoid arthritis therapy].

    Science.gov (United States)

    Nemec, P

    2007-11-01

    Rheumatoid arthritis (RA) is a serious, chronic, inflammatory disorder that damages the joints. The chronic destructive process causes pain to patients with RA and leads to the development of permanent disability. At present, great emphasis is placed on timely and effective therapy for RA, which is able to halt or slow the development of the disorder. At present we do not have any means of curing RA, the main objective for treatment is to induce remission of the disorder and prevent structural damage to the joints and the development of permanent disability. The relatively frequent failure of disease modifying medications (DMARDs) lead to efforts to find new resources for the treatment of RA. So called biological medicines were recently introduced into therapeutic use. These were mainly TNFalpha blockers. Experience has shown that approximately a third of patients with RA do not respond even to treatment with such medicines. Rituximab (MabThera), a monoclonal antibody against CD20 positive B-lymphocytes, is a new biological medicine approved for RA therapy. It represents a new hope for patients with active RA, for whom earlier therapy with TNFa blockers has failed. PMID:18277630

  8. Acute antibody-mediated rejection after ABO-incompatible kidney transplantation treated successfully with antigen-specific immunoadsorption

    DEFF Research Database (Denmark)

    Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik; Koefoed-Nielsen, Pernille; Bistrup, Claus

    2010-01-01

    ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated reje...... that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime.......ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody......-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest...

  9. Acute antibody-mediated rejection after AB0-incomptible kidney transplantation treated successfully with antigen-specific immunoadsorption

    DEFF Research Database (Denmark)

    Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik; Kofoed-Nielsen, Pernille Bundgaard; Bistrup, Claus

    2009-01-01

    ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated reje...... that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime.......ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody......-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest...

  10. SpeB proteolysis with imaged capillary isoelectric focusing for the characterization of domain-specific charge heterogeneities of reference and biosimilar Rituximab.

    Science.gov (United States)

    Zhang, Zichuan; Perrault, Ronel; Zhao, Yun; Ding, Julia

    2016-05-01

    The charge variations of therapeutic monoclonal antibody reveal important information of the post-translational modifications that may potentially impact the potency and safety of pharmaceutical products, especially during the evaluation of biosimilarity of therapeutic proteins. In this work, a novel SpeB-based proteolysis strategy coupling with imaged capillary isoelectric focusing was developed for the determination of domain-specific charge heterogeneities of innovator and generic Rituximab drug products from United States, European and Indian markets. It was observed that innovator Rituximab from the United States and Europe share highly similar peak distributions and charge heterogeneities with 26.2-26.6% Fc/2, 28.9-29.3% LC and 44.4-44.5% Fd peak areas detected, respectively, while multiple basic variations of Fc/2 and less acidic LC and Fd species were found from generic Rituximab from India with 20.9% Fc/2, 32.3% LC and 46.9% Fd peak areas detected. It was also demonstrated that structural changes caused by Carboxypeptidase B treatment and deamidation study at pH extremes could be sensitively captured with the established method, with the results further indicating that the generic product's basic variations of Fc/2 were un-cleaved Lysine residues, while the lack of certain acidic peaks on LC and Fd probably was due to the lower level of deamidation. This new strategy could become a useful tool to reveal domain-specific charge heterogeneities profiles of a variety of therapeutic monoclonal antibodies in regulated environments. PMID:27038651

  11. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    International Nuclear Information System (INIS)

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy

  12. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Michio [Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867 (Japan); Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina, E-mail: jbaranow@unmc.edu [Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

    2011-05-25

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.

  13. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    OpenAIRE

    Elizabeth Mack; Michio Abe; Zbigniew P. Kortylewicz; Enke, Charles A.; Janina Baranowska-Kortylewicz

    2011-01-01

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of ...

  14. PET/CT Imaging and Radioimmunotherapy of Prostate Cancer

    DEFF Research Database (Denmark)

    Bouchelouche, Kirsten; Tagawa, Scott T; Goldsmith, Stanley J;

    2011-01-01

    disease (ideal for antigen access and antibody delivery). Furthermore, prostate cancer is also radiation sensitive. Prostate-specific membrane antigen is expressed by virtually all prostate cancers, and represents an attractive target for RIT. Antiprostate-specific membrane antigen RIT demonstrates...

  15. Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome. Conceptual chances

    International Nuclear Information System (INIS)

    The prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term disease-free survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myelblative conditioning before SCT. This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand. (orig.)

  16. Pharmacokinetics of Yttrium-90-labeled epratuzumab in the consolidation radioimmunotherapy of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Full text of publication follows. Aim: Yttrium-90-labeled epratuzumab has been studied in the consolidation radioimmunotherapy of non-Hodgkin's lymphoma. The pharmacokinetics of the labeled antibody was monitored to assess the variability of its biodistribution and elimination. Materials and methods: 75 elderly patients with diffuse large B-cell lymphoma were accrued in a phase II clinical trial sponsored by the French LYSA group, assessing 6 cycles of R-CHOP14 followed 8 weeks later by 2 infusions of Yttrium-90-labeled epratuzumab tetraxetan (555 MBq/m2), 7 days apart. Blood samples were collected at selected time intervals after the first injection and counted. The kinetics of the antibody was assessed by correction for radioactive decay assuming that catabolism products are eliminated faster than the intact molecule. Then a two-compartment pharmacokinetic model was used to simulate the blood kinetics using a population kinetics approach. The kinetics of the circulating Yttrium-90 activity was also studied using the same approach to estimate the total number of disintegration in blood and finally the absorbed dose in blood. Results: The epratuzumab blood kinetics could be studied in 43 of the 75 accrued patients. They were well-fitted by a two compartment model but were found quite variable from one patient to another. For example the population blood clearance was estimated at 11.5 ± 5.5 ml/hr, but varied from 0.6 to 25.0 ml/hr with a 33% CV within the population. Part of the variability was due to later time points and the variability of the activity kinetics was more limited (25 % CV). The total number of disintegration in blood thus varied from 3.9 to 11.2 x 1010 disintegrations corresponding to a blood absorbed dose of 4.5 to 12.8 Gy and to a blood-derived bone marrow absorbed dose of 1.3 to 3.8 Gy. These values did not correlate with observed hematological toxicities. Conclusion: blood pharmacokinetics was found quite variable from one patient to

  17. Studies on the optimization of leukemia and non-Hodgkin lymphoma therapies using opioids, chemotherapy and radioimmunotherapy

    International Nuclear Information System (INIS)

    Despite complex treatment schedules for cancer, the occurrence of resistances and relapses is a major concern in oncology. Hence, novel treatment options are needed. In this thesis, different approaches using radioimmunotherapy and the opioid D,L-methadone alone or in combination with doxorubicin were analyzed regarding their cytotoxic potential and the triggered signalling pathways in sensitive and resistant leukaemia and non-Hodgkin lymphoma (NHL). The radioimmunoconjugates [Bi-213]anti-CD33 and [Bi-213]anti-CD20 for treatment of acute myeloid leukaemia (AML) or NHL, respectively, were applied exemplary for the use of targeted alpha-therapies (TAT). Depending on the analyzed cell lines, the used activity concentrations and specific activities (MBq/μg antibody) apoptosis was induced abrogating radio- and chemo-cross-resistances specifically. The cell death was caspase-dependent activating the mitochondrial pathway and was executed by downregulation of the anti-apoptotic proteins XIAP and Bcl-xL. D,L-Methadone induces apoptosis in vitro and in vivo in opioid-receptor (OR) expressing cells depending on the OR density and the used concentrations. Resistances could be overcome and proliferation was inhibited. In combination with doxorubicin, a synergistic effect regarding cytotoxicity in ex vivo patient cells and cell lines was observed. This effect depends on the increase of doxorubicin uptake co-administering D,L-methadone whereas doxorubicin enhances OR expression. The activation of OR leads to the downregulation of cAMP playing a pivotal role in apoptosis induction. In vivo, the therapeutic potential of D,L-methadone alone or in combination with doxorubicin could be proven as mice transplanted with human T-ALL-cells could be identified as tumour free. In summary, these studies show that TAT using [Bi-213]anti-CD33 and [Bi-213]anti-CD20 as well as the opioid D,L-methadone harbour the potential to optimize conventional treatment modalities for leukaemia and NHL.

  18. Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide

    Energy Technology Data Exchange (ETDEWEB)

    Frampas, Eric; Maurel, Catherine; Remaud-Le Saec, Patricia; Mauxion, Thibault; Faivre-Chauvet, Alain; Davodeau, Francois; Bardies, Manuel; Barbet, Jacques [Universite de Nantes, Inserm, UMR 892, Centre de Recherche en Cancerologie Nantes-Angers (CRCNA), Nantes (France); Goldenberg, David M. [Immunomedics, Inc., Morris Plains, NJ (United States); Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, NJ (United States)

    2011-12-15

    We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses. LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for {sup 131}I, {sup 177}Lu, {sup 90}Y, {sup 211}At, and {sup 213}Bi using realistic specific activities. Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached {proportional_to}9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), {sup 211}At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. {sup 90}Y and {sup 213}Bi would also deliver high absorbed doses to tumor (18.6 for {sup 90}Y and 26.5 Gy for {sup 213}Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity. Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially {sup 211}At, with kidneys being the dose-limiting organ. {sup 177}Lu and {sup 131}I should be considered for repeated injections. (orig.)

  19. Human-Mouse Dosimetry in Clinical Radioimmunotherapy - Special Emphasis on Pediatric Applications

    International Nuclear Information System (INIS)

    Monoclonal antibody ('MAB') has been developed for targeting secretory alpha-fetoprotein in hepatic tissue. We have used these MABs for radioimmunotherapy and dose planning of recurrent hepatoblastoma, a rare childhood malignancy This MAB has been labelled with In- 111 and Y-90 for clinical purposes, and can be applied for diagnosis and therapy of liver neoplasms. Physiology based pharmacokinetic (PBPK) modeling and simulation is a useful method for prediction of biodistribution of macromolecules, it can enhance our understanding of the underlying mechanisms and hence may help in rational design of diagnostic and therapeutic agents. Here we also discuss PBPK modeling and simulation of this MAB in mice without tumor and in a pediatric patient. In the clinical study, radiopharmacokinetic parameters for this MAB (111In-DOTA-hAFP31 IgG) were calculated after serial quantitative whole body scans in a child with hepatoblastoma. A 3-D dose planning computer program was used to calculate tumor doses for In-111 and Y-90, the active tumor was delineated on PET/CT images and tumor dose calculation was done based on the In-111-MAB SPECT data using dose point kernel approach both for In-111 and Y-90. The results were compared with MIRD doses obtained for organs in SPECT imaging field, i.e. bone marrow, heart, kidneys, liver, spleen, lungs. The simulated results were fitted to experimental time series data by varying parameters which were not fixed a priori. From quantitative serial imaging based on 8 whole body images at 0-168 hrs using In-111- MAB, the half-lives of spleen, lungs, kidneys and whole body were 502 hrs, 230 hrs, 193 hrs and 490 hrs, respectively. The measured blood half-life was 132 hrs, after a total MAB dose of 50 mg and In-111 activity of 105 MBq. The presumed Y-90 dose based on this kinetic behavior was 43 MBq which should had given 0.3Gy bone marrow dose with assumption of bone marrow: blood ratio 0.4 for IgG. The calculated MIRD Y-90 doses were for cardiac

  20. A systematic review of the use of rituximab as induction therapy in renal transplantation.

    Science.gov (United States)

    Macklin, Philip S; Morris, Peter J; Knight, Simon R

    2015-04-01

    Rituximab is a B-lymphocyte depleting agent used to treat lymphoma and autoimmune diseases. There has been recent interest in its use both for management of highly-sensitised and ABO-incompatible recipients but also for induction therapy before transplantation. This systematic review evaluates the evidence for its use as part of induction protocols in ABO-compatible, non-sensitised recipients. 4 databases and 3 trial registries were searched for studies of the use of rituximab as part of induction protocols. The small number of identified studies precluded meta-analysis and thus a narrative review was conducted. 12 manuscripts met the inclusion criteria, relating to 5 individual studies. No significant improvements in patient and graft survival or acute rejection rates were identified with rituximab induction. A single small study reported a trend towards improved graft function with the addition of rituximab induction to a standard immunosuppressive regimen. Rituximab was not found to be associated with increased infectious complications in any study but concerns were raised over possible associations with leukopaenia and cardiovascular mortality. Overall, no convincing benefit of rituximab induction was found and some safety concerns were identified. The results of on-going trials are awaited but further studies may be required before we can draw firm conclusions regarding the efficacy and safety of rituximab in this setting. PMID:25555541

  1. Resolution of diarrhea in an immunocompromised patient with chronic norovirus gastroenteritis correlates with constitution of specific antibody blockade titer.

    Science.gov (United States)

    Knoll, Bettina M; Lindesmith, Lisa C; Yount, Boyd L; Baric, Ralph S; Marty, Francisco M

    2016-08-01

    Norovirus gastroenteritis in immunocompromised hosts can result in a serious and prolonged diarrheal illness. We present a case of chronic norovirus disease during rituximab-bendamustine chemotherapy for non-Hodgkin's lymphoma. We show for the first time a correlation between norovirus strain-specific antibody blockade titers and symptom improvement in an immunocompromised host. PMID:26825307

  2. Macroglobulinemia de Waldenström - remissão completa após tratamento com rituximabe Successful outcome in Waldenström's macroglobulinemia treated with rituximab

    Directory of Open Access Journals (Sweden)

    Flavia C. F. Pimenta

    2008-10-01

    blood. Waldenström's macroglobulinemia presents hypergammaglobulinemia with a monoclonal peak of serum proteins seen by electrophoresis, high IgM levels and other normal or diminished immunoglobulin levels, immunophenotyping with CD19+, CD20+ and CD24+ B lymphocytes aspirated from hypercellular bone marrow and hypercellular bone marrow biopsy with diffuse infiltration of lymphocytes, plasmocytoid lymphocytes and plasmocytes. Currently, monoclonal antibodies are successfully being used in the treatment of Waldenström's macroglobulinemia. Rituximab, an anti-CD20 monoclonal antibody, has shown excellent results in the treatment of Waldenström's macroglobulinemia even for individuals who did not obtain satisfactory responses to conventional treatment. This work reports the case of a 78-year-old woman with a history of fatigue, asthenia, anorexia, somnolence, restlessness, urticaria, difficulties in walking, and excessive weight loss (approximately 22 Kg within a period of 5 months who was successfully treated using rituximab. The objective of this report is to present the case of this patient and to review current clinical and therapeutic aspects of the disease.

  3. Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience.

    Science.gov (United States)

    Bourcier, J; Gastinne, T; Leux, C; Moreau, A; Bossard, C; Mahé, B; Blin, N; Dubruille, V; Touzeau, C; Voldoire, M; Guillaume, T; Peterlin, P; Gallas, P; Garnier, A; Maisonneuve, H; Moreau, P; Juge-Morineau, N; Jardel, H; Chevallier, P; Moreau, P; Le Gouill, S

    2016-08-01

    We retrospectively evaluated the role of rituximab (R) in maintenance treatment after autologous stem cell transplantation performed in patients with relapsed follicular lymphoma. We compared the outcome of 67 follicular lymphoma (FL) patients according to the use of rituximab maintenance (RM) or not. All patients received rituximab plus chemotherapy before autologous stem-cell transplantation (ASCT). Patients received median of two lines of prior therapy. The RM schedule was one injection of rituximab every 3 months for 2 years. Median follow-up is 4.6 years. The 3-year progression-free survival (PFS) after ASCT was 86 % with RM vs. 46 % without (p = 0.0045). Median is not reached in the RM arm vs. 31 months in non-RM arm. The 3-year OS was 96 % with RM vs. 78 % without (p = 0.059). The present monocentric study shows that 2 years of RM after ASCT significantly increases response duration for non-naive rituximab relapsed FL patients compared with observation. PMID:27297970

  4. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    Energy Technology Data Exchange (ETDEWEB)

    Frost, Sophia; Frayo, Shani; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Back, Tom; Fisher, Darrell R.; Press, Oliver W.

    2015-03-01

    Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.

  5. New Antibody Conjugates in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Serengulam V. Govindan

    2010-01-01

    Full Text Available Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions.

  6. Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Caroline eBodet-Milin

    2015-11-01

    Full Text Available Objectives. A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096 was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA to optimize bispecific antibody and labelled peptide doses, as well as the delay between their injections.Methods. Three cohorts of 3 patients received the anti-CEA x anti-histamine-succinyl-glycine (HSG humanized trivalent bispecific antibody (TF2 and the IMP288 bivalent HSG-peptide. Patients underwent a pre-therapeutic imaging session S1 (44 or 88 nmol/m2 of TF2 followed by 4.4 nmol/m2, 185 MBq, of 111In-labelled IMP288, and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m2 of TF2 followed by 24 nmol/m2, 1.1 GBq/m2, 177Lu-labeled IMP288. The pretargeting delay was 24 or 48 hours. The dose schedule was defined based on pre-clinical TF2 pharmacokinetic studies, on our previous clinical data using the previous anti-CEA pretargeting system and on clinical results observed in the first patients injected using the same system in the Netherlands.Results. TF2 pharmacokinetics (PK was represented by a two-compartment model in which the central compartment volume was linearly dependent on the patient's surface area. PK were remarkably similar, with a clearance of 0.33 +/- 0.03 L/h per m2. 111In- and 177Lu-IMP288 PK were also well represented by a two-compartment model. IMP288 PK were faster (clearance 1.4 to 3.3 l/h. The central compartment volume was proportional to body surface area and IMP288clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modelling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumour activity PK were variable. Organ absorbed doses were not significantly different in the 3 cohorts, but the tumour dose was significantly higher with the higher molar doses of TF2 (p < 0.002. S1 imaging predicted absorbed doses calculated in S2. Conclusion. The best

  7. Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer.

    Science.gov (United States)

    Phaeton, Rebecca; Jiang, Zewei; Revskaya, Ekaterina; Fisher, Darrell R; Goldberg, Gary L; Dadachova, Ekaterina

    2016-01-01

    Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer. PMID:26625938

  8. Radioimmunotherapy of micrometastases in lung with vascular targeted213Bi

    OpenAIRE

    Kennel, S. J.; Boll, R.; Stabin, M; Schuller, H M; Mirzadeh, S

    1999-01-01

    A model system has been used to test the efficacy of vascular targeting of α-particle emitter213Bi for therapy of small, ‘artificial’ metastases in mouse lung. Specific monoclonal antibody (mAb) 201B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of t...

  9. Clinical responses to rituximab in a case of neuroblastoma with refractory opsoclonus myoclonus ataxia syndrome.

    Science.gov (United States)

    Alavi, Samin; Kord Valeshabad, Ali; Moradveisi, Borhan; Aminasnafi, Ali; Arzanian, Mohammad Taghi

    2012-01-01

    Opsoclonus myoclonus ataxia syndrome (OMS) is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient was a 3.5-year-old girl referred for ataxia and dancing eye movements starting since 1.5 years ago. She was diagnosed with neuroblastoma on imaging studies on admission. The OMS was refractory to surgical resection, chemotherapy, corticosteroids, and intravenous immunoglobulin. Patient received rituximab simultaneously with chemotherapy. The total severity score decreased by 61.1% after rituximab. Patient's ataxia markedly improved that she was able to walk independently after 6 months. Our case confirmed the clinical efficacy and safety of rituximab in a refractory case of OMS. PMID:23198199

  10. Clinical Responses to Rituximab in a Case of Neuroblastoma with Refractory Opsoclonus Myoclonus Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Samin Alavi

    2012-01-01

    Full Text Available Opsoclonus myoclonus ataxia syndrome (OMS is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient was a 3.5-year-old girl referred for ataxia and dancing eye movements starting since 1.5 years ago. She was diagnosed with neuroblastoma on imaging studies on admission. The OMS was refractory to surgical resection, chemotherapy, corticosteroids, and intravenous immunoglobulin. Patient received rituximab simultaneously with chemotherapy. The total severity score decreased by 61.1% after rituximab. Patient's ataxia markedly improved that she was able to walk independently after 6 months. Our case confirmed the clinical efficacy and safety of rituximab in a refractory case of OMS.

  11. Expression and biological characterization of an anti-CD20 biosimilar candidate antibody: a case study.

    Science.gov (United States)

    Dorvignit, Denise; Palacios, Julio L; Merino, Maylin; Hernández, Tays; Sosa, Katya; Casaco, Angel; López-Requena, Alejandro; Mateo de Acosta, Cristina

    2012-01-01

    The CD20 molecule is a non-glycosylated protein expressed mainly on the surface of B lymphocytes. In some pathogenic B cells, it shows an increased expression, thus becoming an attractive target for diagnosis and therapy. Rituximab is a chimeric antibody that specifically recognizes the human CD20 molecule. This antibody is indicated for the treatment of non-Hodgkin lymphomas and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In this work, we describe the stable expression and biological evaluation of an anti-CD20 biosimilar antibody. While rituximab is produced in fed-batch culture of recombinant Chinese hamster ovary (CHO) cells, our biosimilar antibody expression process consists of continuous culture of recombinant murine NS0 myeloma cells. The ability of the purified biosimilar antibody to recognize the CD20 molecule on human tumor cell lines, as well as on peripheral blood mononuclear cells from humans and primates, was demonstrated by flow cytometry. The biosimilar antibody induced complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and apoptosis on human cell lines with high expression of CD20. In addition, this antibody depleted CD20-positive B lymphocytes from peripheral blood in monkeys. These results indicate that the biological properties of the biosimilar antibody compare favorably with those of the innovator product, and that it should be evaluated in future clinical trials. PMID:22647435

  12. Expression and biological characterization of an anti-CD20 biosimilar candidate antibody

    Science.gov (United States)

    Dorvignit, Denise; Palacios, Julio L.; Merino, Maylin; Hernández, Tays; Sosa, Katya; Casacó, Angel; López-Requena, Alejandro; Mateo de Acosta, Cristina

    2012-01-01

    The CD20 molecule is a non-glycosylated protein expressed mainly on the surface of B lymphocytes. In some pathogenic B cells, it shows an increased expression, thus becoming an attractive target for diagnosis and therapy. Rituximab is a chimeric antibody that specifically recognizes the human CD20 molecule. This antibody is indicated for the treatment of non-Hodgkin lymphomas and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In this work, we describe the stable expression and biological evaluation of an anti-CD20 biosimilar antibody. While rituximab is produced in fed-batch culture of recombinant Chinese hamster ovary (CHO) cells, our biosimilar antibody expression process consists of continuous culture of recombinant murine NS0 myeloma cells. The ability of the purified biosimilar antibody to recognize the CD20 molecule on human tumor cell lines, as well as on peripheral blood mononuclear cells from humans and primates, was demonstrated by flow cytometry. The biosimilar antibody induced complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and apoptosis on human cell lines with high expression of CD20. In addition, this antibody depleted CD20-positive B lymphocytes from peripheral blood in monkeys. These results indicate that the biological properties of the biosimilar antibody compare favorably with those of the innovator product, and that it should be evaluated in future clinical trials. PMID:22647435

  13. USE OF RITUXIMAB IN AUTOIMMUNE DISEASES: NEW ASPECTS

    Directory of Open Access Journals (Sweden)

    Dmitry Evgenyevich Karateyev

    2010-09-01

    Full Text Available It has been noted that off-label indication for Rituximab (RTX in rheumatological care indubitably requires its confirmation in the randomized clinical trials. A particular cautious approach should be taken in extending the indications for therapy with gene-engineering biologicals because of the intricacy and interaction of different immunoregulatory mechanisms. Nonetheless, it is stated that much clinical experience with RTX used in most severely ill therapy-resistant patients may serve as a basis for its prescription in a number of most complex inflammatory rheumatic diseases (RDs. There is new evidence for the use of RTX in various RDs differing in their clinical picture, course, and pathogenesis, such as spondyloarthritis, systemic lupus erythematosus, systemic vasculitis.

  14. USE OF RITUXIMAB IN AUTOIMMUNE DISEASES: NEW ASPECTS

    Directory of Open Access Journals (Sweden)

    Dmitry Evgenyevich Karateyev

    2010-01-01

    Full Text Available It has been noted that off-label indication for Rituximab (RTX in rheumatological care indubitably requires its confirmation in the randomized clinical trials. A particular cautious approach should be taken in extending the indications for therapy with gene-engineering biologicals because of the intricacy and interaction of different immunoregulatory mechanisms. Nonetheless, it is stated that much clinical experience with RTX used in most severely ill therapy-resistant patients may serve as a basis for its prescription in a number of most complex inflammatory rheumatic diseases (RDs. There is new evidence for the use of RTX in various RDs differing in their clinical picture, course, and pathogenesis, such as spondyloarthritis, systemic lupus erythematosus, systemic vasculitis.

  15. Rituximab is Indispensable for Pediatric Heart Transplant Recipients Developing Post Transplant Lymphoproliferative Disorders

    OpenAIRE

    Taheri S MD; Karbasi-Afshar R MD

    2013-01-01

    Abstract Rituximab, an anti-CD20 agent, has been suggested as an effective strategy to deal with post transplant lymphoproliferative disorders (PTLD). In the current study, we aim to evaluate the efficacy of rituximab therapy in heart transplant population developing PTLD. A comprehensive search of the literature was performed to gather the available data on lymphoproliferative disorders occurring in heart transplant patients. Finally, data of 125 patients from 26 previously published studies...

  16. Retrospective analysis of rituximab therapy and splenectomy in childhood chronic and refractory immune thrombocytopenic purpura.

    Science.gov (United States)

    Ay, Yilmaz; Karapinar, Tuba H; Oymak, Yesim; Toret, Ersin; Demirag, Bengu; Ince, Dilek; Ozcan, Esin; Moueminoglou, Nergial; Koker, Sultan A; Vergin, Canan

    2016-06-01

    Immune thrombocytopenic purpura (ITP) results from accelerated platelet destruction mediated by autoantibodies to platelet glycoproteins. Some patients with chronic ITP are refractory to all therapies [steroids, intravenous immunoglobulin (IVIG), anti-D and immunosuppresive drugs] and have chronic low platelet counts and episodic bleeding. We retrospectively evaluated the efficacy and safety of rituximab treatment and splenectomy in paediatric patients diagnosed with chronic and refractory ITP who were unresponsive to steroids, IVIG, cyclosporine and mycophenolate mofetil. Records of patients with chronic and refractory ITP in 459 patients with primary ITP who were followed up in our hospital from January 2005 to December 2014 were reviewed. Fifteen of patients received rituximab and/or applied splenectomy. Fifteen chronic ITP patients (10 boys, five girls) with a mean age of 10 years were enrolled in the study. Two of these patients were suffering from Evans syndrome. The median time since diagnosis of ITP was 10 years. The median follow-up duration after starting Rituximab and splenectomy were 13 and 9.5 months, respectively.None of the seven patients who were treated with rituximab achieved a response. A splenectomy was performed in six of the seven patients who had been treated with rituximab. Complete and partial responses were achieved in 67 and 33% of the patients, respectively. We evaluated the clinical characteristics and responses of chronic ITP patients who did not receive rituximab therapy and underwent a splenectomy. The success rate was 100% in the eight patients with chronic and refractory ITP. Rituximab therapy might not be beneficial for some children with severe chronic ITP who are refractory to standard agents. A splenectomy might be useful and preferable to rituximab. PMID:26656905

  17. Novel CD20 monoclonal antibodies for lymphoma therapy

    Directory of Open Access Journals (Sweden)

    Cang Shundong

    2012-10-01

    Full Text Available Abstract Rituximab (RTX, a monoclonal antibody (mAb against CD20, has been widely used for lymphoma therapy. RTX in combination with cyclophosphamide /doxorubicin /vincristine /prednisone (R-CHOP remains the standard frontline regimen for diffuse large B-cell lymphoma. However, suboptimal response and /or resistance to rituximab have remained a challenge in the therapy of B-cell non-Hodgkin’s lymphoma (NHL. Novel agents are under active clinical trials. This review will summarize the latest development in new mAbs against CD20, which include second-generation mAbs, ofatumumab, veltuzumab (IMMU-106, ocrelizumab (PRO70769, and third-generation mAbs, AME-133v (ocaratuzumab, PRO131921 and GA101 (obinutumumab.

  18. Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

    Science.gov (United States)

    Delfau-Larue, Marie-Hélène; de Leval, Laurence; Joly, Bertrand; Plonquet, Anne; Challine, Dominique; Parrens, Marie; Delmer, Alain; Salles, Gilles; Morschhauser, Franck; Delarue, Richard; Brice, Pauline; Bouabdallah, Reda; Casasnovas, Olivier; Tilly, Hervé; Gaulard, Philippe; Haioun, Corinne

    2012-01-01

    Background In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20+ large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. Design and Methods Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. Results A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06). Conclusions We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20+ B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted. PMID:22371178

  19. 联合利妥昔单抗的人源化抗程序性死亡分子1单抗治疗复发滤泡性淋巴瘤的Ⅱ期临床试验:第54届美国血液学会年会深度报道%Phase Ⅱ clinical trail of patients with relapsed follicular lymphoma treated with a humanized anti-programmed death-1 monoclonal antibody combined with rituximab:report in the 54th ASH annual meeting

    Institute of Scientific and Technical Information of China (English)

    褚福亮; Neelapu SS; 杨林; Westin JR; 张明; 靖彧; 李亚芬; 汤金乐; 宗云辉; 刘彬; Davis RE

    2013-01-01

    Objective A phase Ⅱ trial of anti-programmed death-1 (PD-1) monoclonal antibody CT-011,an anti PD-1 humanized monoclonal antibody combined with rituximab therapy in patients with relapsed follicular lymphoma (FL) were conducted.Methods In order to evaluate the safety and efficacy of CT-011,the impacts of CT-011 on immune cells both from the peripheral blood (PB) samples and tumor microenvironment were examined.PB and core needle biopsies from involved lymph nodes were collected prior to and on day 14 after the first infusion of CT-011.PB mononuclear cells (PBMC) were analyzed by multiparametric flow cytometry to determine various immune cell subsets.Whole genome gene expression profiling (GEP) was performed on core needle biopsies.Results A significant increase in the absolute number of PB immune cells were observed in day 14 samples compared with baseline including total lymphocyte count (P < 0.01),CD+3 T cells (P =0.01),CD+4 T cells (P < 0.01).Comparison of GEP from core needle biopsies obtained pretreatment and day 14 (n =8 pairs) showed up regulation of several genes associated with T cell activation.Conclusion Administration of CT-011 was associated with increase in the numbers of CD+4 T cells and resulted in activation of T cells in the PB and the tumor microenvironment in FL.These results provide insight into the mechanism of action of CT-011 and offer a predictive biomarker for selection of patients for future clinical trials with this class of agents in FL.%目的 对进行的人源化抗人程序性死亡分子1 (PD-1)单克隆抗体CT-011合并利妥昔单抗治疗复发性滤泡性淋巴瘤的Ⅱ期临床试验中,CT-011的安全性和效果进行评价.方法 采集治疗前和注射CT-011第14天的30例患者外周血和恶性淋巴结活检标本,通过多参数流式细胞术分析外周血单个核细胞各个免疫细胞亚群的比例,使用QiagenRNeasy试剂盒从活检组织中抽提RNA,使用Illumina HumanRef-8基因芯片分析活检

  20. Linfoma hepático primario: Evolución favorable con quimioterapia combinada con rituximab Primary hepatic lymphoma: favorable outcome with chemotherapy plus rituximab

    Directory of Open Access Journals (Sweden)

    I. Serrano-Navarro

    2008-11-01

    Full Text Available Comunicamos el caso de una paciente con un linfoma hepático primario tratado con éxito con quimioterapia combinada con rituximab. Utilizando los "encabezamientos estándar para búsquedas bibliográficas informatizadas" (Medical Subject Heading revisamos los casos publicados hasta la fecha de esta infrecuente entidad.This article describes the case of a patient with a non-Hodgkin primary hepatic lymphoma who was successfully treated with chemotherapy combined with rituximab. Using the Medical Subject Headings the published reports of this rare entity were reviewed.

  1. Image correlation: meaning in clinical radioimmunotherapy dosimetry for treatment planning

    International Nuclear Information System (INIS)

    Image correlation has many potential applications in Nuclear Medicine: the combination of the high resolution anatomical delineation of structures as achievable with MRI/CT and the less spatially resolved but functional biochemical images from SPECT, benefits both modalities and is successful in clinical applications. In particular this is fundamental to obtain 1) the volume determination of tumours and normal organs and 2) the quantitation of the activity of radiolabelled antibodies in tumours and normal organs, necessary for the development of treatment strategies. Clinical reports of treatment planning in cerebral gliomas are showed in this paper: the modalities used are CT and SPECT with DTPA. The last has the property of showing the contour of the skull allowing an easier correlation by comparing it to the one that is even more visible by CT. This suggests to use anatomic markers or even surface fitting (Pellizzari algorithm)

  2. Proliferation and the advantage of longer-lived radionuclides in radioimmunotherapy

    OpenAIRE

    Howell, Roger W.; Goddu, S. Murty; Rao, Dandamudi V.

    1998-01-01

    In our previous study we used the linear-quadratic model [J. Nucl. Med. 35, 1861 (1994)] to confirm our initial finding, based on the time-dose-fractionation model [J. Nucl. Med. 34, 1801 (1993)], that longer-lived radionuclides (e.g., 32P, 91Y) can offer a substantial therapeutic advantage over the shorter-lived radionuclides presently used in radioimmunotherapy (e.g., 90Y). The original calculations using the linear-quadratic (LQ) model did not account for proliferation of the tumor and cri...

  3. Antibody-mediated rejection after ABO-incompatible pediatric living donor liver transplantation for propionic acidemia: A case report.

    Science.gov (United States)

    Honda, Masaki; Sakamoto, Seisuke; Sakamoto, Rieko; Matsumoto, Shirou; Irie, Tomoaki; Uchida, Koushi; Shimata, Keita; Kawabata, Seiichi; Isono, Kaori; Hayashida, Shintaro; Yamamoto, Hidekazu; Endo, Fumio; Inomata, Yukihiro

    2016-09-01

    We herein present the case of a four-yr-old boy with PA who developed AMR after ABO-incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO-incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor-type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re-administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO-incompatible LDLT if B cell reactivation is suspected. PMID:27436684

  4. Development of 177Lu-DOTA-anti-CD20 for radioimmunotherapy

    International Nuclear Information System (INIS)

    Rituximab was successively labeled with 177Lu-lutetium chloride. 177Lu chloride was obtained by thermal neutron flux (4 x 1013 n cm-2 s-1) of natural Lu2O3 sample with a specific activity of 2.6-3 GBq/mg. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 deg C using DOTA, N-hydroxy succinimide (NHS) in CH2Cl2. DOTA-rituximab was obtained by the addition of 1 mL of a rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH 7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 deg C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 deg C in 24 h. Radio-thin layer chromatography showed an overall radiochemical purity of >98% at optimized conditions (specific activity = 444 MBq/mg, labeling efficacy; 82%). The final isotonic 177Lu-DOTA-rituximab complex was checked by gel electrophoresis for structure integrity control. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rats were carried out to determine complex distribution of the radioimmunoconjugate up to 168 h. The biodistribution data were in accordance with other antiCD20 radioimmunoconjugates already reported. (author)

  5. In vivo modulators of antibody kinetics

    International Nuclear Information System (INIS)

    The aim of the present study was to summarize the effect of in vivo modulation of antibody kinetics and to present new data on the in vivo effect of the cell membrane active detergent Tween 80 and the cytokine interleukin-2 (IL-2) on the accumulation and clearance of a radioactive antibody. Mice bearing Lewis lung carcinoma xenografts and rats bearing DMBA-induced mammary carcinomas were studied after injecting I-125 labeled IgG1 monoclonal antibody (3c4c7g6) raised against a tyrosine kinase receptor protein Tie. Expression of Tie is known to be abundant in vascular endothelia and possibly related to malignant angiogenesis. Tween 80 was administered intratumorally (0.04% of tumor volume), whereas IL-2 was administered intraperitoneally. In the Lewis lung tumor model, the absolute tumor uptake varied between 2 and 5% ID/g, and maximum uptake was achieved after 24 h with Tween, and after 48 h without Tween. Tween manipulation did not increase the uptake in any normal organ, but it enhanced antibody clearance form the blood. In the DMBA rat model, IL-2 had no effect on blood clearance, but enhanced the uptake of Tie antibody into the tumor from 2.5-0.9 to 4.5-0.4% ID/g at 48 h. These data indicate that antibody biodistribution and pharmacokinetics can be modulated by a surface detergent and a cytokine, giving decreased exposure to critical organs, and increased uptake into the tumor. This type of manipulation provides an opportunity to optimize radioimmunotherapy. (orig.)

  6. Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial

    OpenAIRE

    Cutler, Corey; Kim, Haesook T.; Bindra, Bhavjot; Sarantopoulos, Stefanie; Ho, Vincent T.; Chen, Yi-Bin; Rosenblatt, Jacalyn; McDonough, Sean; Watanaboonyongcharoen, Phandee; Armand, Philippe; Koreth, John; Glotzbecker, Brett; Alyea, Edwin; Blazar, Bruce R; Soiffer, Robert J.

    2013-01-01

    Rituximab prevents steroid-requiring chronic graft-vs-host disease when given after peripheral blood stem cell transplantation.Overall survival is improved with rituximab after allogeneic peripheral blood stem cell transplantation when compared with a control cohort.

  7. Radioimmunotherapy for non-Hodgkin's lymphoma: A review for radiation oncologists

    International Nuclear Information System (INIS)

    Purpose: The aim of this study was to review advances in radioimmunotherapy (RIT) for non-Hodgkin's lymphoma (NHL) and to discuss the role of Radiation oncologist in administering this important new form of biologically targeted radiotherapy. Methods and Materials: A review of articles and abstracts on the clinical efficacy, safety, and radiation safety of yttrium Y 90 (9Y) ibritumomab tiuxetan (Zevalin) and iodine I 131 tositumomab (Bexxar) was performed. Results: The clinical efficacy of RIT in NHL has been shown in numerous clinical trials of 9Y ibritumomab tiuxetan and 131I tositumomab. Both agents have produced significant responses in patients with low-grade, follicular, or transformed NHL, including patients with disease that had not responded or had responded poorly to previous chemotherapy or immunotherapy. Reversible toxicities such as neutropenia, thrombocytopenia, and anemia are the most common adverse events with both agents. Conclusions: Radioimmunotherapy is safe and effective in many patients with B-cell NHL. 9Y ibritumomab tiuxetan and 131I tositumomab can produce clinically meaningful and durable responses even in patients in whom chemotherapy has failed. Treatment with RIT requires a multispecialty approach and close communication between Radiation oncologist and other members of the treatment team. Radiation oncologist plays an important role in treating patients with RIT and monitoring them for responses and adverse events after treatment

  8. Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation; Myeloablative Radioimmuntherapien zur Konditionierung bei Patienten mit AML, MDS und multiplem Myelom vor Stammzelltransplantation

    Energy Technology Data Exchange (ETDEWEB)

    Buchmann, I. [Abt. fuer Nuklearmedizin, Universitaetsklinik Heidelberg (Germany)

    2008-06-15

    Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. {sup 90}Y, {sup 188}Re and {sup 131}I are the most frequently used {beta}{sup -}-particles. Of these, {sup 90}Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate {sup 90}Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The {sup 90}Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow < 25%. The specific doses (Gy/GBq) are 10.2 {+-} 1.8 (bone marrow), 2.7 {+-} 2 (liver) and < 1 (kidneys). In contrast, radiolabeled anti-CD33- and anti-CD45-antibodies bind to both, most of white blood cells and

  9. Single-dose anti-CD138 radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment of multiple myeloma in a preclinical model

    Directory of Open Access Journals (Sweden)

    Nolwenn eFichou

    2015-11-01

    Full Text Available Objectives: Radioimmunotherapy (RIT has emerged as a potential treatment option for multiple myeloma (MM. In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to 213Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with 213Bi for α-RIT or 177Lu for β-RIT.Methods: A new monoclonal anti-CD138 antibody, 9E7.4, was generated by immunizing a rat with a murine CD138-derived peptide. Antibody specificity was validated by flow cytometry, biodistribution and α-RIT studies. Then, a β-RIT dose-escalation assay with the 177Lu-radiolabeled 9E7.4 mAb was performed in KalwRij C57/BL6 mice 10 days after i.v. engraftment with 5T33 MM cells. Animal survival and toxicological parameters were assessed to define the optimal activity.Results: α-RIT performed with 3.7 MBq of 213Bi-labeled 9E7.4 anti-CD138 mAb increased median survival to 80 days compared to 37 days for the untreated control and effected cure in 45% of animals. β-RIT performed with 18.5 MBq of 177Lu-labeled 9E7.4 mAb was well tolerated and significantly increased mouse survival (54 versus 37 days in the control group; however, no mice were cured with this treatment.Conclusion: This study revealed the advantages of α-RIT in the treatment of MM in a preclinical model where β-RIT shows almost no efficacy.

  10. Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Schoffelen, Rafke; Woliner-van der Weg, Wietske; Visser, Eric P.; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Medical Center, Department of Radiology and Nuclear Medicine, PO Box 9101, Nijmegen (Netherlands); Goldenberg, David M. [Garden State Cancer Center, Morris Plains, NJ (United States); Immunomedics, Inc., Morris Plains, NJ (United States); IBC Pharmaceuticals, Inc., Morris Plains, NJ (United States); Sharkey, Robert M.; McBride, William J.; Chang, Chien-Hsing [Immunomedics, Inc., Morris Plains, NJ (United States); Rossi, Edmund A. [IBC Pharmaceuticals, Inc., Morris Plains, NJ (United States); Graaf, Winette T.A. van der [Radboud University Medical Center, Department of Medical Oncology, Nijmegen (Netherlands)

    2014-08-15

    Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies (bsMAb) and a radiolabeled peptide reduces the radiation dose to normal tissues. Here we report the accuracy of an {sup 111}In-labeled pretherapy test dose for personalized dosing of {sup 177}Lu-labeled IMP288 following pretargeting with the anti-CEA x anti-hapten bsMAb, TF2, in patients with metastatic colorectal cancer (CRC). In 20 patients bone marrow absorbed doses (BMD) and doses to the kidneys were predicted based on blood samples and scintigrams acquired after {sup 111}In-IMP288 injection for individualized dosing of PRIT with {sup 177}Lu-IMP288. Different dose schedules were studied, varying the interval between the bsMAb and peptide administration (5 days vs. 1 day), increasing the bsMAb dose (75 mg vs. 150 mg), and lowering the peptide dose (100 μg vs. 25 μg). TF2 and {sup 111}In/{sup 177}Lu-IMP288 clearance was highly variable. A strong correlation was observed between peptide residence times and individual TF2 blood concentrations at the time of peptide injection (Spearman's ρ = 0.94, P < 0.0001). PRIT with 7.4 GBq {sup 177}Lu-IMP288 resulted in low radiation doses to normal tissues (BMD <0.5 Gy, kidney dose <3 Gy). Predicted {sup 177}Lu-IMP288 BMD were in good agreement with the actual measured doses (mean ± SD difference -0.0026 ± 0.028 mGy/MBq). Hematological toxicity was mild in most patients, with only two (10 %) having grade 3-4 thrombocytopenia. A correlation was found between platelet toxicity and BMD (Spearman's ρ = 0.58, P = 0.008). No nonhematological toxicity was observed. These results show that individual high activity doses in PRIT in patients with CEA-expressing CRC could be safely administered by predicting the radiation dose to red marrow and kidneys, based on dosimetric analysis of a test dose of TF2 and {sup 111}In-IMP288. (orig.)

  11. Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10. Therapeutic efficacy largely depends on radiosensitivity

    International Nuclear Information System (INIS)

    Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 (90Y)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of 90Y-MAb 92-13. FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with 90Y-MAb 92-13 in vitro. Biodistribution study of indium-111 (111In)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with 90Y-MAb 92-13 (100, 150, and 200 μCi), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor. Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of 111In-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0±4.2 and 22.0±4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with 90Y-MAb 92-13 (tumor volume decreased to less than 0.1 cm3 at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with 90Y-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor. The therapeutic efficacy of radioimmunotherapy (RIT) seems to largely depend on the tumor radiosensitivity. (author)

  12. Y-90-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Griffiths, Gary L.(Immunomedics, Inc.); Govindan, Serengulam V.(Immunomedics, Inc.); Sharkey, Robert M.(Immunomedics, Inc.); Fisher, Darrell R.(BATTELLE (PACIFIC NW LAB)); Goldenberg, David M.(Immunomedics, Inc.)

    2003-01-01

    The goal of this work was to determine an optimal radioimmunotherapy agent for non-Hodgkin's lymphoma. We established the stability profile of yttrium-90-labeled humanized LL2 (hLL2) monoclonal antibody prepared with different chelating agents, and from these data estimated the improvement using the most stable yttrium-90 chelate-hLL2 complex. Methods: The complementary-determining region- (cdr)-grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to derivatives of DTPA and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). The conjugates were labeled with Y-90 and tested against a 10,000-fold molar excess of free DTPA and against human serum. The conjugates were also labeled with Y-88 and compared for biodistribution in normal and lymphoma xenograft-bearing athymic mice. In vivo data were analyzed for uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and dosimetry calculations were made for each. Results: Y-90-DOTA -mAb were stable to either DTPA or serum challenge. DTPA complexes of hLL2 lost 3-4% of Y-90 (days 1-4) and 10-15% thereafter. In vivo, stability differences showed lower Y-90 uptake in bone using DOTA. Absorbed doses per 37 MBq (1 mCi) Y-90-mAb were 3555 and 5405 cGy for bone, and 2664 and 4524 cGy for washed-bone for 90Y-DOTA-hLL2 and 90Y-MxDTPA-hLL2, respectively, amounting to 52% and 69.8% increases in absorbed radiation doses for bone and washed-bone when switching from a DOTA to a Mx-DTPA chelate. Conclusion: Y-90-hLL2 prepared with the DOTA chelate represents a preferred agent for RAIT of non-Hodgkin's lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, as compared to yttrium-90-hLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this will result in a substantial toxicological advantage for a DOTA-based hLL2 conjugate.

  13. Antithyroid microsomal antibody

    Science.gov (United States)

    Thyroid antimicrosomal antibody; Antimicrosomal antibody; Microsomal antibody; Thyroid peroxidase antibody; TPOAb ... Granulomatous thyroiditis Hashimoto thyroiditis High levels of these antibodies have also been linked to an increased risk ...

  14. Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I-, and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts

    Directory of Open Access Journals (Sweden)

    S. Lucas

    2015-01-01

    Full Text Available Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like 131I or 90Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of 90Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as 90Y, 177Lu, 131I, 124I, and 188Re are used. Tumour control probability (TCP and normal tissue complication probability (NTCP curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC. 90Y and 188Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases.

  15. Successful Rituximab Therapy in Steroid-Resistant, Cryptogenic Organizing Pneumonia: A Case Series.

    Science.gov (United States)

    Shitenberg, Dorit; Fruchter, Oren; Fridel, Ludmila; Kramer, Mordechai R

    2015-01-01

    Cryptogenic organizing pneumonia (COP) is an interstitial lung disease that is usually responsive to corticosteroid treatment. The treatment of COP has not been studied in randomized controlled trials; thus, treatment decisions are based on practice guidelines. We herein present, for the first time, 4 cases of patients with biopsy-proven COP who did not respond to corticosteroids but benefited from rituximab therapy. This report consists of a retrospective case series of patients who experienced steroid-resistant, biopsy-proven COP. Patients included in this case series suffered from acute or chronic COP and did not respond to corticosteroid treatment for a few weeks to months but later responded to rituximab. In a series of 4 patients, 1 patient had a complete radiological and clinical response after rituximab therapy, and the steroids could be gradually tapered. Three patients had a chronic course but had been able to lower steroid dosage or even discontinue the drug after being treated with rituximab. Since 40% of the patients with COP do not respond to or stay dependent on steroids, we think that even the ability to lower the steroid dosage by using rituximab as a steroid-sparing agent with a good safety profile is worth the effort. However, further studies are warranted. PMID:26045243

  16. MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab

    DEFF Research Database (Denmark)

    Peterfy, Charles; Emery, Paul; Tak, Paul P;

    2014-01-01

    two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from......OBJECTIVE: To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. METHODS: Patients were randomised to receive...... baseline at week 24. RESULTS: Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (-0.30, 0...

  17. EXPERIENCE WITH RITUXIMAB IN PATIENTS WITH ANKYLOSING SPONDYLITIS

    Directory of Open Access Journals (Sweden)

    Mikhail Sergeyevich Protopopov

    2013-02-01

    Full Text Available Objective: to analyze the efficacy of rituximab (RTM in patients with active ankylosing spondylitis (AS resistant to conventional therapy. Subjects and methods. The trial enrolled 10 male patients with the reliable and valid diagnosis of AS who received therapy with RTM used in cases of steadily high AS activity, resistance to standard therapy, and contraindications to the use of tumor necrosis factor-α inhibitors. The number of patients meeting the Assessment of Spondyloarthritis International Society (ASAS criteria for 20% improvements 24 weeks after treatment initiation was the main indicator of therapeutic effectiveness. Results. After 24-week therapy, 7 and 4 of the 10 patients showed 20 and 40% improvements, respectively; and 2 patients had partial remission according to the ASAS criteria. During the treatment, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI significantly decreased (p = 0.046, the Bath Ankylosing Spondylitis Functional Index (BASFI remained substantially unchanged. Treatment response did not depend on the development of an early (at 2 weeks complete depletion of CD20 lymphocytes. No significant effect could be achieved in patients with high baseline BASDAI and BASFI scores. Conclusion. RTM used patients with AS can ensure clinical improvement and even remission in a number of cases; however, it is unpromising in cases of high disease activity and severe functional failure.

  18. Monoclonal Antibodies for Systemic Lupus Erythematosus (SLE

    Directory of Open Access Journals (Sweden)

    Gabriella Moroni

    2010-01-01

    Full Text Available A number of monoclonal antibodies (mAb are now under investigation in clinical trials to assess their potential role in Systemic Lupus Erythematosus (SLE. The most frequently used mAb is rituximab, which is directed against CD20, a membrane protein expressed on B lymphocytes. Uncontrolled trials reported an improvement of SLE activity in non-renal patients and other studies even reported an improvement of severe lupus nephritis unresponsive to conventional treatments. However two randomized trials failed to show the superiority of rituximab over conventional treatment in non renal SLE and in lupus nephritis. Preliminary trials reported promising results with epratuzumab, a humanized mAb directed against CD22, and with belimumab, a human mAb that specifically recognizes and inhibits the biological activity of BLyS a cytokine of the tumornecrosis-factor (TNF ligand superfamily. Other clinical trials with mAb directed against TNF-alpha, interleukin-10 (Il-10, Il-6, CD154, CD40 ligand, IL-18 or complement component C5 are under way. At present, however, in spite of good results reported by some studies, no firm conclusion on the risk-benefit profile of these mAbs in patients with SLE can be drawn from the available studies.

  19. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Gruenberg, Juergen; Lindenblatt, Dennis; Cohrs, Susan; Fischer, Eliane [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); Dorrer, Holger [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); Zhernosekov, Konstantin [ITG Isotope Technologies Garching GmbH, Garching (Germany); Koester, Ulli [Institut Laue-Langevin, Grenoble (France); Tuerler, Andreas [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); University of Bern, Department of Chemistry and Biochemistry, Berne (Switzerland); Schibli, Roger [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

    2014-10-15

    The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with {sup 67}Cu- and {sup 177}Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide {sup 177}Lu and the potential alternative {sup 161}Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched {sup 160}Gd targets. {sup 161}Tb and {sup 177}Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of {sup 177}Lu- and {sup 161}Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. {sup 177}Lu- and {sup 161}Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. {sup 161}Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the {sup 177}Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the {sup 161}Tb-DOTA-chCE7 than the {sup 177}Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM {sup 161}Tb RIT is more effective compared to {sup 177}Lu RIT in ovarian cancer xenografts

  20. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

    International Nuclear Information System (INIS)

    The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with 67Cu- and 177Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide 177Lu and the potential alternative 161Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched 160Gd targets. 161Tb and 177Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of 177Lu- and 161Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. 177Lu- and 161Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. 161Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the 177Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the 161Tb-DOTA-chCE7 than the 177Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM 161Tb RIT is more effective compared to 177Lu RIT in ovarian cancer xenografts. These results suggest that 161Tb is a promising candidate for future clinical applications in

  1. Rituximab as a first-line agent for the treatment of dermatomyositis.

    LENUS (Irish Health Repository)

    2012-02-01

    B cells may play a pivotal role in the pathophysiology of DM, and reports have claimed that targeting B cells is a viable treatment option in patients with dermatomyositis. A 20-year-old girl presented in October 2007, with few weeks\\' history of proximal muscle weakness. Gottron\\'s papules were noted on her knuckles. She had normal inflammatory markers and negative autoantibody screen. Her CPK was 7,000 U\\/L (normal range 0-170) with an LDH of 1,300 U\\/L (normal range 266-500). EMG and muscle biopsy was consistent with active myositis. She had normal pulmonary function tests. HRCT showed no interstitial lung disease. She was started with 60 mg glucocorticoids (1 mg\\/kg), with a good clinical response. However, any attempt to taper down the steroid dose led to recurrence of her symptoms. The options of available immunosuppressive therapies, including the experimental usage of rituximab, were discussed with her; averse to long-term systemic treatments, she opted to try a course of rituximab. She had rituximab 1,000 mg on days 0 and 14, and her glucocorticoids were tapered in next few weeks. Now, 24 months since her rituximab infusions, she remains in complete clinical and biochemical remission and is naive to other immunosuppressive agents apart from glucocorticoids and rituximab. Depleting peripheral B cells with rituximab (one course) in our patient has led not only to complete resolution of muscle and skin disease (induction) but also remains off all immunosuppressives including glucocorticoids.

  2. Immunosuppression associated with novel chemotherapy agents and monoclonal antibodies.

    Science.gov (United States)

    Morrison, Vicki A

    2014-11-15

    The introduction of novel agents to the therapeutic armamentarium for oncologic, rheumatologic, and neurologic disorders has resulted in major clinical advances. These agents impact immune function, resulting in a discrete spectrum of infectious complications. Purine analogues and alemtuzumab alter cell-mediated immunity, resulting in opportunistic viral/fungal infections. Herpes zoster incidence increases with bortezomib. Hepatitis B reactivation may occur with rituximab. Cases of progressive multifocal leukoencephalopathy have occurred following monoclonal antibody therapy. Tumor necrosis factor-α inhibitor therapy is complicated by tuberculosis reactivation and fungal infections. We summarize the impact of these therapies on pathogenesis and spectrum of infection complicating their usage. PMID:25352632

  3. Successful rituximab treatment in an elderly patient with recurrent thrombotic thrombocytopenic purpura.

    Science.gov (United States)

    Matsubara, Etsuko; Yamanouchi, Jun; Hato, Takaaki; Takeuchi, Kazuto; Niiya, Toshiyuki; Yasukawa, Masaki

    2016-07-01

    An 81-year-old man presenting with fever, neurological symptoms, thrombocytopenia, and hemolytic anemia was diagnosed with acquired idiopathic thrombotic thrombocytopenic purpura (TTP). His disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was TTP recurrence based on ADAMTS13 activity TTP in Japan, we report the efficacy and safety of rituximab in an elderly patient with recurrent TTP. We suggest that rituximab therapy should be started as soon as possible for recurrent TTP in patients with high titers of ADAMTS13 inhibitor. PMID:27498731

  4. Treatment of Antibody-Mediated Rejection in Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Magdalena Durlik

    2013-07-01

    Full Text Available Antibody-mediated rejection (AMR is a relatively rare but severe complication in kidney transplantation associated with increased risk of graft loss. Diagnosis of acute and chronic AMR is based on typical histological hallmarks, deposition of C4d in peritubular capillaries and presence of donor-specific antibodies (DSA. Many novel and attractive treatment options have become available in recent years: antibody removal and production inhibition (plasmapheresis, IVIg, B cell depletion (rituximab, plasma cell depletion and apoptosis (bortezomib, and complement activation inhibition (eculizumab. Standard therapy is based on PP and IVIg. Preliminary results with new agents are encouraging but require randomised clinical trials and long-term follow-up.

  5. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors

    Directory of Open Access Journals (Sweden)

    Chatal Jean-Francois

    2009-09-01

    Full Text Available Radioimmunotherapy (RIT has been proven effective in the treatment of radiosensitive non-Hodgkin lymphoma but, for radioresistant solid tumors, new approaches are necessary to improve the clinical effectiveness. A real improvement has been the introduction of the pretargeting technology which appeared to be able to significantly increase tumor-to-normal organ uptake ratios.Another very promising approach consists in associating RIT with other treatment modalities. Finally the use of alpha particle-emitting radionuclides such as astatin-211 or bismuth-213 (alpha-RIT should allow to efficiently eradicate disseminated microscopic clusters of tumor cells or isolated tumor cells which fit well with the short path length of alpha particles.

  6. Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells

    International Nuclear Information System (INIS)

    Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-xL, a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies. (orig.)

  7. Low incidence of radionecrosis in children treated with conventional radiation therapy and intrathecal radioimmunotherapy.

    Science.gov (United States)

    Kramer, Kim; Pandit-Taskar, Neeta; Zanzonico, Pat; Wolden, Suzanne L; Humm, John L; DeSelm, Carl; Souweidane, Mark M; Lewis, Jason S; Cheung, Nai-Kong V

    2015-06-01

    Radionecrosis is a potentially devastating complication of external beam radiotherapy (XRT). Intraventricular compartmental radioimmunotherapy (cRIT) using (131)I-3F8 or (131)I-8H9 can eradicate malignant cells in the CSF. The incidence of radionecrosis using cRIT (131)I based intraventricular radioimmunotherapy, when used alone or in combination with conventional craniospinal CSI-XRT is unknown. We retrospectively analyzed the incidence of radionecrosis in two cohorts of pediatric patients treated with both CSI-XRT and cRIT at MSKCC since 2003: patients with metastatic CNS neuroblastoma (NB) and medulloblastoma (MB). 94 patients received both CSI-XRT and cRIT, two received cRIT alone, median follow up 41.5 months (6.5-124.8 months). Mean CSI-XRT dose was 28 Gy (boost to the primary tumor site up to 54 Gy) in the MB cohort, and CSI XRT dose 18-21 Gy (boost to 30 Gy for focal parenchymal mass) in the NB cohort. For MB patients, 20 % had focal re-irradiation for a second or more subsequent relapse, mean repeat-XRT dose was 27.5 Gy; seven patients with NB had additional focal XRT. Median CSF cRIT dose was 18.6 Gy in the MB cohort and 32.1 in the NB cohort. One asymptomatic patient underwent resection of 0.6-cm hemorrhagic periventricular white-matter lesion confirmed to be necrosis and granulation tissue, 2.5 years after XRT. The risk of radionecrosis in children treated with XRT and cRIT appears minimal (~1 %). No neurologic deficits secondary to radionecrosis have been observed in long-term survivors treated with both modalities, including patients who underwent re-XRT. Administration of cRIT may safely proceed in patients treated with conventional radiotherapy without appearing to increase the risk of radionecrosis. PMID:25944385

  8. B-lymfocytdepletring og andre biologiske behandlingsmuligheder ved Graves' oftalmopatiTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    El, Fassi D.; Hegedus, L.; Nielsen, Claus Henrik

    2008-01-01

    The current medical treatment options for Graves' ophthalmopathy (GO) are unsatisfactory. Recent treatment of GO patients with the B-lymphocyte depleting monoclonal antibody rituximab or with the anti-tumor necrosis factor-alpha agents etanercept and infliximab has shown promising results. We...

  9. Monoclonal antibodies in treatment of multiple sclerosis

    Science.gov (United States)

    Rommer, P S; Dudesek, A; Stüve, O; Zettl, UK

    2014-01-01

    Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and transplant rejection prevention. Since the introduction and reintroduction of the anti-alpha4-integrin mAb natalizumab in 2004 and 2006, mAbs have gained relevance in the treatment of multiple sclerosis (MS). At present, numerous mAbs have been tested in clinical trials in relapsing–remitting MS, and in progressive forms of MS. One of the agents that might soon be approved for very active forms of relapsing–remitting MS is alemtuzumab, a humanized mAb against CD52. This review provides insights into clinical studies with the mAbs natalizumab, alemtuzumab, daclizumab, rituximab, ocrelizumab and ofatumumab. PMID:24001305

  10. Rituximab is an effective and safe treatment of relapse in elderly patients with resistant warm AIHA.

    Science.gov (United States)

    Laribi, Kamel; Bolle, Delphine; Ghnaya, Habib; Sandu, Andrea; Besançon, Anne; Denizon, Nathalie; Truong, Catherine; Pineau-Vincent, Fabienne; de Materre, Alix Baugier

    2016-04-01

    We evaluated the efficacy and safety of rituximab for the treatment of 23 elderly patients (median age 78 years) with warm autoimmune haemolytic anaemia (AIHA). The median follow-up was 31 months. Patients had received one to five previous treatments. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for 4 weeks. The OR rate was 86.9 % (CR = 39.1 %, PR = 47.8 %). Median OS was 87 months. The median OS of patients who reached CR could not be calculated, and that of patients with PR was 67 months. At last follow-up, eight of the 20 responding patients, including one patient in CR and seven in PR, had relapsed after a median of 6 months. Failure to achieve CR was a risk factor for relapse (p = 0.028). We did not identify any pretreatment characteristics predictive of response to rituximab. In conclusion, rituximab is an effective treatment for elderly patients with refractory warm AIHA. PMID:26858026

  11. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma

    DEFF Research Database (Denmark)

    Pettengell, Ruth; Schmitz, Norbert; Gisselbrecht, Christian;

    2013-01-01

    The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma...

  12. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    M.H. Buch; J.S. Smolen; N. Betteridge; F.C. Breedveld; G. Burmester; T. Dörner; G. Ferraccioli; J.E. Gottenberg; J. Isaacs; T.K. Kvien; X. Mariette; E. Martin-Mola; K. Pavelka; P.P. Tak; D. van der Heijde; R.F. van Vollenhoven; P. Emery

    2011-01-01

    Background Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituxim

  13. Burkitt Lymphoma Preceded by Autoimmune Hemolytic Anemia due to Anti-D Antibody.

    Science.gov (United States)

    Mizuno, Yoshimi; Shimura, Yuji; Horiike, Shigeo; Takimoto, Tomoko; Maegawa, Saori; Tanba, Kazuna; Matsumura-Kimoto, Yayoi; Sumida, Yukari; Tatekawa, Shotaro; Tsukamoto, Taku; Chinen, Yoshiaki; Mizutani, Shinsuke; Nagoshi, Hisao; Yamamoto-Sugitani, Mio; Matsumoto, Yosuke; Kobayashi, Tsutomu; Kuroda, Junya; Taniwaki, Masafumi

    2016-01-01

    We herein report a rare case of Burkitt lymphoma (BL) preceded by autoimmune hemolytic anemia (AIHA) caused by autoantibodies against D antigen. After a partial response to AIHA with prednisolone (PSL) treatment for 7 months, the patient developed BL with a t(8;22)(q24;q11.2) chromosomal translocation. Intensive immunochemotherapy, including rituximab, led to a complete response (CR) of BL; however, anti-D antibody remained detectable in the plasma and antibody-dissociated solution from erythrocytes, thus continuous therapy with PSL was necessary even after achievement of the CR. BL with AIHA is extremely rare, with only one previously reported case in the literature. PMID:27523004

  14. Anti-CD45 Pretargeted Radioimmunotherapy using Bismuth-213: High Rates of Complete Remission and Long-Term Survival in a Mouse Myeloid Leukemia Xenograft Model

    Energy Technology Data Exchange (ETDEWEB)

    Pagel, John M; Kenoyer, Aimee L; Back, Tom; Hamlin, Donald K; Wilbur, D Scott; Fisher, Darrell R; Park, Steven I; Frayo, Shani; Axtman, Amanda; Orgun, Nural; Orozoco, Johnnie; Shenoi, Jaideep; Lin, Yukang; Gopal, Ajay K; Green, Damian J; Appelbaum, Frederick R; Press, Oliver W

    2011-07-21

    Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path-length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with Acute Myeloid Leukemia (AML). Accordingly, we have used 213Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of 213Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5 ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor. α imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after 213Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide (90Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of 213Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi- or 90Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for >100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of AML.

  15. Anti-CD45 radioimmunotherapy with 90Y but not 177Lu is effective treatment in a syngeneic murine leukemia model.

    Directory of Open Access Journals (Sweden)

    Johnnie J Orozco

    Full Text Available Radioimmunotherapy (RIT for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11 targeted hematologic tissues, as at 24 hours 48.8 ± 21.2 and 156 ± 14.6% injected dose per gram of tissue (% ID/g of 90Y-DOTA-30F11 and 54.2 ± 9.5 and 199 ± 11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model.

  16. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

    Science.gov (United States)

    Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

  17. RITUXIMAB TREATMENT FOR INTERSTITIAL LUNG INJURY IN SCLERODERMA SYSTEMATICA

    Directory of Open Access Journals (Sweden)

    Lidia Petrovna Ananieva

    2013-12-01

    Full Text Available Objective: to study the efficiency and tolerance of rituximab (RTM treatment in patients with scleroderma systematica (SDS with interstitial lung injury (ILI.Subjects and methods. The trial included 27 patients (26 women and 1 man (mean age 45.7±13.0 years, with diffuse (n=13 and circumscribed (n = 14 forms and a disease duration of > 5 years in 63%. All the patients underwent chestcomputed tomography; examination of external respiratory function, including forced vital capacity (FVC and diffusing capacity of the lung (DCL, as well as echocardiographic study. The efficiency of the treatment was evaluated from changes in FVC, skin score, and disease activity index. The indicators were compared prior to the treatment and one year after the first administration of RTM. The latter was injected with premedication (125–500 mg of methylprednisolone intravenously 500–1000 mg per administration. The mean dose of RTM was low and amounted to 1.3 g per year.Results. As estimated by the physician, good, satisfactory, no effects were seen in 81.5, 14.8, and 3.7% of the patients, respectively. There was a significant increase in mean FVC one year after the first administration of RTM and a reduction in the total activity of the disease, including skin syndrome. DCL was substantially unchanged in the entire group. In the diffuse and circumscribed forms of the disease, FVC increased significantly and to the same extent. A clinically significant increase in FVC (by 11% was achieved in patients with a disease duration of ≤5 years and mild lung injury. In people with a more than 5-year disease duration, FVC was initially decreased to a greater extent and the treatment-induced increase was only 3.7%. A significant and permanent decline in peripheral blood B lymphocytes was noted when both the standard dose (2 g of RTM and its lower doses (0.5–1 g were administered. RTM treatment was well tolerated, but complicated by mild intercurrent infections

  18. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey.

    Science.gov (United States)

    Baer Ii, William H; Maini, Archana; Jacobs, Ira

    2014-01-01

    Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia. PMID:24810947

  19. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey

    Directory of Open Access Journals (Sweden)

    William H. Baer II

    2014-05-01

    Full Text Available Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin’s lymphoma (NHL and chronic lymphocytic leukemia (CLL. Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia.

  20. Effectiveness of Intravenous Immunoglobulin Plus Plasmapheresis on Antibody-mediated Rejection or Thrombotic Microangiopathy in Iranian Kidney Transplant Recipient

    OpenAIRE

    Dashti-Khavidaki, Simin; Shojaie, Lida; Hosni, Amin; Khatami, Mohammad Reza; Jafari, Atefeh

    2015-01-01

    Background: Antibody mediated rejection (AMR) and thrombotic microangiopathy (TMA) after kidney transplantation are difficult to differentiate most of the times and both play important roles in kidney allograft loss. Common treatment strategies of these two conditions include plasmapheresis, intravenous immunoglobulin (IVIG) and rituximab. Objectives: This study was designed to assess the efficacy of routine treatment of AMR/TMA in Iranian kidney transplant recipients, which comprises of plas...

  1. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words.

    Science.gov (United States)

    Mirick, G R; Bradt, B M; Denardo, S J; Denardo, G L

    2004-12-01

    The United States Food and Drug Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM ((90)yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ((131)I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) anti-CD20 MAbs for use in radioimmunotherapy (RIT) of non-Hodgkin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, assays were developed to determine HAGA (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to ''humanize'' MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades. PMID:15640788

  2. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words

    Energy Technology Data Exchange (ETDEWEB)

    Mirick, G. R.; Bradt, B. M.; Denardo, S. J.; Denardo, G. L. [Calfornia Univ., Sacramento (United States). Davis Medical Center

    2004-12-01

    The United States Food and Drugs Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM ({sup 9}0yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ({sup 1}31I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) antiCD20 MAns for use in radioimmunotherapy (RIT) of non-Hodgikin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, essays were developed to determine HAGE (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to humanize MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades.

  3. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words

    International Nuclear Information System (INIS)

    The United States Food and Drugs Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM (90yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM (131I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) antiCD20 MAns for use in radioimmunotherapy (RIT) of non-Hodgikin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, essays were developed to determine HAGE (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to humanize MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades

  4. Rapid Reduction in Donor-Specific Anti-Human Leukocyte Antigen Antibodies and Reversal of Antibody-Mediated Rejection With Bortezomib in Pediatric Heart Transplant Patients

    Science.gov (United States)

    Morrow, William Robert; Frazier, Elizabeth A.; Mahle, William T.; Harville, Terry O.; Pye, Sherry E.; Knecht, Kenneth R.; Howard, Emily L.; Smith, R. Neal; Saylors, Robert L.; Garcia, Xiomara; Jaquiss, Robert D.B.; Woodle, E. Steve

    2013-01-01

    Background High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce antihuman leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. Methods Patients received four intravenous dose of bortezomib (1.3 mg/m2) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. Results AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. Conclusions Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA. PMID:22179403

  5. Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) – a multicenter phase IV trial

    International Nuclear Information System (INIS)

    In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel

  6. Atualização do tratamento das vasculites associadas a anticorpo anticitoplasma de neutrófilos Treatment of antineutrophil cytoplasmic antibody-associated vasculitis: update

    Directory of Open Access Journals (Sweden)

    Alfredo Nicodemos Cruz Santana

    2011-12-01

    Full Text Available As vasculites antineutrophil cytoplasmic antibody (ANCA, anticorpo anticitoplasma de neutrófilos associadas (VAAs são caracterizadas por uma inflamação sistêmica das artérias de pequeno e médio calibre (especialmente no trato respiratório superior e inferior, e nos rins. As VAAs compreendem a granulomatose de Wegener (agora chamada de granulomatose com poliangeíte, poliangeíte microscópica, VAA limitada ao rim e a síndrome de Churg-Strauss. Neste artigo, discutiremos as fases de tratamento dessas vasculites, como fase de indução (com ciclofosfamida ou rituximab e fase de manutenção (com azatioprina, metotrexato ou rituximab. Além disso, discutiremos como manusear os casos refratários à ciclofosfamida.In its various forms, antineutrophil cytoplasmic antibody (ANCA-associated vasculitis (AAV is characterized by a systemic inflammation of the small and medium-sized arteries (especially in the upper and lower respiratory tracts, as well as in the kidneys. The forms of AAV comprise Wegener's granulomatosis (now called granulomatosis with polyangiitis, microscopic polyangiitis, renal AAV, and Churg-Strauss syndrome. In this paper, we discuss the phases of AAV treatment, including the induction phase (with cyclophosphamide or rituximab and the maintenance phase (with azathioprine, methotrexate, or rituximab. We also discuss how to handle patients who are refractory to cyclophosphamide.

  7. Radioimmunotherapy with Y-90-epratuzumab in patients with previously treated B-cell lymphoma. A fractionated dose-escalation study

    International Nuclear Information System (INIS)

    Aim: Fractionated RIT may improve outcome by decreasing heterogeneity in absorbed dose and by increasing therapeutic window. The humanised anti-CD22 antibody, Epratuzumab, (Immunomedics, Inc., Morris Plains, NJ) can be given repeatedly with minimal risk of neutralising Ab (HAHA), making fractionated treatment with 90Y-labelled epratuzumab possible. Materials and Methods: Patients with previously treated B-cell lymphoma received increasing number (2-4) of weekly infusions of 90Y-epratuzumab. Patients received either 185 MBq/m2 per infusion (group A), or, if they had a history of high-dose chemotherapy with stem-cell rescue, 92.5 MBq/m2 per infusion (group B). The first infusion included 150 MBq of 111Indium for scintigraphic verification of tumour targeting and dosimetry. 1.5 mg/kg epratuzumab was administered with each infusion. The treatment could be repeated once after 3 m. Results: Of 23 patients, 16 in group A and 6 in group B were evaluable for response. The RR in group A was 62% objective response (OR) and 25% CR/CRu. One patient in group B showed OR. OR was seen in aggressive and indolent lymphoma. Response was also long-lasting and event-free survival of patients showing CR/CRu was 14 to 25+ months. In group A all seven patient, receiving three infusions, showed less than grade 3 platelet and neutrophil toxicity, except for two patients suffering grade 3 neutropenia. Of five patients with 4 weekly infusions there were two patients with dose-limiting haematological toxicity (DLT), both recently treated with high dose cytosar before RIT. With criteria used the maximal tolerated dose was three infusions 185 MBq/m2. In group B no patient suffered DLT and one patient exhibited OR. Seven patients were retreated after 3 months with minor toxicity, but improvement in OR in two cases. No patient has developed HAHA. CD22 expression on tumour cells, as assessed by flow cytometry, is available in 18 of 22 patients. In group A, seven of eight patients with unequivocal

  8. Improved radioimmunotherapy of hematologic malignancies. Progress report, November 1, 1993--October 31, 1994

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.

    1994-08-04

    This report summaries progress made during the time interval between November 1, 1993 and October 31, 1994 and briefly describes studies on the metabolism of antibodies targeting B cell antigens, retention of labeled antibodies by human B cell lymphocytes, and tissue distribution of Chloramine T and tyramine cellobiose labeled antibodies in mice harboring a human erythroleukemia tumor transplant.

  9. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: A prospective randomized HOVON trial

    OpenAIRE

    Vellenga, Edo; van Putten, Wim; Veer, Mars; Zijlstra, Josée; Fibbe, Willem; Oers, Marinus; Verdonck, Leo; Wijermans, Pierre; van Imhoff, Gustaaf; Lugtenburg, Pieternella; Huijgens, Peter

    2008-01-01

    textabstractWe evaluated the role of rituximab during remission induction chemotherapy in relapsed aggressive CD20+non-Hodgkin lymphoma. Of 239 patients, 225 were evaluable for analysis. Randomized to DHAP (cisplatin-cytarabine- dexamethasone)-VIM (etoposide-ifosfamide-methotrexate)-DHAP (cisplatin- cytarabine-dexamethasone) chemotherapy with rituximab (R; R-DHAP arm) were 119 patients (113 evaluable) and to chemotherapy without rituximab (DHAP arm) 120 patients (112 evaluable). Patients in c...

  10. Combined treatment of advanced oropharyngeal cancer with external radiotherapy and three-step radioimmunotherapy

    International Nuclear Information System (INIS)

    The prognosis of patients with locally advanced head and neck cancer remains grim due to poor locoregional tumour control. In the attempt to eradicate residual disease, various novel modalities have been tested, among which radioimmunotherapy (RIT) has shown some potential. We present a case of locally advanced oropharyngeal carcinoma successfully treated with a combination of various treatments including surgery, radio-chemotherapy and three-step RIT, with the avidin-biotin pretargeting system. A partial tumour response was achieved after surgery and radio-chemotherapy; persistent disease was documented at computed tomography (CT), ultrasound (US) and immunoscintigraphy (ISG) 10 weeks after the end of chemo-radiotherapy. The good correlation between the tracer localization in the scintigraphic images and residual mass visualized at CT suggested the application of three-step RIT using systemic administration of yttrium-90 (py) biotin. At present, 17 months after RIT, the patient is alive with no evidence of disease as documented by magnetic resonance imaging (MRI) and US. This is the first case of complete clinical remission of a head and neck carcinoma induced by combined treatment including pretargeted RIT with 90Y-biotin. (orig.)

  11. Rituximab enhances radiation-triggered apoptosis in non-Hodgkin's lymphoma cells via caspase-dependent and - independent mechanisms

    International Nuclear Information System (INIS)

    Rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, is currently employed in the treatment of malignant non-Hodgkin's lymphoma (NHL) either alone or in combination with other cytotoxic approaches. The present study examines the effects of ionizing radiation in combination with RTX on proliferation and apoptosis development in B-lymphoma RL and Raji cells. RTX was used at a concentration of 10 μg/mL 24 hours prior to irradiation at a single dose of 9 Gy. CD20 expression, cell viability, apoptosis, mitochondrial membrane potential and apoptosis-related proteins were evaluated in the treated B cells. The constitutive level of CD20 expression in RL and Raji lymphoma cells did not play an essential role in RTX-induced cell growth delay. Both lymphoma cells showed similar inhibition of cell proliferation without apoptosis development in response to RTX treatment. Exposure to ionizing radiation induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance and activation of cell growth at 24 hours after irradiation, which was accompanied by increased radiation-triggered CD20 expression. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX abrogated radioresistance of Raji cells and significantly enhanced cell growth delay and apoptosis in RL cells. X-linked inhibitor of apoptosis protein (XIAP) and the inducible form of heat shock protein 70 (Hsp70) were positively modulated by RTX in combination with ionizing radiation in order to induce apoptosis. Furthermore, it was demonstrated that mitochondrial membrane potential dissipation is not an essential component to induce apoptosis-inducing factor (AIF) maturation and apoptosis. Our results show that RTX-triggered enhancement of radiation-induced apoptosis and cell growth delay is achieved by modulation of proteins involved in programmed cell death. (author)

  12. Leuconostoc sp. Meningitis in a Patient Treated with Rituximab for Mantle Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Hrvoje Holik

    2015-09-01

    Full Text Available We present a 64-year-old man who was treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone chemoimmunotherapy for mantle cell lymphoma and developed purulent meningitis, probably caused by Leuconostoc sp. The patient had severe hypogammaglobulinemia, which is a possible complication of rituximab therapy. To our knowledge and after reviewing the available medical literature, this is the first described case of purulent meningitis caused by Leuconostoc sp. in a patient with mantle cell lymphoma that appeared after treatment with the R-CHOP protocol. The diagnosis of purulent meningitis was based on clinical, laboratory and cytological cerebrospinal fluid findings, in addition to blood culture results in which we isolated Leuconostoc sp. The patient was treated with meropenem with full recovery.

  13. Clinical Responses to Rituximab in a Case of Neuroblastoma with Refractory Opsoclonus Myoclonus Ataxia Syndrome

    OpenAIRE

    Samin Alavi; Ali Kord Valeshabad; Borhan Moradveisi; Ali Aminasnafi; Mohammad Taghi Arzanian

    2012-01-01

    Opsoclonus myoclonus ataxia syndrome (OMS) is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient w...

  14. Brain Abscess following Rituximab Infusion in a Patient with Pemphigus Vulgaris

    OpenAIRE

    Al-Harbi, Talal M.; Muammer, Shahad A.; Ellis, Ronald J.

    2015-01-01

    Patient: Female, 52 Final Diagnosis: Brain abscess Symptoms: Fever • headache • weakness, left sided Medication: Prednisolone • Azathioprine • Rituximab Clinical Procedure: Stereotactic brain biopsy and LP Specialty: Neurology Objective: Rare disease Background: Immunocompromised patients are at increased risk for developing meningitis or, rarely, brain abscess with opportunistic organisms like Listeria monocytogenes. Case Report: A 52 year-old Saudi Arabian woman who was diagnosed with pemph...

  15. Bispecific antibodies.

    Science.gov (United States)

    Kontermann, Roland E; Brinkmann, Ulrich

    2015-07-01

    Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with 'two-target' functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or inflammatory processes. BsAbs can also place targets into close proximity, either to support protein complex formation on one cell, or to trigger contacts between cells. Examples of 'forced-connection' functionalities are bsAbs that support protein complexation in the clotting cascade, or tumor-targeted immune cell recruiters and/or activators. Following years of research and development (R&D), the first bsAb was approved in 2009. Another bsAb entered the market in December 2014 and several more are in clinical trials. Here, we describe the potentials of bsAbs to become the next wave of antibody-based therapies, focusing on molecules in clinical development. PMID:25728220

  16. Recurrence of light chain deposit disease after renal allograft transplantation: potential role of rituximab?

    Science.gov (United States)

    Kuypers, Dirk R J; Lerut, Evelyne; Claes, Kathleen; Evenepoel, Pieter; Vanrenterghem, Yves

    2007-04-01

    Light chain deposit disease (LCDD) is a monoclonal plasma cell disorder characterized by tissue deposition of nonamyloid immunoglobulin light chains, predominantly kappa chains, causing renal insufficiency. LCDD reoccurs almost invariably after renal grafting, leading to early graft loss, usually within a time span of months to years. We describe a female patient with LCDD who lost her first living donor graft after 1 year due to extensive recurrence of kappa chain deposition. Rituximab was administered on the seventh day after her second transplantation with a graft from a deceased donor, in order to prevent early recurrence of LCDD. The 2-year protocol biopsy - similarly to the completely normal 1-year protocol biopsy - revealed persistent absence of light chain deposition on light microscopy but immunohistochemical staining and electron microscopy showed very mild recurrence of light chain deposits. A second 4-week course of rituximab was repeated because of these electron microscopic findings. Subsequently, free kappa light chain concentration decreased from 693 to 74 mg/l and remained low 4 months after completion of therapy. Rituximab could be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response. PMID:17326779

  17. Rituximab and new regimens for indolent lymphoma: a brief update from 2012 ASCO Annual Meeting

    Directory of Open Access Journals (Sweden)

    Zhao Jiangning

    2012-08-01

    Full Text Available Abstract Indolent lymphoma (IL, the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone remains the standard frontline regimen for diffuse Large B –cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial, R-CHOP was compared with R-CVP (cyclophosphamide, vincristine, prednisone and R-FM (fludarabine, mitoxantrone. The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.

  18. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia

    DEFF Research Database (Denmark)

    Gudbrandsdottir, Sif; Birgens, Henrik Sverre; Frederiksen, Henrik;

    2013-01-01

    In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding...... symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained...... response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in...

  19. Activities of AREVA Med. Extraction and purification of the 212Pb isotope from Thorium for radio-immunotherapy

    International Nuclear Information System (INIS)

    After having recalled the definition of radio-immunotherapy (RIT) and the benefits of alpha RIT for the treatment of some cancers, this document explains the choice of the 212-Pb isotope instead of the 212-Bi isotope (the first one has a longer half-life than the second). The Pb isotope in fact progressively transforms itself into the Bi isotope. The production process is evoked with its important steps. A second part reports the first clinic tests performed in the Alabama Centre for the treatment of different cancer (breast, colon, ovarian, pancreas, stomach). Processes and doses are discussed

  20. Conventional and Pretargeted Radioimmunotherapy Using Bismuth-213 to Target and Treat Non-Hodgkin Lymphomas Expressing CD20: A Preclinical Model toward Optimal Consolidation Therapy to Eradicate Minimal Residual Disease

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease (MRD) because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (213Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)4SA fusion protein (FP), followed by a dendrimeric clearing agent and (213Bi)DOTA-biotin. After 90 min, tumor uptake for 1F5(scFv)4SA was 16.5 ± 7.0 % injected dose per gram (ID/g) compared with 2.3 ± 0.9 % ID/g for the control FP. Mice treated with anti-CD20 PRIT and 600 (micro)Ci (213Bi)DOTA-biotin exhibited marked tumor growth delays compared to controls (mean tumor volume 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared to 23 days for the control FP (p 213Bi-labeled anti-CD20 PRIT.

  1. Anti-Apoptotic Effects of Lentiviral Vector Transduction Promote Increased Rituximab Tolerance in Cancerous B-Cells

    Science.gov (United States)

    Ranjbar, Benyamin; Krogh, Louise Bechmann; Laursen, Maria Bach; Primo, Maria Nascimento; Marques, Sara Correia; Dybkær, Karen; Mikkelsen, Jacob Giehm

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is characterized by great genetic and clinical heterogeneity which complicates prognostic prediction and influences treatment efficacy. The most common regimen, R-CHOP, consists of a combination of anthracycline- and immuno-based drugs including Rituximab. It remains elusive how and to which extent genetic variability impacts the response and potential tolerance to R-CHOP. Hence, an improved understanding of mechanisms leading to drug tolerance in B-cells is crucial, and modelling by genetic intervention directly in B-cells is fundamental in such investigations. Lentivirus-based gene vectors are widely used gene vehicles, which in B-cells are an attractive alternative to potentially toxic transfection-based methodologies. Here, we investigate the use of VSV-G-pseudotyped lentiviral vectors in B-cells for exploring the impact of microRNAs on tolerance to Rituximab. Notably, we find that robust lentiviral transduction of cancerous B-cell lines markedly and specifically enhances the resistance of transduced germinal center B-cells (GCBs) to Rituximab. Although Rituximab works partially through complement-mediated cell lysis, increased tolerance is not achieved through effects of lentiviral transduction on cell death mediated by complement. Rather, reduced levels of PARP1 and persistent high levels of CD43 in Rituximab-treated GCBs demonstrate anti-apoptotic effects of lentiviral transduction that may interfere with the outcome and interpretation of Rituximab tolerance studies. Our findings stress that caution should be exercised exploiting lentiviral vectors in studies of tolerance to therapeutics in DLBCL. Importantly, however, we demonstrate the feasibility of using the lentiviral gene delivery platform in studies addressing the impact of specific microRNAs on Rituximab responsiveness. PMID:27045839

  2. Synergistic anti-cancer response to chemotherapy and 177Lu-labelled APOMABR radioimmunotherapy in a preclinical model of lung cancer

    International Nuclear Information System (INIS)

    . However, combination of chemotherapy and 177Lu-labelled APOMABR had a synergistic response, resulting in a significant decrease in tumour growth and increased survival of tumour-bearing mice. Bio-distribution analysis revealed that radio-labelled APOMABR targeted tumour tissue, and chemotherapy specifically increased tumour uptake of radio-labelled APOMABR. Importantly, chemotherapy was not associated with increased normal tissue uptake of radio-labelled APOMABR. Conclusions: We have demonstrated both in vitro and in vivo that APOMABR is a dead tumour-cell specific antibody, and that 177Lu-labelled APOMABR is a safe and effective anti-cancer treatment when combined with chemotherapy. Given the safety and efficacy of a single cycle of β-radioimmunotherapy, multiple cycles of treatment, the substitution of an alpha-emitting radionuclide, or both, may provide further benefit and increase the anti-tumour response. (authors)

  3. Dosimetric model for intraperitoneal targeted liposomal radioimmunotherapy of ovarian cancer micrometastases

    Energy Technology Data Exchange (ETDEWEB)

    Syme, A M [Department of Physics, University of Alberta, 412 Avadh Bhatia Physics Laboratory, Edmonton, Alberta T6G 2J1 (Canada); McQuarrie, S A [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 3118 Dentistry/Pharmacy Centre, Edmonton, Alberta T6G 2N8 (Canada); Middleton, J W [Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario K1N 6N5 (Canada); Fallone, B G [Departments of Physics and Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta T6G 1Z2 (Canada)

    2003-05-21

    A simple model has been developed to investigate the dosimetry of micrometastases in the peritoneal cavity during intraperitoneal targeted liposomal radioimmunotherapy. The model is applied to free-floating tumours with radii between 0.005 cm and 0.1 cm. Tumour dose is assumed to come from two sources: free liposomes in solution in the peritoneal cavity and liposomes bound to the surface of the micrometastases. It is assumed that liposomes do not penetrate beyond the surface of the tumours and that the total amount of surface antigen does not change over the course of treatment. Integrated tumour doses are expressed as a function of biological parameters that describe the rates at which liposomes bind to and unbind from the tumour surface, the rate at which liposomes escape from the peritoneal cavity and the tumour surface antigen density. Integrated doses are translated into time-dependent tumour control probabilities (TCPs). The results of the work are illustrated in the context of a therapy in which liposomes labelled with Re-188 are targeted at ovarian cancer cells that express the surface antigen CA-125. The time required to produce a TCP of 95% is used to investigate the importance of the various parameters. The relative contributions of surface-bound radioactivity and unbound radioactivity are used to assess the conditions required for a targeted approach to provide an improvement over a non-targeted approach during intraperitoneal radiation therapy. Using Re-188 as the radionuclide, the model suggests that, for microscopic tumours, the relative importance of the surface-bound radioactivity increases with tumour size. This is evidenced by the requirement for larger antigen densities on smaller tumours to affect an improvement in the time required to produce a TCP of 95%. This is because for the smallest tumours considered, the unbound radioactivity is often capable of exerting a tumouricidal effect before the targeting agent has time to accumulate

  4. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Huang, C.Y. [University of Sydney, Camperdown, NSW (Australia); Guatelli, S [University of Wollongong, Wollongong, NSW (Australia); Oborn, B [Illawarra Cancer Care Centre, Wollongong, NSW (Australia); Allen, B [University of Western Sydney, Liverpool, NSW (Australia)

    2014-06-01

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes ({sup 211}At, {sup 213}Bi, {sup 223}Ra and {sup 225}Ac) and 6 beta emitters ({sup 32}P, {sup 33}P, {sup 67}Cu, {sup 90}Y, {sup 131}I and {sup 177}Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.

  5. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    International Nuclear Information System (INIS)

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes (211At, 213Bi, 223Ra and 225Ac) and 6 beta emitters (32P, 33P, 67Cu, 90Y, 131I and 177Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development

  6. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.

    Science.gov (United States)

    Gastaldi, Matteo; Thouin, Anaïs; Vincent, Angela

    2016-01-01

    Over the last 15 years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies. PMID:26692392

  7. The future of CD20 monoclonal antibody therapy in B-cell malignancies.

    Science.gov (United States)

    Czuczman, Myron S; Gregory, Stephanie A

    2010-06-01

    Limitations of therapeutic options for chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) have necessitated the development of novel treatments/strategies. Rituximab (chimeric anti-CD20 monoclonal antibody [mAb]) considerably improved therapeutic outcomes for patients with B-cell malignancies, particularly when combined with chemotherapy; outcomes, however, are limited by rituximab resistance or reduced response upon re-treatment. Novel anti-CD20 mAbs are in development that may enhance mAb therapy. Ofatumumab (human anti-CD20 mAb) induces highly potent cell lysis, including in cells with low CD20 expression, and is the most clinically advanced new anti-CD20 mAb. Positive phase III interim data for ofatumumab in fludarabine-refractory CLL that is also refractory to alemtuzumab or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy has led to FDA approval of this agent in this population. Preclinical and early clinical assessment of other novel anti-CD20 mAbs include: ocrelizumab, veltuzumab, GA101, AME-133v, and PRO131921; data suggest potential for improved efficacy over rituximab that will require substantiation in large-scale clinical trials. New treatment strategies and novel anti-CD20 mAbs have the potential to enhance long-term outcomes for CLL and NHL. PMID:20367564

  8. Different sensitivity of rituximab-treatment to B-cells between ABO-incompatible kidney and liver transplantation.

    Science.gov (United States)

    Morimoto, Hiroshi; Ide, Kentaro; Tanaka, Yuka; Ishiyama, Kohei; Ohira, Masahiro; Tahara, Hiroyuki; Akita, Tomonori; Tanaka, Junko; Ohdan, Hideki

    2016-06-01

    A desensitization protocol with rituximab is currently widely used for kidney transplantation (KT) and liver transplantation (LT) across the ABO blood group-incompatible (ABO-I) barrier. However, it remains to be elucidated whether rituximab is equally effective for B-cell and T-cell immune responses in both KT and LT recipients. To clarify these effects of rituximab, we enrolled 46 KT and 77 LT recipients in this study. The proportion of peripheral blood B-cells was determined at the perioperative period. T-cell responses to allostimulation were evaluated by a mixed lymphocyte reaction (MLR) assay. One week after rituximab administration, peripheral B-cells became undetectable in ABO-I KT recipients but remained detectable in some of the ABO-I LT recipients; B-cells were undetectable in both groups by week 2. B-cells remained below the detection limit throughout the first year in the ABO-I KT recipients, whereas they reappeared in the periphery after 6months in the ABO-I LT recipients. There were no significant differences in alloreactive T-cell responses based on MLR analyses between ABO-I and ABO-compatible groups. This study indicates that rituximab has differing B-cell sensitivity between KT and LT recipients and a minimal effect on the alloreactive T-cell responses in KT and LT recipients. PMID:27085793

  9. A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia.

    LENUS (Irish Health Repository)

    Maung, Su W

    2013-10-01

    This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg\\/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24\\/34) with 26·5% (9\\/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87·5% (21\\/24) and 3 months in 12·5% (3\\/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12\\/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg\\/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.

  10. Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20+ malignancies: An international retrospective study.

    Science.gov (United States)

    Ceppi, Francesco; Weitzman, Sheila; Woessmann, Wilhelm; Davies, Kimberly; Lassaletta, Alvaro; Reismüller, Bettina; Mellgren, Karin; Uyttebroeck, Anne; Maia, Iris; Abdullah, Shaker; Miakova, Natasha; Glaser, Darryl; Cohn, Richard; Abla, Oussama; Attarbaschi, Andishe; Alexander, Sarah

    2016-05-01

    Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted. Am. J. Hematol. 91:486-491, 2016. © 2016 Wiley Periodicals, Inc. PMID:26872652

  11. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed

    DEFF Research Database (Denmark)

    Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny;

    2011-01-01

    To assess the 6-month effectiveness of the first rituximab (RTX) course in rheumatoid arthritis (RA) and to identify possible predictors of response.......To assess the 6-month effectiveness of the first rituximab (RTX) course in rheumatoid arthritis (RA) and to identify possible predictors of response....

  12. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study

    OpenAIRE

    Flinn, Ian W.; van der Jagt, Richard; Kahl, Brad S.; Wood, Peter; Hawkins, Tim E.; MacDonald, David; Hertzberg, Mark; Kwan, Yiu-Lam; Simpson, David; Craig, Michael; Kolibaba, Kathryn; Issa, Samar; Clementi, Regina; Hallman, Doreen M.; Munteanu, Mihaela

    2014-01-01

    The complete response rate for first-line bendamustine/rituximab was statistically noninferior to R-CHOP or R-CVP in indolent NHL or MCL.The safety profile of bendamustine/rituximab is distinct from that of R-CHOP/R-CVP.

  13. High-Dose 131I-Tositumomab (Anti-CD20) Radioimmunotherapy for Non-Hodgkin's Lymphoma: Adjusting Radiation Absorbed Dose to Actual Organ Volumes

    International Nuclear Information System (INIS)

    Radioimmunotherapy (RIT) using 131I-tositumomab has been used successfully to treat relapsed or refractory B-cell non-Hodgin's lymphoma (NHL). Our approach to treatment planning has been to determine limits on radiation absorbed close to critical nonhematopoietic organs. This study demonstrates the feasibility of using CT to adjust for actual organ volumes in calculating organ-specific absorbed dose estimates. Methods: Records of 84 patients who underwent biodistribution studies after a trace-labeled infusion of 131I-tositumomab for RIT (January 1990 and April 2003) were reviewed. Serial planar -camera images and whole-body Nal probe counts were obtained to estimate 131I-antibody source-organ residence times as recommended by the MIRD Committee. The source-organ residence times for standard man or woman were adjusted by the ratio of the MIRD phantom organ mass to the CT-derived organ mass. Results: The mean radiation absorbed doses (in mGy/MBq) for our data using the MIRD model were lungs= 1.67; liver= 1.03; kidneys= 1.08; spleen= 2.67; and whole body= 0.3; and for CT volume-adjusted organ volumes (in mGy/MBq) were lungs= 1.30; liver= 0.92; kidneys= 0.76; spleen= 1.40; and whole body= 0.22. We determined the following correlation coefficients between the 2 methods for the various organs; lungs, 0.49; (P= 0.0001); liver, 0.64 (P= 0.004); kidneys, 0.45 (P= 0.0001), for the residence times. For therapy, patients received mean 131I administered activities of 19.2 GBq (520 mCi) after adjustment for CT-derived organ mass compared with 16.0 GBq (433 mCi) that would otherwise have been given had therapy been based only using standard MIRD organ volumes--a statistically significant difference (P= 0.0001). Conclusion: We observed large variations in organ masses among our patients. Our treatments were planned to deliver the maximally tolerated radiation dose to the dose-limiting normal organ. This work provides a simplified method for calculating patient-specific radiation

  14. 124I-L19-SIP for immuno-PET imaging of tumour vasculature and guidance of 131I-L19-SIP radioimmunotherapy

    International Nuclear Information System (INIS)

    The human monoclonal antibody (MAb) fragment L19-SIP is directed against extra domain B (ED-B) of fibronectin, a marker of tumour angiogenesis. A clinical radioimmunotherapy (RIT) trial with 131I-L19-SIP was recently started. In the present study, after GMP production of 124I and efficient production of 124I-L19-SIP, we aimed to demonstrate the suitability of 124I-L19-SIP immuno-PET for imaging of angiogenesis at early-stage tumour development and as a scouting procedure prior to clinical 131I-L19-SIP RIT. 124I was produced in a GMP compliant way via 124Te(p,n)124I reaction and using a TERIMO trademark module for radioiodine separation. L19-SIP was radioiodinated by using a modified version of the IODO-GEN method. The biodistribution of coinjected 124I- and 131I-L19-SIP was compared in FaDu xenograft-bearing nude mice, while 124I PET images were obtained from mice with tumours of 3. 124I was produced highly pure with an average yield of 15.4 ± 0.5 MBq/μAh, while separation yield was ∝90% efficient with 2. Overall labelling efficiency, radiochemical purity and immunoreactive fraction were for 124I-L19-SIP: ∝80, 99.9 and >90%, respectively. Tumour uptake was 7.3±2.1, 10.8±1.5, 7.8±1.4, 5.3±0.6 and 3.1±0.4%ID/g at 3, 6, 24, 48 and 72 h p.i., resulting in increased tumour to blood ratios ranging from 6.0 at 24 h to 45.9 at 72 h p.i. Fully concordant labelling and biodistribution results were obtained with 124I- and 131I-L19-SIP. Immuno-PET with 124I-L19-SIP using a high-resolution research tomograph PET scanner revealed clear delineation of the tumours as small as 50 mm3 and no adverse uptake in other organs. 124I-MAb conjugates for clinical immuno-PET can be efficiently produced. Immuno-PET with 124I-L19-SIP appeared qualified for sensitive imaging of tumour neovasculature and for predicting 131I-L19-SIP biodistribution. (orig.)

  15. α-Imaging Confirmed Efficient Targeting of CD₄₅-Positive Cells After ²¹¹At-Radioimmunotherapy for Hematopoietic Cell Transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Frost, Sophia; Miller, Brian W.; Back, Tom; Santos, E. B.; Hamlin, Donald K.; Knoblaugh, E.; Frayo, Shani; Kenoyer, Aimee L.; Storb, Rainer; Press, O. W.; Wilbur, D. Scott; Pagel, John M.; Sandmaier, B. M.

    2015-09-03

    Alpha-radioimmunotherapy (α-RIT) targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-²¹¹(²¹¹At)-RIT, extending the analysis to include intra-organ ²¹¹At activity distribution and α-imaging-based small-scale dosimetry, along with imunohistochemical staining. Methods: Eight normal dogs were injected with either 0.75 (n=5) or 1.00 mg/kg (n=3) of ²¹¹At-B10-CA12.10C12 (11.5–27.6 MBq/kg). Two were euthanized and necropsied 19–22 hours postinjection (p.i.), and six received autologous HCT three days after ²¹¹At-RIT, following lymph node and bone marrow biopsies at 2–4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. ²¹¹At localization and small scale dosimetry were assessed using two α-imaging : α-camera and iQID. Results: Uptake of ²¹¹At was highest in spleen (0.31–0.61 %IA/g), lymph nodes (0.02–0.16 %IA/g), liver (0.11–0.12 %IA/g), and marrow (0.06–0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either MAb dose. Lymph nodes remained unsaturated, but displayed targeted ²¹¹At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.9, 3.0, and 4.2 Gy/210 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; 1 treated with 1.00 mg MAb/kg developed ascites and was euthanized 136 days after HCT. Conclusion: ²¹¹At-anti-CD45 RIT with 0.75 mg MAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient ²¹¹At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT.

  16. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.

    Science.gov (United States)

    Daneshmanesh, A H; Hojjat-Farsangi, M; Khan, A S; Jeddi-Tehrani, M; Akhondi, M M; Bayat, A A; Ghods, R; Mahmoudi, A-R; Hadavi, R; Österborg, A; Shokri, F; Rabbani, H; Mellstedt, H

    2012-06-01

    ROR1 is a receptor tyrosine kinase (RTK) recently identified to be overexpressed at the gene and protein levels in chronic lymphocytic leukemia (CLL). Monoclonal antibodies (MAbs) against RTKs have been successfully applied for therapy of solid tumors. We generated five MAbs against the Ig (n = 1), cysteine-rich (CRD) (n = 2) and kringle (KNG) (n = 2) domains, respectively, of the extracellular part of ROR1. All CLL patients (n = 20) expressed ROR1 on the surface of the leukemic cells. A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. All five MAbs alone induced apoptosis in the absence of complement or added effector cells (Annexin-V and MTT, as well as cleavage of poly-(ADP ribose)-polymerase, caspase-8 and caspase-9) of CLL cells but not of normal B cells. Most effective were MAbs against CRD and KNG, significantly superior to rituximab (P < 0.005). Cross-linking of anti-ROR1 MAbs using the F(ab')(2) fragments of anti-Fc antibodies significantly augmented apoptosis. Two of the MAbs induced complement-dependent cytotoxicity (CDC) similar to that of rituximab and one anti-ROR1 MAb (KNG) (IgG1) showed killing activity by antibody-dependent cellular cytotoxicity. The identified ROR1 epitopes may provide a basis for generating human ROR1 MAbs for therapy. PMID:22289919

  17. CHALLENGES IN TREATMENT OF RENAL GRAFT ACUTE ANTIBODY-MEDIATED REJECTION

    Directory of Open Access Journals (Sweden)

    A. I. Sushkov

    2016-01-01

    Full Text Available Diagnostic criteria and treatment protocols for acute antibody-mediated rejection (AMR of kidney allograft remain controversial. We report the case of early severe AMR after primary kidney transplantation. The graft removal was considered in the absence of treatment efficacy and in the presence of systemic infl ammatory response syndrome. However, at surgery the graft looked normal and it was not removed. The repeated treatment course (plasmapheresis, antithymocyte globulin, intravenous immunoglobulin and rituximab was effective. The patient has good and stable graft function in 1 year after transplantation. 

  18. INTRAVENOUS IMMUNOGLOBULIN ADMINISTRATION FOR DESENSITIZATION BEFORE RENAL TRANSPLANTATION AND MANAGING ANTIBODY-MEDIATED REJECTION

    Directory of Open Access Journals (Sweden)

    A. I. Sushkov

    2011-06-01

    Full Text Available Much attention has been placed recently in transplantation in highly HLA-sensitized patients. In attempts to remove these antibodies and enable successful renal transplantation, several approaches have been developed. Intravenous immunoglobulin (IVIG was found to be effective in the treatment of autoimmune and inflammatory disorders (e. g. Kawasaki disease, Guillain-Barre syndrome. Recently, a beneficial effect of IVIG on the reduc- tion of anti-HLA antibodies was described. The anti-inflammatory effect of IVIG provides hopeful opportunities in antibody-mediated rejection (AMR management. There are several protocols of IVIG administration for pre-transplant desensitization and AMR treatment: high-dose IVIG, low-dose IVIG + plasmapheresis, IVIG + plasmapheresis + rituximab. These advancements have enabled transplantation in patients previously considered untransplantable and in concert with new diagnostic techniques has resulted in new approaches to management of AMR. 

  19. The generation of rhenium-188-labeled antibodies by direct labeling methods

    International Nuclear Information System (INIS)

    Rhenium-188 having similar chemistry to Tc-99m and favorable decay properties, is an attractive agent for radioimmunotherapy, despite the greater difficulties in antibody labeling with this element. The authors have succeeded in generating a reproducible process for the production of 188Re-IgC conjugates in near quantitative yield with highly preserved immunoreactivity. Incubation of perrhenate with a thiol-containing antibody in the presence of a reductant gives rise to radiolabeled antibody in yields approaching > 95% at 1-3 hr time periods, with unreduced perrhenate as the only other species. 188Re from a 188W/188Re generator system has been used to label antibody with a specific activity up to 15 mCi/mg. Animal biodistribution in LS174T tumor bearing nude mice out to 96 hours verified its stability with good tumor/non-tumor ratios being seen, while the strong uptake and retention in the tumor further reinforced this conclusion. Use of this approach, with the readily available 188Re source from the generator, gives a clinically viable procedure for the generation of 188Re antibody conjugates ready for immediate therapeutic use in as simple a manner as the corresponding technetium conjugates are now used for radioimmunodetection

  20. Cytomegalovirus infection in autologous stem cell transplant recipients in the era of rituximab.

    Science.gov (United States)

    Jain, Tania; John, Jisha; Kotecha, Aditya; Deol, Abhinav; Saliminia, Tanaz; Revankar, Sanjay; Chandrasekar, Pranatharthi

    2016-08-01

    The incidence of cytomegalovirus (CMV) reactivation/disease after autologous stem cell transplant (ASCT) is much lower than that after allogeneic stem cell transplantation. With the recent use of rituximab during cancer chemotherapy or conditioning regimens prior to transplantation, there has been an increasing concern of opportunistic infections including CMV. In the present study, we reviewed the patients undergoing ASCT from December 2007 to December 2013 to identify those developing CMV reactivation/disease. Out of the 978 patients who underwent ASCT at the Karmanos Cancer Institute, 239 patients were tested for symptomatic CMV reactivation based on clinical suspicion. Of the tested patients, 7/239 (2.9 %) were documented to have CMV reactivation within 90 days of ASCT. The median time to develop CMV viremia was 32 days from transplantation. Of the 239 patients tested, CMV viremia was detected in 3 out of 72 patients who received rituximab as compared to 4 out of 167 patients who did not. Three of these seven viremic patients were treated with anti-viral drugs; viremia resolved in all patients at a median of 24 days. Three patients were found to develop other bacterial and/or fungal infections following CMV viremia. Two of the seven patients died during 1-year follow-up, due to primary disease progression or Candida sepsis. None of the patients developed proven tissue-invasive CMV disease. The study did not evaluate the incidence of asymptomatic CMV infection/reactivation. Despite prior publications based on limited data, rituximab does not appear to contribute to an increased frequency of symptomatic CMV reactivation following ASCT. PMID:27225264

  1. Comparative Study on Rituximab Combined with Chemotherapy and Single Chemotherapy for Diffuse Large B Cell Lymphoma

    Institute of Scientific and Technical Information of China (English)

    FENG Ji-feng

    2015-01-01

    Objective:To explore the clinical efifcacy and safety of rituximab combined with chemotherapy and single chemotherapy for diffuse large B cell lymphoma (DLBCL). Methods:A total of 97 patients with DLBCL were selected. Patients treated by single chemotherapy were designed as control group, while those by rituximab combined with chemotherapy as observational group. All patients were treated for at least 4 cycles. The short-term and long-term efifcacy and related adverse reactions of 2 groups were observed. Results:The rate of complete remission (CR) in observational group was signiifcantly higher than in control group (χ2=4.6589,P=0.0309). However, there was no signiifcant difference in objective remission rate (ORR) between 2 groups (P=0.3651). The rates of 3-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) were 80.30% (53/66), 69.70% (46/66) and 59.09% (39/66) in observational group, and 61.29% (19/31), 58.06% (18/31) and 58.06% (18/31) in control group, respectively. The OS in observational group was signiifcantly longer than in control group (P=0.035). However, there was no signiifcant difference in PFS, DFS and rate adverse reactions between 2 groups (P=0.089;P=0.438;χ2=0.1562,P=0.6927). Conclusion: Rituximab combined with chemotherapy can improve the efficacy of DLBCL without increasing the adverse reactions, which can be used as the ifrst-line treatment for DLBCL, thus deserving to be widely applied in clinic.

  2. Is rituximab effective for induction of remission in ANCA-associated vasculitis?

    OpenAIRE

    Carmen Rain; Tatiana Yáñez; Gabriel Rada

    2015-01-01

    La adición de rituximab al tratamiento con corticoides se ha planteado como alternativa terapéutica para inducir remisión en las vasculitis asociadas a anticuerpos anticitoplasma de neutrófilos (ANCA), especialmente en pacientes con deseo de preservar fertilidad que persisten activos después del tratamiento estándar, o en aquellos que tienen contraindicación o mala tolerancia a ciclofosfamida. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases d...

  3. Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma.

    Science.gov (United States)

    Bauwens, Deborah; Maerevoet, Marie; Michaux, Lucienne; Théate, Ivan; Hagemeijer, Anne; Stul, Michel; Danse, Etienne; Costantini, Sabrina; Vannuffel, Pascal; Straetmans, Nicole; Vekemans, Marie-Christiane; Deneys, Véronique; Ferrant, Augustin; Van Den Neste, Eric

    2005-11-01

    We evaluated the combination of rituximab with chlorambucil in patients with mantle cell lymphoma (MCL) not eligible for aggressive therapy. Fourteen patients (male/female: 9/5) were included (two newly diagnosed, 12 relapsed/refractory). The toxicities were neutropenia, thrombopenia and infection. Nine (64%) patients responded; five (36%) achieved complete remission and four (29%) achieved partial remission. The median progression-free survival for responders was 26 months (95% CI, 4-48). Marrow polymerase chain reaction negativity was attained in seven responders. These results suggest that this schedule may have notable antitumour activity in patients with MCL, including patients in relapse after autologous stem cell transplantation. PMID:16225653

  4. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

    DEFF Research Database (Denmark)

    Da Roit, F.; Engelberts, P. J.; Taylor, R. P.;

    2015-01-01

    The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-delta inhibitor idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated...... the possible positive or negative impact of these drugs on all known mechanisms of action of both type I and type II anti-CD20 antibodies. Pretreatment with ibrutinib for 1 hour did not increase direct cell death of cell lines or chronic lymphocytic leukemia samples mediated by anti-CD20 antibodies....... Pre-treatment with ibrutinib did not inhibit complement activation or complement-mediated lysis. In contrast, ibrutinib strongly inhibited all cell-mediated mechanisms induced by anti-CD20 antibodies rituximab, ofatumumab or obinutuzumab, either in purified systems or whole blood assays. Activation of...

  5. Comparative efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    International Nuclear Information System (INIS)

    Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibodystreptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTAbiotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in

  6. Addendum to report of the research co-ordination meeting on labelling techniques of biomolecules for targeted radiotherapy. Country report: Hungary. Preparation, quality control and animal testing of 125I and 131I labelled monoclonal antibody for radiotherapy

    International Nuclear Information System (INIS)

    Radiolabelled monoclonal antibodies (MoAbs) against tumour-associated antigens have been used to detect tumour deposits. Since gamma camera imaging of patients injected with radiolabelled MoAbs has demonstrated, selective tumour uptake of MoAbs, antibody-directed radiotherapy has gained greater interest. Prior to employing antibodies for radioimmunotherapy, their tumour and normal tissue uptake and pharmacokinetics as well as therapeutic efficacy in the animal tumour model must be determined. The therapeutic radiopharmaceuticals consist of two components the radionuclide (beta, alpha, Anger and conversion electron emitters) and the biological carrier (from peptide- to antibody). In the first step of our research program anti CEA MoAb inj. labelled with iodine-125 and 131I isotopes were used to study therapeutic efficacy in nude mice bearing human gastric adenocarcinoma xenografts

  7. Monoclonal antibodies

    International Nuclear Information System (INIS)

    Monoclonal antibodies (MAbs) are antibodies having single specificity for a given antigen site (epitope). The development of hybridoma technology and the relative ease by which MAbs can be prepared has revolutionized many aspects of serological applications in diagnosis and differentiation of disease producing agents. The property of monospecificity offers advantages in diagnostic applications over polyclonal sera in that tests can be defined exactly with regard to the antigen detected and the affinity of reaction between the given antigenic site and the monoclonal reagent. In addition, MAbs offer better possibilities for test standardization, because the same reagent can be used in different laboratories. Such an MAb can be supplied by a central laboratory or 'grown' from hybridoma cells, ensuring that the resultant product is identical from laboratory to laboratory and that the part of the test involving the MAb reaction is the same. The methodologies for inoculation regimes, mice, cloning methods, selection of fusion partners, etc., have been validated extensively in developed country laboratories. The decision to establish a MAb production facility must be examined on a strict cost-benefit basis, since it is still expensive to produce a product. There are many MAbs available that should be sought to allow exploitation in developing tests. If a production facility is envisaged, it should produce reagents for national needs, i.e. there should be a clear problem oriented approach whereby exact needs are defined. In the field of veterinary applications, MAbs are the central reagent in many immunoassays based on the enzyme linked immunosorbent assay (ELISA). The development of specific tests for diagnosing diseases is dominated by MAbs and has been fuelled by a strong research base, mainly in developed countries allied to developing countries through the study of related diseases. Thus, there are very many assays dependent on MAbs, some of which form the basis of

  8. Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy:risk factors and survival

    Institute of Scientific and Technical Information of China (English)

    Kai-Lin Chen; De-Hui Zou; Li-Yang Hu; Michael Lucas Wirian; Qing-Qing Cai; Jie Chen; Hui-Lan Rao; Ying Guo; Hui-Qiang Huang; Liang Zhang; Jian-Yong Shao; Tong-Yu Lin; Wen-Qi Jiang

    2015-01-01

    Introduction:Hepatitis B virus (HBV) reactivation has been reported in B-cel lymphoma patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg]-negative and hepatitis B core antibody [HBcAb]-positive). This study aimed to assess HBV reactivation and hepatitis occurrence in diffuse large B-cel lymphoma (DLBCL) patients with resolved hepatitis B receiving rituximab-containing chemotherapy compared with HBsAg-negative/HBcAb-negative patients to identify risk factors for HBV reactivation and hepatitis occurrence and to analyze whether HBV reactivation and hepatitis affect the survival of DLBCL patients with resolved hepatitis B. Methods:We reviewed the clinical data of 278 patients with DLBCL treated with rituximab-containing therapy between January 2004 and May 2008 at Sun Yat-sen University Cancer Center, China. Predictive factors for HBV reactivation, hepatitis development, and survival were examined by univariate analysis using the chi-square or Fisher’s exact test and by multivariate analysis using the Cox regression model. Results:Among the 278 patients, 165 were HBsAg-negative. Among these 165 patients, 6 (10.9%) of 55 HBcAb-positive (resolved HBV infection) patients experienced HBV reactivation compared with none (0%) of 110 HBcAb-negative patients (P=0.001). Patients with resolved hepatitis B had a higher hepatitis occurrence rate than HBsAg-negative/HBcAb-negative patients (21.8%vs. 8.2%, P=0.013). HBcAb positivity and elevated baseline alanine aminotransferase (ALT) levels were independent risk factors for hepatitis. Among the 55 patients with resolved hepatitis B, patients with elevated baseline serum ALT or aspartate aminotransferase (AST) levels were more likely to develop hepatitis than those with normal serum ALT or AST levels (P=0.037, P=0.005, respectively). An elevated baseline AST level was an independent risk factor for hepatitis in these patients. Six patients with HBV reactivation recovered after immediate antiviral therapy, and

  9. Prolonged extracorporeal membrane oxygenation therapy for severe acute respiratory distress syndrome in a child affected by rituximab-resistant autoimmune hemolytic anemia: a case report

    Directory of Open Access Journals (Sweden)

    Beretta Chiara

    2009-04-01

    Full Text Available Abstract Introduction Autoimmune hemolytic anemia in children younger than 2 years of age is usually characterized by a severe course, with a mortality rate of approximately 10%. The prolonged immunosuppression following specific treatment may be associated with a high risk of developing severe infections. Recently, the use of monoclonal antibodies (rituximab has allowed sustained remissions to be obtained in the majority of pediatric patients with refractory autoimmune hemolytic anemia. Case presentation We describe the case of an 8-month-old Caucasian girl affected by a severe form of autoimmune hemolytic anemia, which required continuous steroid treatment for 16 months. Thereafter, she received 4 weekly doses of rituximab (375 mg/m2/dose associated with steroid therapy, which was then tapered over the subsequent 2 weeks. One month after the last dose of rrituximab, she presented with recurrence of severe hemolysis and received two more doses of rrituximab. The patient remained in clinical remission for 7 months, before presenting with a further relapse. An alternative heavy immunosuppressive therapy was administered combining cyclophosphamide 10 mg/kg/day for 10 days with methylprednisolone 40 mg/kg/day for 5 days, which was then tapered down over 3 weeks. While still on steroid therapy, the patient developed an interstitial pneumonia with Acute Respiratory Distress Syndrome, which required immediate admission to the intensive care unit where extracorporeal membrane oxygenation therapy was administered continuously for 37 days. At 16-month follow-up, the patient is alive and in good clinical condition, with no organ dysfunction, free from any immunosuppressive treatment and with a normal Hb level. Conclusions This case shows that aggressive combined immunosuppressive therapy may lead to a sustained complete remission in children with refractory autoimmune hemolytic anemia. However, the severe life-threatening complication presented by our

  10. Parenteral Treatment of Multiple Sclerosis: The Advent of Monoclonal Antibodies.

    Science.gov (United States)

    Singer, Barry A

    2016-04-01

    Improved disease control is critical for enhancing the lives of those living with multiple sclerosis. With specific immunologic targets, monoclonal antibody (mAb) treatments are highly effective options for relapsing forms of multiple sclerosis. The mechanism, efficacy, and current safety profiles are detailed for the two mAb therapies, natalizumab and alemtuzumab, with regulatory approval in multiple countries. Daclizumab, which targets the interleukin-2 receptor, and ocrelizumab, which depletes B cells, have convincing phase 3 clinical trial data and may very well provide new options in the near future. Trial results of other B-cell-directed therapies, ofatumumab and rituximab, are reviewed. Less-frequent dosing of glatiramer acetate and interferon β-1a highlight developments in the first generation of parenteral immunomodulatory therapy. Remyelination using mAbs has moved into clinical trials with the first agents, anti-LINGO-1, rHIgM22, and anti-SEMA 4D. PMID:27116720

  11. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial

    NARCIS (Netherlands)

    M.H.J. van Oers; R. Klasa; R.E. Marcus; M. Wolf; E. Kimby; R.D. Gascoyne; A. Jack; M. van't Veer; A. Vranovsky; H. Holte; M. van Glabbeke; I. Teodorovic; C. Rozewicz; A. Hagenbeek

    2006-01-01

    We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CH

  12. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy

    Directory of Open Access Journals (Sweden)

    Al-Shammari AM

    2016-04-01

    Full Text Available Ahmed Majeed Al-Shammari,1 Huda Rameez,2 Maha F Al-Taee2 1Department of Experimental Therapy, Iraqi Center for Cancer and Medical Genetic Research, Mustansiriyah University, 2Department of Biotechnology, College of Science, Baghdad University, Baghdad, IraqAbstract: Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou–Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies.Keywords: oncolytic viruses, virotherapy, combination therapy

  13. Rapid infusion with rituximab: short term safety in systemic autoimmune diseases

    DEFF Research Database (Denmark)

    Larsen, Janni Lisander; Jacobsen, Soren

    2013-01-01

    To describe the incidence, types and severity of adverse events, related to an accelerated regime of rituximab infusion in patients with various autoimmune diseases. Fifty-four patients with systemic autoimmune disease, to be treated with 1,000 mg of rituximab twice 2 weeks apart, participated. Pre......-medication (oral prednisolone, anti-histamine and paracetamol) was administered 1-4 h before infusion start. The first infusion was administered over a period of 195 min. The second infusion over a period of 90 min. Any adverse events were classified using the Clinical Trials Classification of Adverse Events...... (CTCAE) v. 3.0. Ten patients (18.5%) experienced at least one infusion-related reaction (IRR) ever. The first infusion was associated with reactions in 4 CTCAE categories of which rhinitis were the most frequent. The CTCAE severity grading showed six patients (11.1%) had a grade 1 reaction. One patient...

  14. Monoclonal antibodies.

    Science.gov (United States)

    2009-01-01

    The ability to produce and exploit monoclonal antibodies (mAbs) has revolutionized many areas of biological sciences. The unique property of an mAb is that it is a single species of immunoglobulin (IG) molecule. This means that the specificity of the interaction of the paratopes on the IG, with the epitopes on an antigenic target, is the same on every molecule. This property can be used to great benefit in immunoassays to provide tests of defined specificity and sensitivity, which improve the possibilities of standardization. The performance of assays can often be determined relating the actual weight of antibody (hence the number of molecules) to the activity. Often the production of an mAb against a specific epitope is the only way that biological entities can be differentiated. This chapter outlines the areas involving the development of assays based on mAbs. The problems involved address include the physical aspects of mAbs and how they may affect assay design and also the implications of results based on monospecific reagents. Often these are not fully understood, leading to assays that are less than satisfactory, which does not justify the relatively high cost of preparing and screening of mAbs. There are many textbooks and reviews dealing with the preparation of mAbs, the principles involved, and various purification and manipulative methods for the preparation of fragments and conjugation. There has been little general information attempting to summarize the best approaches to assay design using mAbs. Much time can be wasted through bad planning, and this is particularly relevant to mAbs. A proper understanding of some basic principles is essential. It is beyond the scope of this chapter to discuss all aspects, but major areas are highlighted. PMID:19219589

  15. A refractory case of subclinical antibody-mediated rejection due to anti-HLA-DQ antibody in a kidney transplant patient.

    Science.gov (United States)

    Fujimoto, Toshinari; Nakada, Yasuyuki; Yamamoto, Izumi; Kobayashi, Akimitsu; Tanno, Yudo; Yamada, Hiroki; Miki, Jun; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases. PMID:26031594

  16. Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab.

    Science.gov (United States)

    Barboza, Nora M; Medina, Daniel J; Budak-Alpdogan, Tulin; Aracil, Miguel; Jimeno, José M; Bertino, Joseph R; Banerjee, Debabrata

    2012-01-15

    Plitidepsin (Aplidin), an antitumor agent of marine origin, presently is undergoing phase II/III clinical trials, and has shown promise for the treatment of lymphoma. Here, we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death. Several Diffuse Large Cell Lymphoma (DLCL) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituximab. All DLCL and Burkitt lymphoma cell lines were inhibited by plitidepsin in nanomolar concentrations, while rituximab sensitivity varied among different cell lines. Ramos and the RL cell lines proved sensitive to rituximab and were used to test the effects of each of the two drugs. The two agents exhibited synergism at all tested concentrations. For in vivo studies, irradiated athymic nude mice were engrafted with the Ramos lymphoma. Treatment was initiated when the tumors were ~0.5 cm in diameter, and toxic and therapeutic effects were monitored. In the in vivo study, additive effects of the combined two drugs, was demonstrated without an increase in host toxicity. The in vitro synergy and the in vivo additive antitumor effects without an increase in host toxicity with two relatively non-marrow suppressive agents encourages further development of this combination for treatment of aggressive B-cell lymphomas. PMID:22336911

  17. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis

    NARCIS (Netherlands)

    Beum, Paul V.; Lindorfer, Margaret A.; Beurskens, Frank; Stukenberg, P. Todd; Lokhorst, Henk M.; Pawluczkowycz, Andrew W.; Parren, Paul W. H. I.; van de Winkel, Jan G. J.; Taylor, Ronald P.

    2008-01-01

    Binding of the CD20 mAb rituximab (RTX) to B lymphocytes in normal human serum (NHS) activates complement (C) and promotes C3b deposition on or in close proximity to cell-bound RTX. Based on spinning disk confocal microscopy analyses, we report the first real-time visualization of C3b deposition and

  18. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma

    DEFF Research Database (Denmark)

    Andersen, Niels S; Pedersen, Lone B; Laurell, Anna;

    2009-01-01

    PURPOSE: Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell...

  19. Anti-Apoptotic Effects of Lentiviral Vector Transduction Promote Increased Rituximab Tolerance in Cancerous B-Cells

    DEFF Research Database (Denmark)

    Ranjbar, Benyamin; Krogh, Louise Bechmann; Laursen, Maria Bach; Primo, Maria Nascimento; Marques, Sara Correia; Dybkær, Karen; Mikkelsen, Jacob Giehm

    2016-01-01

    achieved through effects of lentiviral transduction on cell death mediated by complement. Rather, reduced levels of PARP1 and persistent high levels of CD43 in Rituximab-treated GCBs demonstrate anti-apoptotic effects of lentiviral transduction that may interfere with the outcome and interpretation of...

  20. A report of the medical technology assessment on radioimmunotherapy for B-cell non-Hodgkin lymphoma patients using yttrium-90 ibritumomab tiuxetan

    International Nuclear Information System (INIS)

    Radioimmunotherapy with unsealed source 90Y-ibritumomab tiuxetan requires physicians and paramedics who have adequate knowledge and experience as to anti-cancer chemotherapy, radiation therapy, handling of radioactive materials, etc. as well as adequate facilities, equipments and safety management system. The Japanese Society of Nuclear Medicine and the Japanese Society for Therapeutic Radiology and Oncology recently conducted an economic evaluation about radioimmunotherapy using 90Y-ibritumomab tiuxetan based on the medical technology assessment at the 16 medical facilities. As a result of this survey, the necessity to improve the current reimbursement system under national health insurance has been suggested, so that the cost (4450 ten for five times) for this therapy at the medical facility can be appropriately reimbursed for the proper dissemination of this therapy. (author)

  1. The antibody-linked chelating polymers for nuclear therapy and diagnostics

    International Nuclear Information System (INIS)

    This review deals with the problem of protein modification with chelating polymers. The main purpose of this approach is the preparation of monoclonal antibodies labeled with heavy metal isotopes (α-, β-, and δ-emitting metals and metals used for NMR-tomography). Traditional binding of metals with proteins via chelating agents directly coupled to protein molecule does not allow binding a high number of metal atoms per single protein molecule and can also alter protein specific properties. At the same time, metal-to-protein binding via intermediate chelating polymer makes possible the binding of several dozen metal atoms per single protein without affecting its specific properties. Moreover, the variations in polymer properties and molecular weight allow controlled modified antibody biodistribution and clearance rate. Modified antibodies can be used successfully for nuclear and NMR diagnostics and for nuclear therapy. The following problems are discussed: the chemistry of the coupling of chelating groups to polymer backbone; the binding of chelating polymers to proteins, including monoclonal antibodies; the ability of chelating polymer-to-protein conjugates to bind heavy metals; the influence of the modification on protein conformation and specific properties; the behavior of metal-containing conjugates in vivo; the practical use of conjugates obtained for radioimmunoimaging, radioimmunotherapy, NMR-tomography, and in vitro immunoassays. Future prospects of the approach are also discussed.101 references

  2. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER).

    Science.gov (United States)

    Merrill, Jt; Buyon, Jp; Furie, Ra; Latinis, Km; Gordon, C; Hsieh, H-J; Brunetta, P

    2011-06-01

    The EXPLORER study was designed to assess the response to rituximab versus placebo in patients with moderate to severe extrarenal systemic lupus erythematosus (SLE) receiving background immunosuppression. The definition of response required reduced clinical activity without subsequent flares over 52 weeks, and the study did not meet its efficacy endpoint. The current exploratory analysis assessed flare rates in patients who achieved initial low disease activity response (British Isles Lupus Assessment Group [BILAG] C or better in all organs) during the study. Exploratory reanalysis of data from the EXPLORER trial was conducted, considering alternative definitions for flare. No difference was found between rituximab and placebo in preventing or delaying moderate to severe flares. However, when severe (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent first A flare (hazard ratio = 0.61; p = 0.052) and lowered mean ± SD annualized A flare rates (0.86 ± 1.47 vs. 1.41 ± 2.14; p = 0.038). Eighty-four (49.7%) rituximab-treated patients achieved low disease activity without subsequent A flares versus 31 (35.2%) placebo-treated patients (p = 0.027). Prednisone rescue for A flares was similar in rituximab- (24%) and placebo-treated (14%) patients (p = 0.204). This post hoc analysis evaluates the hypothesis that assessment of BILAG A flares may distinguish potential treatment effects with greater sensitivity than assessment of BILAG B flares. PMID:21478286

  3. Binding Affinity, Specificity and Comparative Biodistribution of the Parental Murine Monoclonal Antibody MX35 (Anti-NaPi2b and Its Humanized Version Rebmab200.

    Directory of Open Access Journals (Sweden)

    Sture Lindegren

    Full Text Available The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics.

  4. Binding Affinity, Specificity and Comparative Biodistribution of the Parental Murine Monoclonal Antibody MX35 (Anti-NaPi2b) and Its Humanized Version Rebmab200.

    Science.gov (United States)

    Lindegren, Sture; Andrade, Luciana N S; Bäck, Tom; Machado, Camila Maria L; Horta, Bruno Brasil; Buchpiguel, Carlos; Moro, Ana Maria; Okamoto, Oswaldo Keith; Jacobsson, Lars; Cederkrantz, Elin; Washiyama, Kohshin; Aneheim, Emma; Palm, Stig; Jensen, Holger; Tuma, Maria Carolina B; Chammas, Roger; Hultborn, Ragnar; Albertsson, Per

    2015-01-01

    The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics. PMID:25970341

  5. Current status of cancer immunodetection with radiolabeled human monoclonal antibodies.

    Science.gov (United States)

    De Jager, R; Abdel-Nabi, H; Serafini, A; Pecking, A; Klein, J L; Hanna, M G

    1993-04-01

    abdominal and pelvic tumors: 68% versus 40% (P < .05). The combination of antibody scan and CT scan was superior to CT scan alone: 80% versus 40% (P < .01). Lesions as small as 0.5 cm in diameter were detected by antibody scan. The CT scan appears superior to the antibody scan for liver metastases. Patients with a high serum titer of HAMA from previous exposure to murine antibodies were successfully imaged. Antibody scans obtained with 99mTc-88BV59 have imaging characteristics similar to murine antibody scans obtained with radiolabeled IgGs. The absence or weak immunogenicity of the human monoclonal antibodies makes them good candidates for radioimmunodetection and radioimmunotherapy. PMID:8511602

  6. Combination of microwave ablation and 131I labeled tumor necrosis therapy chimeric antibody in the treatment of lung cancer

    International Nuclear Information System (INIS)

    Microwave ablation (MWA) has been considered as an advanced, minimally invasive technique in the treatment of lung cancer with a high local efficiency. MWA can inactivate tumor cells based on microwave heating mechanisms. It has a high local control rate of primary peripheral lung cancer and metastatic lung cancer result from percutaneous microwave antennas injection under ultrasound, CT and MRI guidance. However, for the lesions those are greater than 3.0 cm in diameter or abutting the hilars and the diffuse lesions there is less effective. 131I labeled tumor necrosis therapy chimeric antibody (131I-chTNT), a novel radioimmunotherapy which uses cell of degeneration or necrotic tumor cell nuclear antigen as target provides a new therapeutic approach for lung cancer, but the complete response is low. MWA can induce a mass tumor necrosis under the action of microwave thermal effect which greatly increases the targeting area for 131I-chTNT radioimmunotherapy. Therefore, combination of MWA and 131I-chTNT will enhance the treatment efficacy of lung cancer. (authors)

  7. Experimental radioimmunotherapy of a xenografted human colonic tumor (GW-39) producing carcinoembryonic antigen

    International Nuclear Information System (INIS)

    Experiments were undertaken to evaluate the antitumor effects of 131I-labeled goat antibody immunoglobulin G prepared against carcinoembryonic antigen in hamsters bearing the carcinoembryonic antigen-producing GW-39 human colonic carcinoma. At a single injection of 1 mCi 131I and higher, a marked growth inhibition of GW-39 tumors, as well as a considerable increase in the survival time of the tumor-bearing hamsters, could be achieved. At a dose of 1 mCi, the radioactive affinity-purified antibody appeared to be superior to radioactive normal goat immunoglobulin G in influencing tumor growth and survival time, but no significant difference could be seen at the higher dose of 2 mCi given. Radiobiological calculations indicated that the tumors received, at up to 20 days after therapy, 1325 rads for the specific antibody and only 411 rads for the normal immunoglobulin G preparation. These findings encourage the further evaluation of antibodies to tumor markers for isotopic cancer therapy

  8. Studies on the optimization of leukemia and non-Hodgkin lymphoma therapies using opioids, chemotherapy and radioimmunotherapy; Studien zur Optimierung von Leukaemie- und non-Hodgkin-Lymphom-Therapien durch den Einsatz von Opioiden, Chemotherapeutika und Radioimmuntherapien

    Energy Technology Data Exchange (ETDEWEB)

    Roscher, Mareike

    2013-05-24

    Despite complex treatment schedules for cancer, the occurrence of resistances and relapses is a major concern in oncology. Hence, novel treatment options are needed. In this thesis, different approaches using radioimmunotherapy and the opioid D,L-methadone alone or in combination with doxorubicin were analyzed regarding their cytotoxic potential and the triggered signalling pathways in sensitive and resistant leukaemia and non-Hodgkin lymphoma (NHL). The radioimmunoconjugates [Bi-213]anti-CD33 and [Bi-213]anti-CD20 for treatment of acute myeloid leukaemia (AML) or NHL, respectively, were applied exemplary for the use of targeted alpha-therapies (TAT). Depending on the analyzed cell lines, the used activity concentrations and specific activities (MBq/μg antibody) apoptosis was induced abrogating radio- and chemo-cross-resistances specifically. The cell death was caspase-dependent activating the mitochondrial pathway and was executed by downregulation of the anti-apoptotic proteins XIAP and Bcl-xL. D,L-Methadone induces apoptosis in vitro and in vivo in opioid-receptor (OR) expressing cells depending on the OR density and the used concentrations. Resistances could be overcome and proliferation was inhibited. In combination with doxorubicin, a synergistic effect regarding cytotoxicity in ex vivo patient cells and cell lines was observed. This effect depends on the increase of doxorubicin uptake co-administering D,L-methadone whereas doxorubicin enhances OR expression. The activation of OR leads to the downregulation of cAMP playing a pivotal role in apoptosis induction. In vivo, the therapeutic potential of D,L-methadone alone or in combination with doxorubicin could be proven as mice transplanted with human T-ALL-cells could be identified as tumour free. In summary, these studies show that TAT using [Bi-213]anti-CD33 and [Bi-213]anti-CD20 as well as the opioid D,L-methadone harbour the potential to optimize conventional treatment modalities for leukaemia and NHL.

  9. High-Dose [131I]Tositumomab (anti-CD20) Radioimmunotherapy and Autologous Hematopoietic Stem Cell Transplantation for Adults (ge) 60 Years Old with Relapsed or Refractory B-Cell Lymphoma

    International Nuclear Information System (INIS)

    Purpose: The majority of patients with relapsed or refractory B-cell, non-Hodgkin's lymphoma (NHL) are over 60 years of age, yet they are often denied potentially curative high-dose therapy and autologous stem cell transplants (ASCT) due to the risk of excessive treatment-related morbidity and mortality. Myeloablative anti-CD20 radioimmunotherapy (RIT) can deliver curative radiation doses to tumor sites while limiting exposure to normal organs and may be particularly suited for older adults requiring high-dose therapy. Methods: Patients over age 60 with relapsed B-NHL received infusions of tositumomab anti-CD20 antibody labeled with 5-10mCi I-131 tracer for dosimetry purposes followed 10 days later by individualized therapeutic infusions of I-131-tositumomab (median 525 mCi, range 328-1154 mCi) to deliver 25-27Gy to the critical normal organ receiving the highest radiation dose. ASCT was performed approximately 2 weeks after therapy. Results: Twenty-four patients with a median age of 64 (range 60-76) who had received a median of four prior regimens (range 2-14) were treated. Thirteen (54%) had chemotherapy-resistant disease. The estimated 3-year overall and progression-free survivals were 59% and 51%, respectively with a median follow-up of 2.9 years (range 1-6 years). All patients experienced expected myeloablation with engraftment of platelets ((ge) 20K/(micro)L) and neutrophils ((ge)500/(micro)L) occurring a median of 9 and 15 days, respectively following ASCT. There were no treatment-related deaths, and only two patients experienced grade 4 non-hematologic toxicity. Conclusions: Myeloablative RIT and ASCT is a safe and effective therapeutic option for older adults with relapsed B-NHL

  10. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    International Nuclear Information System (INIS)

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens 177Lu-or 86Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq 177Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm3) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm3 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten 86Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  11. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity {sup 86}Y- or {sup 177}Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    Energy Technology Data Exchange (ETDEWEB)

    Cheal, Sarah M.; Lee, Sang-gyu; Punzalan, Blesida; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Xu, Hong; Guo, Hong-fen [Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States); Chalasani, Sandhya; Carrasquillo, Jorge A. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Fung, Edward K. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Jungbluth, Achim [Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY (United States); Zanzonico, Pat B.; O' Donoghue, Joseph [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Smith-Jones, Peter M. [Stony Brook University, Department of Psychiatry and Behavioral Science, Stony Brook, NY (United States); Stony Brook University, Department of Radiology, Stony Brook, NY (United States); Wittrup, K.D. [Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA (United States); Cheung, Nai-Kong V. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States)

    2016-05-15

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens {sup 177}Lu-or {sup 86}Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq {sup 177}Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm{sup 3}) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm{sup 3} tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten {sup 86}Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  12. A plasmablast biomarker for nonresponse to antibody therapy to CD20 in rheumatoid arthritis.

    Science.gov (United States)

    Owczarczyk, Kasia; Lal, Preeti; Abbas, Alexander R; Wolslegel, Kristen; Holweg, Cecile T J; Dummer, Wolfgang; Kelman, Ariella; Brunetta, Paul; Lewin-Koh, Nicholas; Sorani, Marco; Leong, Diane; Fielder, Paul; Yocum, David; Ho, Carole; Ortmann, Ward; Townsend, Michael J; Behrens, Timothy W

    2011-09-21

    An important goal for personalized health care is the identification of biomarkers that predict the likelihood of treatment responses. Here, we tested the hypothesis that quantitative mRNA assays for B lineage cells in blood could serve as baseline predictors of therapeutic response to B cell depletion therapy in subjects with rheumatoid arthritis (RA). In samples from the REFLEX trial of rituximab in inadequate responders to antibodies to tumor necrosis factor-α, a 25% subgroup of treated subjects with elevated baseline mRNA levels of IgJ, a marker for antibody-secreting plasmablasts, showed reduced clinical response rates. There were no significant efficacy differences in the placebo arm subjects stratified by this marker. Prospective testing of the IgJ biomarker in the DANCER and SERENE rituximab clinical trial cohorts and the SCRIPT ocrelizumab cohort confirmed the utility of this marker to predict nonresponse to anti-CD20 therapy. A combination mRNA biomarker, IgJhiFCRL5lo, showed improved test performance over IgJhi alone. This study demonstrates that baseline blood levels of molecular markers for late-stage B lineage plasmablasts identify a ~20% subgroup of active RA subjects who are unlikely to gain substantial clinical benefit from anti-CD20 B cell depletion therapy. PMID:21937757

  13. Antibody-Mediated Rejection: Pathogenesis, Prevention, Treatment, and Outcomes

    Directory of Open Access Journals (Sweden)

    Olivia R. Blume

    2012-01-01

    Full Text Available Antibody-mediated rejection (AMR is a major cause of late kidney transplant failure. It is important to have an understanding of human-leukocyte antigen (HLA typing including well-designed studies to determine anti-MHC-class-I-related chain A (MICA and antibody rejection pathogenesis. This can allow for more specific diagnosis and treatment which may improve long-term graft function. HLA-specific antibody detection prior to transplantation allows one to help determine the risk for AMR while detection of DSA along with a biopsy confirms it. It is now appreciated that biopsy for AMR does not have to include diffuse C4d, but does require a closer look at peritubular capillary microvasculature. Although plasmapheresis (PP is effective in removing alloantibodies (DSAs from the circulation, rebound synthesis of alloantibodies can occur. Splenectomy is used in desensitization protocols for ABO incompatible transplants as well as being found to treat AMR refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade which are bortezomib rituximab and eculizumab, respectively.

  14. Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma.

    Science.gov (United States)

    Mihara, Keichiro; Yanagihara, Kazuyoshi; Takigahira, Misato; Kitanaka, Akira; Imai, Chihaya; Bhattacharyya, Joyeeta; Kubo, Takanori; Takei, Yoshifumi; Yasunaga, Shin'ichiro; Takihara, Yoshihiro; Kimura, Akiro

    2010-10-01

    Using artificial receptors, it is possible to redirect the specificity of immune cells to tumour-associated antigens, which is expected to provide a useful strategy for cancer immunotherapy. Given that B-cell non-Hodgkin lymphoma (B-NHL) cells invariably express CD19 and CD38, these antigens may be suitable molecular candidates for such immunotherapy. We transduced human peripheral T cells or a T-cell line with either anti-CD19-chimeric receptor (CAR) or anti-CD38-CAR, which contained an anti-CD19 or anti-CD38 antibody-derived single-chain variable domain respectively. Retroviral transduction led to anti-CD19-CAR or anti-CD38-CAR expression in T cells with high efficiency (>60%). The T cell line, Hut78, when transduced with anti-CD19-CAR or anti-CD38-CAR, exerted strong cytotoxicity against the B-NHL cell lines, HT and RL, and lymphoma cells isolated from patients. Interestingly, use of both CARs had an additive cytotoxic effect on HT cells in vitro. In conjunction with rituximab, human peripheral T cells expressing either anti-CD19-CAR or anti-CD38-CAR enhanced cytotoxicity against HT-luciferase cells in xenografted mice. Moreover, the synergistic tumour-suppressing activity was persistent in vivo for over 2 months. These results provide a powerful rationale for clinical testing of the combination of rituximab with autologous T cells carrying either CAR on aggressive or relapsed B-NHLs. PMID:20678160

  15. CD20 mutations involving the rituximab epitope are rare in diffuse large B-cell lymphomas and are not a significant cause of R-CHOP failure

    OpenAIRE

    Johnson, Nathalie A.; Leach, Stephen; Woolcock, Bruce; deLeeuw, Ronald J; Bashashati, Ali; Sehn, Laurie H.; Connors, Joseph M; Chhanabhai, Mukesh; Brooks-Wilson, Angela; Gascoyne, Randy D.

    2009-01-01

    The findings of this study indicate that CD20 mutations nvolving the rituximab epitope are rare in both de novo and relapsed diffuse large B-cell lymphoma, and do not represent a significant cause of R-CHOP resistance.

  16. B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves' ophthalmopathy the latest addition to an expanding family

    DEFF Research Database (Denmark)

    Nielsen, Claus H; El Fassi, Daniel; Hasselbalch, Hans K;

    2007-01-01

    In this review, the authors summarise the clinical results obtained after therapy with rituximab in autoimmune diseases, including Graves' disease and Graves' ophthalmopathy. On the basis of qualitative and quantitative analyses of B- and T-cell subsets, and autoantibody levels obtained in other...... diseases before and after rituximab therapy, the authors interpret the results of the only two clinical investigations of the efficacy of rituximab in the treatment of Graves' disease and Graves' opthalmopathy reported so far. No significant effect on autoantibody levels was observed. Nonetheless, 4 out of...... 10 Graves' disease patients remained in remission 400 days after rituximab treatment versus none in the control group, and remarkable improvements in the eye symptoms of patients with Graves' ophthalmopathy were observed. This supports a role for B cells in the pathogenesis of Graves' ophthalmopathy...

  17. Drug: D02994 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02994 Drug Rituximab (genetical recombination) (JAN); Rituximab (USAN/INN); Rituxa...r Antitumors D02994 Rituximab (genetical recombination) (JAN); Rituximab (USAN/INN) Anatomical Therapeutic C...2] Antineoplastics Monoclonal Antibodies Rituximab D02994 Rituximab (genetical re...ntigens CD20 [HSA:931] [KO:K06466] Rituximab [ATC:L01XC02] D02994 Rituximab (genetical recombination) (JAN);... [ATC:L01XC02] D02994 Rituximab (genetical recombination) (JAN); Rituximab (USAN/

  18. Clopidogrel-induced refractory thrombotic thrombocytopenic purpura successfully treated with rituximab.

    Science.gov (United States)

    Khodor, Sara; Castro, Miguel; McNamara, Colin; Chaulagain, Chakra P

    2016-06-01

    Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by microvascular aggregation of platelets and fibrin strands causing thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction. TTP can develop as a result of a deficiency in ADAMTS13 enzyme activity due to either a genetic defect or, more commonly, the development of anti-ADAMTS13 autoantibodies. TTP can also be associated with pregnancy, organ transplant, lupus, infections, and drugs. Here, we present a case of TTP that developed shortly after the start of clopidogrel treatment for acute ischemic stroke and acute myocardial infarction, and describe the clinical presentation, refractory course of the disease, and successful induction of remission through the use of rituximab in a setting of pre-existing autoimmune diseases. PMID:26684918

  19. Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma:

    OpenAIRE

    Horvat, Mateja; Novakovic, Barbara Jezersek

    2010-01-01

    Background The introduction of rituximab into the treatment of patients with non-Hodgkin’s lymphomas has improved the overall response rate, as well as the response duration and the overall survival of patients with B-cell lymphomas. But only a few studies have addressed the question whether the better response (complete response) and the early introduction of rituximab into the treatment translate into the better survival. The aim of this retrospective study was to assess the potential relat...

  20. Hyperinfection by Strongyloides stercoralis probably associated with Rituximab in a patient with mantle cell lymphoma and hyper eosinophilia Hiperinfección por Strongyloides stercoralis probablemente asociada con Rituximab en una paciente con linfoma e hipereosinofilia

    OpenAIRE

    Renzo Nino Incani; Marcos Hernández; María Elena González

    2010-01-01

    The first report to our knowledge, of hyperinfection by Strongyloides stercoralis (HS) and hypereosinophilia, associated to immune suppression by Rituximab (the only drug received for the last one year and 10 months), in a patient with mantle-cell lymphoma (MCL), is presented. The patient has a 3-year history of MCL, and developed two accesses of HS during 2008, including meningitis, pneumonia and presence of larvae of S. stercoralis in the lungs. We had a unique chance to look at cytotoxicit...

  1. Antibodies and Selection of Monoclonal Antibodies.

    Science.gov (United States)

    Hanack, Katja; Messerschmidt, Katrin; Listek, Martin

    2016-01-01

    Monoclonal antibodies are universal binding molecules with a high specificity for their target and are indispensable tools in research, diagnostics and therapy. The biotechnological generation of monoclonal antibodies was enabled by the hybridoma technology published in 1975 by Köhler and Milstein. Today monoclonal antibodies are used in a variety of applications as flow cytometry, magnetic cell sorting, immunoassays or therapeutic approaches. First step of the generation process is the immunization of the organism with appropriate antigen. After a positive immune response the spleen cells are isolated and fused with myeloma cells in order to generate stable, long-living antibody-producing cell lines - hybridoma cells. In the subsequent identification step the culture supernatants of all hybridoma cells are screened weekly for the production of the antibody of interest. Hybridoma cells producing the antibody of interest are cloned by limited dilution till a monoclonal hybridoma is found. This is a very time-consuming and laborious process and therefore different selection strategies were developed since 1975 in order to facilitate the generation of monoclonal antibodies. Apart from common automation of pipetting processes and ELISA testing there are some promising approaches to select the right monoclonal antibody very early in the process to reduce time and effort of the generation. In this chapter different selection strategies for antibody-producing hybridoma cells are presented and analysed regarding to their benefits compared to conventional limited dilution technology. PMID:27236550

  2. Dermatomiositis refractaria asociada a neumonía en organización tratada con rituximab: Reporte de un caso Refractory dermatomyositis associated with chronic organizing pneumonia treated with rituximab: Report of one case

    Directory of Open Access Journals (Sweden)

    Jorge Yáñez V

    2009-01-01

    Full Text Available Chronic organizing pneumonia (COP has often been reported as a pulmonary manifestation of collagen vascular diseases, mainly rheumatoid arhritis, but the association of COP and dermatomyositis (DM has rarely been documented. We report a 55 year-old woman with well-documented DM and a COP. She was refractory to steroids and two other immunosuppressive agents therapy (cyclophosphamide and azathioprine. Therefore, rituximab (2 x 1 g infusions was used for treatment. During the following weeks her strength gradually increased while creatine kinase (CK, C reactive protein and erythrocyte sedimentation rate normalized. After 6 months, she had a relapse with increased muscle enzymes, fever and modérate muscle weakness. After a second course of rituximab (2 x 1 g infusions, the patient demonstrated a remarkable clinical response as indicated by an increase in muscle strength and moderate decline in creatine kinase levels. Lung abnormalities resolved significantly on high resolution chest CT sean. Thus, B-cell depletion therapy with rituximab used alone or in combination with other immunosuppressants may be a viable option in patients with polymyositis-dermatomyositis and pneumonia refractory to current therapies.

  3. Rituximab Treatment Strategy for Patients with Diffuse Large B-Cell Lymphoma after First-Line Therapy: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yuan-Rong Ren

    2015-01-01

    Full Text Available Background: Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP significantly prolonged event-free survival in first-line chemotherapy for patients with diffuse large B-cell lymphoma (DLBCL. But relapse and refractory DLBCL occur frequently. Although rituximab is effective, its role in salvage therapy after autologous transplant remains unclear. Maintenance therapy with rituximab in responding patients after first line chemotherapy may be a useful novel approach capable of eradicating minimal residual disease and to bring survival benefit. This systematic review and meta-analysis evaluated the effects of rituximab maintenance treatment and salvage therapy of patients with DLBCL. Methods: We performed a systematic review and meta-analysis of randomized controlled trials and compared rituximab maintenance or salvage therapy at relapse with observation. We searched the Cochrane Library, PubMed, EMBASE, conference proceedings, databases of ongoing trials, and references of published trials. Two reviewers independently assessed the quality of the trials and extracted data. Hazard ratios for time-to-event data were estimated and pooled. Results: Seven trials including 1470 DLBCL patients were included in this systematic review and meta-analysis. Patients treated with maintenance rituximab have better overall survival (OS and event-free survival (EFS than patients in the observation arm, but there was no statistical significance. Patients who received rituximab salvage therapy for relapse or refractory DLBCL have statistically significantly better OS [HR of death = 0.72, 95% CI (0.55-0.94, P = 0.02], progression-free survival (PFS [HR = 0.61, 95% CI (0.52-0.72, P < 0.05], odds ratio (OR [RR = 1.26, 95% CI (1.07-1.47, P = 0.004] than patients in the observation arm. The rate of infection-related adverse events was higher with rituximab treatment [RR = 1.37, 95% CI = (1.14 - 1.65 P =0.001]. Conclusions: After

  4. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design

    OpenAIRE

    Reddy, V; Jayne, D; Close, D.; Isenberg, D

    2013-01-01

    B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells, reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER s...

  5. Formulation and Characterization of “Ready to Use” 1B4M-DTPA-rituximab for Lu-177 Labeling

    OpenAIRE

    Gorgieva, Darinka; Smilkov, Katarina; Janevik-Ivanovska, Emilija

    2014-01-01

    Investigations for NHL treatment are oriented towards radiolabelled therapeutics. This research focuses on formulation and characterization of a new, ready to label immunoconjugate, 1B4M-DTPA-rituximab, which is suitable for labeling with Lu-177. The conjugation was performed using 20-fold molar excess of the bifunctional chelating agent, 1B4M-DTPA and subsequent lyophilization. The characterization of the (radio)immunoconjugate was performed using SE-HPLC, SDS-PAGE and MALDI-TOF-...

  6. Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab

    OpenAIRE

    Barboza, Nora M.; Medina, Daniel J; Budak-Alpdogan, Tulin; Aracil, Miguel; Jimeno, José M; Bertino, Joseph R.; Banerjee, Debabrata

    2012-01-01

    Plitidepsin (Aplidin), an antitumor agent of marine origin, presently is undergoing phase II/III clinical trials, and has shown promise for the treatment of lymphoma. Here, we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death. Several Diffuse Large Cell Lymphoma (DLCL) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituxim...

  7. Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas.

    Science.gov (United States)

    Ruan, J; Shah, B; Martin, P; Schuster, S J

    2016-07-01

    Lenalidomide is an oral immunomodulatory drug with significant activity in indolent B-cell and mantle cell lymphomas. Lenalidomide has a manageable safety profile whether administered as a single agent or in combination with rituximab. The combination of lenalidomide with rituximab, known as the 'R(2)' regimen, enhances efficacy over what has been shown with monotherapy and has demonstrated activity in patients considered resistant to rituximab. Tolerability of these regimens has been consistent among studies. Asymptomatic neutropenia is the most common grade 3/4 adverse event, typically managed by dose interruption, followed by dose reduction once neutrophils have recovered. Nonhematologic toxicities (e.g. fatigue) are generally low-grade, manageable with concomitant treatment, and/or lenalidomide dose modification. More frequent with R(2), immune-related symptoms such as rash and tumor flare are important to recognize as lenalidomide-associated treatment effects in patients with lymphoma who require supportive care and potential dose modifications. Severe tumor flare reactions with painful lymphadenopathy are not typically observed outside of chronic lymphocytic leukemia/small lymphocytic lymphoma. Venous thromboembolism is uncommon in lymphomas, though prophylaxis is recommended. The general safety profile, differences between lenalidomide monotherapy and R(2) treatment, and optimal strategies for managing adverse events are discussed here. PMID:27052651

  8. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia.

    Science.gov (United States)

    Ghobrial, Irene M; Xie, Wanling; Padmanabhan, Swaminathan; Badros, Ashraf; Rourke, Meghan; Leduc, Renee; Chuma, Stacey; Kunsman, Janet; Warren, Diane; Poon, Tiffany; Harris, Brianna; Sam, Amy; Anderson, Kenneth C; Richardson, Paul G; Treon, Steven P; Weller, Edie; Matous, Jeffrey

    2010-09-01

    This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m(2) on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m(2) weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70-98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM. PMID:20652865

  9. Use of PET volume determination by fuzzy logic in the follow up of lymphomas treated by radio-immunotherapy

    International Nuclear Information System (INIS)

    Purposes: the aim of this study was to assess if the evaluation of tumoral volumes by fuzzy logic was workable for clinical use. This study was performed with patients followed up for radio-immunotherapy of non-Hodgkin's lymphomas with a comparison of the respective contributions of this quantification and Standardized Uptake Value (S.U.V.). Materials and methods: thirty patients underwent 18F-FDG PET before treatment and then in an iterative way. The analysis of 217 lesions allowed to evaluate their volumes and S.U.V.. The evolution of these parameters of quantification was compared. Results: these two quantitative parameters did not statistically differ but there were important discrepancies in some examinations. The determination of volumes was sometimes limited by tumoral localization or junction of lesions. Conclusion: this study proved the feasibility of the determination of tumoral volumes by fuzzy method in clinical use. Quantification supplemented the subjective visual analysis, which in most cases was sufficient to appreciate the progression of the disease. This quantification, usually given by the value of the S.U.V., could be improved by the volume data either in a separated way, or combining intensity and volume (total lesion glycolysis). Further work is necessary to specify the predictive value of these parameters in this particular indication. (authors)

  10. RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

    Directory of Open Access Journals (Sweden)

    Weichert Wilko

    2010-11-01

    Full Text Available Abstract Background Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT with the EGFR-inhibitor cetuximab. Methods Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant and overall survival were calculated using Kaplan-Meier estimation. Results Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%; 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS at 2 years and median overall survival were only 62,5% and 22,2 mo respectively. Conclusion While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial.

  11. Synthesis of chelating agents for actinium 225 complexation and its application in radioimmunotherapy

    International Nuclear Information System (INIS)

    Immunotherapy with radiolabeled antibodies should allow fairly specific targeting of certain cancers. However, iodine 131 may not be the best isotope for tumor therapy because of its limited specific activity, low beta-energy, relatively long half life and strong gamma emission. Another approach to improve therapeutic efficacy is the use of replacement isotopes with better physical properties. Chelator that can hold radio-metals with high stability under physiological conditions are essential to avoid excessive damage to non-target cells; Moreover, the development of new bifunctional chelating agents is essential for this purpose. Accordingly, our efforts have been directed, for several years, to the synthesis of original chelating agents likely to form stable complexes in vivo with the numerous potential candidates for such applications. Therefore, we have developed a new simple and efficient synthesis pathway of 2-(4-iso-thio-cyanate-benzyl)-1,4,7,10,13,16- hexa-aza-cyclo-hexadecane- 1,4,7,10,13,16-hexa-acetic acid, though functionalized on the cycle by a termination allowed coupling to an antibody or any other biological substance such as a hapten. (author)

  12. A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.

    Science.gov (United States)

    Rosenberg, A S; Pariser, A R; Diamond, B; Yao, L; Turka, L A; Lacana, E; Kishnani, P S

    2016-04-01

    Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology. PMID:26928739

  13. Development of a method to measure kinetics of radiolabelled monoclonal antibody in human tumour with applications to microdosimetry: positron emission tomography studies of iodine-124 labelled 3F8 monoclonal antibody in glioma

    International Nuclear Information System (INIS)

    We present a method to assess quantitatively the immuhological characteristics of tumours using radiolabelled monoclonal antibody and positron emission tomography (PET) to improve dosimetry for radioimmunotherapy. This method is illustrated with a glioma patient who injected with 96.2 MPq of iodine-124 labelled 3FB, a murine antibody (IgG3) specific against the ganglioside GD2. Serial PET scans and plasma samples were taken over 11 days. A three-compartment model was used to estimate the plasma to tumour transfer constant (K1), the tumour to plasma transfer constant k2, the association and dissociation constants (k3, k4) of antibody binding, and the binding potential. Tumour radioactivity peaked at 18 h at 0.0045% ID/g. The kinetic parameters were estimated to be: K1=0.048 ml h-1 g-1, k2=0.16 h-1, k3=0.03 h-1, k4=0.015 h-1 and BP=2.25. Based on these kinetic parameters, the amount of tumour-bound radiolabelled monoclonal antibody was calculated. This method permits estimates of both macrodosimetry and microdosimetry at the cellular level based on in vivo non-invasive measurement. (orig.)

  14. Antiphospholipid Antibody Syndrome

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Is Antiphospholipid Antibody Syndrome? Antiphospholipid (AN-te-fos-fo-LIP-id) antibody ... weeks or months. This condition is called catastrophic antiphospholipid syndrome (CAPS). People who have APS also are at ...

  15. The antibody mining toolbox

    OpenAIRE

    D'Angelo, Sara; Glanville, Jacob; Ferrara, Fortunato; Naranjo, Leslie; Gleasner, Cheryl D.; Shen, Xiaohong; Bradbury, Andrew RM; Kiss, Csaba

    2013-01-01

    In vitro selection has been an essential tool in the development of recombinant antibodies against various antigen targets. Deep sequencing has recently been gaining ground as an alternative and valuable method to analyze such antibody selections. The analysis provides a novel and extremely detailed view of selected antibody populations, and allows the identification of specific antibodies using only sequencing data, potentially eliminating the need for expensive and laborious low-throughput ...

  16. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

    Directory of Open Access Journals (Sweden)

    Mandrik O

    2015-08-01

    Full Text Available Olena Mandrik,1 Isaac Corro Ramos,2 Saskia Knies,1,3 Maiwenn Al,1,2 Johan L Severens1,2 1Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Institute of Medical Technology Assessment (iMTA, Erasmus University Rotterdam, Rotterdam, the Netherlands; 3National Health Care Institute, Diemen, the Netherlands Abstract: The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients' survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER

  17. Chemo radioimmunotherapy with 5-fluorouracil, cisplatin and interferon-α in pancreatic and peri-ampullary cancer: Results of a feasibility study

    International Nuclear Information System (INIS)

    Background: Recent studies give rise to the hypothesis, that adjuvant chemo radioimmunotherapy with 5-fluorouracil (5-F.U.), cisplatin and interferon-a (I.F.N.-a) might be a possible new treatment of pancreatic cancer in resected patients. We report the up-to-now experience at our institution. Patients and methods: Eleven patients with histological diagnosis of localized carcinoma of the pancreas (n = 7) or peri-ampullary (n = 4) were prospectively analyzed. Four patients were deemed unresectable because of local invasion of adjacent organs (neo-adjuvant setting) and seven patients underwent curative resection (adjuvant setting). Eight patients were classified as T3 carcinomas and three T4 carcinomas. Fifty-five per cent (6/11) of the patients presented with positive lymph node involvement. One histological Grade I, six Grade II and three Grade III were detected. External conformal irradiation to a total dose of 50.4 Gy with 1.8 Gy per day was delivered. All patients received a concomitant chemotherapy with continuous 5-F.U. 200 mg/m2 per day on 28 treatment days and intravenous bolus cisplatin 30 mg/m2 per week (Day 2, 9, 16, 23, 30). A recombinant r-I.F.N.-a was administered on three days weekly during Week one to five of the radiotherapy course as subcutaneous injections with 3*3 Mio. I.U. weekly. Results: The four-year overall survival rate for all patients was 55%. In the neo-adjuvant group, three of four patients died due to progressive disease; in the adjuvant group, combined chemo radioimmunotherapy lead to controlled disease in five of seven patients. The overall toxicity was well-managed. Conclusion: Our data strengthens the hypothesis of concomitant chemo radioimmunotherapy with 5-F.U., I.F.N.-a and cisplatin as a possible new treatment of pancreatic cancer in resected patients. (authors)

  18. Heavy chain only antibodies

    DEFF Research Database (Denmark)

    Moghimi, Seyed Moein; Rahbarizadeh, Fatemeh; Ahmadvand, Davoud;

    2013-01-01

    Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen...

  19. Hepatitis A virus antibody

    International Nuclear Information System (INIS)

    A description is presented of a radioimmunoassay designed to prove the presence of the antibody against the hepatitis A virus (HA Ab, anti-Ha) using an Abbott HAVAB set. This proof as well as the proof of the antibody against the nucleus of the hepatitis B virus is based on competition between a normal antibody against hepatitis A virus and a 125I-labelled antibody for the binding sites of a specific antigen spread all over the surface of a tiny ball; this is then indirect proof of the antibody under investigation. The method is described of reading the results from the number of impulses per 60 seconds: the higher the titre of the antibody against the hepatitis A virus in the serum examined, the lower the activity of the specimen concerned. The rate is reported of incidence of the antibody against the hepatitis A virus in a total of 68 convalescents after hepatitis A; the antibody was found in 94.1%. The immunoglobulin made from the convalescents' plasma showed the presence of antibodies in dilutions as high as 1:250 000 while the comparable ratio for normal immunoglobulin Norga was only 1:2500. Differences are discussed in the time incidence of the antibodies against the hepatitis A virus, the antibodies against the surface antigen of hepatitis B, and the antibody against the nucleus of the hepatitis V virus. (author)

  20. Radiochemical purification of no-carrier-added scandium-47 for radioimmunotherapy

    International Nuclear Information System (INIS)

    A procedure, adaptable to large-scale remote operation, was developed to purify no-carrier-added (NCA) 47Sc from irradiated Ti targets. Methods based on extraction chromatography and cation-exchange chromatography were compared. Results of this comparison led to the development of an optimized procedure based on cation-exchange with Dowex AG 50W-X4 and 47Sc elution with HCl/HF. This method gave 90-97% overall 47Sc recovery, with a Ti separation factor greater than 2.4x10-5, and specific activities ≥0.9 GBq μg-1. Use of the 47Sc product, for labeling monoclonal antibodies, resulted in consistent labeling yields of ≥90%