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Sample records for antibody rituximab radioimmunotherapy

  1. Bifunctional antibodies for radioimmunotherapy.

    Science.gov (United States)

    Chatal, J F; Faivre-Chauvet, A; Bardies, M; Peltier, P; Gautherot, E; Barbet, J

    1995-04-01

    In two-step targeting technique using bifunctional antibodies, a nonradiolabeled immunoconjugate with slow uptake kinetics (several days) is initially injected, followed by a small radiolabeled hapten with fast kinetics (several hours) that binds to the bispecific immunoconjugate already taken up by the tumor target. In patients with colorectal or medullary thyroid cancer, clinical studies performed with an anti-CEA/anti-DTPA-indium bifunctional antibody and an indium-111-labeled di-DTPA-TL bivalent hapten showed that tumor uptake was not modified compared to results for F(ab')2 fragments of the same anti-CEA antibody directly labeled with indium-111, whereas the radioactivity of normal tissues was significantly reduced (3- to 6-fold). The fast tumor uptake kinetics (several hours) and high or very high tumor-to-normal tissue ratios obtained with the bifunctional antibody technique are favorable parameters for efficient radioimmunotherapy.

  2. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy.

    Science.gov (United States)

    Goldenberg, David M; Sharkey, Robert M; Paganelli, Giovanni; Barbet, Jacques; Chatal, Jean-François

    2006-02-10

    This article reviews the methods of pretargeting, which involve separating the targeting antibody from the subsequent delivery of an imaging or therapeutic agent that binds to the tumor-localized antibody. This provides enhanced tumor:background ratios and the delivery of a higher therapeutic dose than when antibodies are directly conjugated with radionuclides, as currently practiced in cancer radioimmunotherapy. We describe initial promising clinical results using streptavidin-antibody constructs with biotin-radionuclide conjugates in the treatment of patients with malignant gliomas, and of bispecific antibodies with hapten-radionuclides in the therapy of tumors expressing carcinoembryonic antigen, such as medullary thyroid and small-cell lung cancers.

  3. Rituximab selectively suppresses specific islet antibodies.

    Science.gov (United States)

    Yu, Liping; Herold, Kevan; Krause-Steinrauf, Heidi; McGee, Paula L; Bundy, Brian; Pugliese, Alberto; Krischer, Jeff; Eisenbarth, George S

    2011-10-01

    The TrialNet Study Group evaluated rituximab, a B-cell-depleting monoclonal antibody, for its effect in new-onset patients with type 1A diabetes. Rituximab decreased the loss of C-peptide over the first year of follow-up and markedly depleted B lymphocytes for 6 months after administration. This article analyzes the specific effect of rituximab on multiple islet autoantibodies. A total of 87 patients between the ages of 8 and 40 years received either rituximab or a placebo infusion weekly for four doses close to the onset of diabetes. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The primary outcome for this autoantibody analysis was the mean level of autoantibodies during follow-up. Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As, and ZnT8As. A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients (P IAAs were markedly suppressed by rituximab in all patients for 1 year and for four patients as long as 3 years despite continuing insulin therapy. Independent of rituximab treatment, the mean level of IAAs at study entry was markedly lower (P = 0.035) for patients who maintained C-peptide levels during the first year of follow-up in both rituximab-treated and placebo groups. A single course of rituximab differentially suppresses IAAs, clearly blocking IAAs for >1 year in insulin-treated patients. For the patients receiving insulin for >2 weeks prior to rituximab administration, we cannot assess whether rituximab not only blocks the acquisition of insulin antibodies induced by insulin administration and/or also suppresses preformed insulin autoantibodies. Studies in prediabetic non-insulin-treated patients will likely be needed to evaluate the specific effects of rituximab on levels of IAAs.

  4. Antibody conjugate radioimmunotherapy of superficial bladder cancer

    International Nuclear Information System (INIS)

    Perkins, Alan; Hopper, Melanie; Murray, Andrea; Frier, Malcolm; Bishop, Mike

    2002-01-01

    The administration of antibody conjugates for cancer therapy is now proving to be of clinical value. We are currently undertaking a programme of clinical studies using the monoclonal antibody C 595 (gG3) which reacts with the MUC1 glycoprotein antigen that is aberrantly expressed in a high proportion of bladder tumours. Radio immuno conjugates of the C 595 antibody have been produced with high radiolabelling efficiency and immuno reactivity using Tc-99 m and In-111 for diagnostic imaging, and disease staging and the cytotoxic radionuclides Cu-67 and Re-188 for therapy of superficial bladder cancer. A Phase I/II therapeutic trail involving the intravesical administration of antibody directly into the bladder has now begun. (author)

  5. Immunoscintigraphy and radioimmunotherapy in Cuba: experiences with labeled monoclonal antibodies for cancer diagnosis and treatment (1993-2013).

    Science.gov (United States)

    Peña, Yamilé; Perera, Alejandro; Batista, Juan F

    2014-01-01

    INTRODUCTION The availability of monoclonal antibodies in Cuba has facilitated development and application of innovative techniques (immunoscintigraphy and radioimmunotherapy) for cancer diagnosis and treatment. Objective Review immunoscintigraphy and radioimmunotherapy techniques and analyze their use in Cuba, based on the published literature. In this context, we describe the experience of Havana's Clinical Research Center with labeled monoclonal antibodies for cancer diagnosis and treatment during the period 1993-2013. EVIDENCE ACQUISITION Basic concepts concerning cancer and monoclonal antibodies were reviewed, as well as relevant international and Cuban data. Forty-nine documents were reviewed, among them 2 textbooks, 34 articles by Cuban authors and 13 by international authors. All works published by the Clinical Research Center from 1993 through 2013 were included. Bibliography was obtained from the library of the Clinical Research Center and Infomed, Cuba's national health telematics network, using the following keywords: monoclonal antibodies, immunoscintigraphy and radioimmunotherapy. RESULTS Labeling the antibodies (ior t3, ior t1, ior cea 1, ior egf/r3, ior c5, h-R3, 14F7 and rituximab) with radioactive isotopes was a basic line of research in Cuba and has fostered their use as diagnostic and therapeutic tools. The studies conducted demonstrated the good sensitivity and diagnostic precision of immunoscintigraphy for detecting various types of tumors (head and neck, ovarian, colon, breast, lymphoma, brain). Obtaining different radioimmune conjugates with radioactive isotopes such as 99mTc and 188Re made it possible to administer radioimmunotherapy to patients with several types of cancer (brain, lymphoma, breast). The objective of 60% of the clinical trials was to determine pharmacokinetics, internal dosimetry and adverse effects of monoclonal antibodies, as well as tumor response; there were few adverse effects, no damage to vital organs, and a positive

  6. Antibody conjugate radioimmunotherapy of superficial bladder cancer

    Directory of Open Access Journals (Sweden)

    Alan Perkins

    2002-09-01

    Full Text Available The administration of antibody conjugates for cancer therapy is now proving to be of clinical value. We are currently undertaking a programme of clinical studies using the monoclonal antibody C595 (IgG3 which reacts with the MUC1 glycoprotein antigen that is aberrantly expressed in a high proportion of bladder tumours. Radioimmunoconjugates of the C595 antibody have been produced with high radiolabelling efficiency and immunoreactivity using Tc-99m and In-111 for diagnostic imaging, and disease staging and the cytotoxic radionuclides Cu-67 and Re-188 for therapy of superficial bladder cancer. A Phase I/II therapeutic trail involving the intravesical administration of antibody directly into the bladder has now begun.A administração de anticorpos conjugados para o tratamento do câncer está agora provando ser de valor clínico. Nós estamos atualmente realizando um programa de estudos clínicos usando o anticorpo monoclonal C595 (IgG3 que reage com a glicoproteína MUC1 que está aberrantemente expressa numa alta proporção de tumores de bexiga. Tem sido produzidos radioimunoconjugados do anticorpo C595, com alta eficiência de radiomarcação e a imunoreatividade, usando-se o Tc-99m e In-111, para o diagnóstico por imagem e estagiamento de doenças. Tem sido produzidos, também, radionuclídeos citotóxicos (Cu-67 e Re-188 para o tratamento de cânceres superficiais de bexiga. A fase terapêutica I/II já se iniciou, envolvendo a administração intravesical do anticorpo diretamente na bexiga.

  7. Secondary antibodies as tools to improve tumor to non tumor ratio at radioimmunolocalisation and radioimmunotherapy

    International Nuclear Information System (INIS)

    Ullen, A.; Riklund Aalstroem, K.; Hietala, S.O.; Nilsson, B.; Aerlestig, L.; Stigbrand, T.

    1996-01-01

    One way of selectively improving the efficiency of radioimmunolocalization and radioimmunotherapy is to eliminate redundant, circulating, non-targeting radiolabeled antibodies after saturation of the target sites. Secondary antibodies of different types have been proposed as clearing agents for such purposes. The conceptually different approaches of the 'secondary antibody' strategy including its advantages and limitations are discussed. This mini-review also presents a model describing the kinetics of the components (the antigen, the primary and secondary antibodies) and approaches required to improve the efficacy of both radioimmunolocalization and radioimmunotherapy. (orig.)

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

    International Nuclear Information System (INIS)

    Massicano, Adriana Vidal Fernandes

    2011-01-01

    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 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 of the

  9. Severe antiphospholipid antibody syndrome - response to plasmapheresis and rituximab.

    Science.gov (United States)

    Gkogkolou, Paraskevi; Ehrchen, Jan; Goerge, Tobias

    2017-09-01

    Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, recurrent abortions and detection of antiphospholipid antibodies. In fulminant cases, involvement of multiple organs can lead to significant morbidity and even fatal outcomes, so that a rapid, interdisciplinary treatment is needed. Here, we describe the case of a 39-year-old woman with a severe hard-to-treat APS with arterial occlusion and progressive skin necrosis, who was successfully treated with a combination therapy with plasmapheresis and rituximab. The treatment led to complete remission of the skin lesions for over a year. Clinical response correlated with a long-lasting reduction of antiphospholipid antibodies and B-cell depletion. This case demonstrates the use of antiphospholipid antibodies for monitoring APS-activity and shows that this severe vascular disease requires rigorous therapeutic approaches.

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

    International Nuclear Information System (INIS)

    Chatal, J. F.

    2000-01-01

    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.)

  11. Rituximab for the Treatment of Relapses in 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.; Clair, E. W. St.; Tchao, N. K.; Viviano, L.; Ding, L.; Ikle, D.; Villarreal, M.; Jepson, B.; 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.

    2014-01-01

    Objective. Disease relapses are frequent in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. Methods. The Rituximab in AAV trial

  12. 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.

  13. Imaging of Early Response to Predict Prognosis in the First-Line Management of Follicular Non-Hodgkin Lymphoma with Iodine-131-Rituximab Radioimmunotherapy.

    Science.gov (United States)

    Kesavan, Murali; Boucek, Jan; MacDonald, William; McQuillan, Andrew; Turner, J Harvey

    2017-05-12

    The purpose of this study was to evaluate prediction of prognosis after first-line radioimmunotherapy (RIT) of advanced follicular non-Hodgkin lymphoma (FL), by imaging with fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography ( 18 F-FDG-PET/CT) three months after induction treatment by Iodine-131-rituximab ( 131 I-rituximab). Objective response was determined using the Deauville 5-point scale in 68 prospective clinical trial patients. Baseline 18 F-FDG-PET/CT studies were used to calculate total-metabolic-tumor-volume (TMTV). Non-imaging studies included the Follicular lymphoma international prognostic index (FLIPI) and absolute baseline monocyte and lymphocyte counts. Patients were monitored for over ten years (median follow-up 59 months), and no patient was lost to follow-up. Complete response (CR) of 88% predicted excellent prognosis with median time-to-next-treatment (TTNT) not yet reached. Those patients (12%) who failed to achieve CR (Deauville ≤ 3) on 18 F-FDG-PET/CT at three months had significantly poorer outcomes ( p < 0.0001) with a median TTNT of 41 months. Requirement for re-treatment was predicted by FLIPI and absolute baseline monocyte count but not lymphocyte count. The TTNT was accurately predicted by 18 F-FDG-PET/CT Deauville response at three months following first-line therapy of FL with RIT. Early response demonstrated by imaging does, therefore, foretell prognosis in the individual FL patients.

  14. 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.

  15. Radioimmunotherapy with monoclonal antibodies. A new horizon in nuclear medicine therapy?

    Science.gov (United States)

    Sautter-Bihl, M L; Bihl, H

    1994-08-01

    Radioimmunotherapy (RIT) with labeled tumor-associated monoclonal antibodies (MAbs) is a promising concept in oncology, which essentially consists of biological targeting of ionising radiation to tumors. Some encouraging clinical results have been achieved with RIT. However, there are severe problems associated with both understanding the mechanisms and predicting the effectiveness of RIT. This paper reviews the results of some major clinical trials, especially in malignant lymphomas and in some solid tumors. Furthermore, problems with RIT are described such as the significance of dose inhomogeneity and dose-rate effects, the appropriate dose calculation method, the toxicity of RIT and the development of HAMAs. It is suggested that newer technologies including chimeric antibodies, multiple-step targeting protocols, bone marrow transplantation, parallel application of external radiation, heat or bioreductive drugs will enable RIT to make an essential contribution to strategies for combating cancer.

  16. Radioimmunotherapy with monoclonal antibodies. A new horizon in nuclear medicine therapy

    Energy Technology Data Exchange (ETDEWEB)

    Sautter-Bihl, M.L. (Dept. of Radiooncology and Nuclear Medicine, Klinikum Karlsruhe (Germany)); Bihl, H. (Dept. of Nuclear Medicine, Katharinenhospital, Stuttgart (Germany))

    1994-08-01

    Radioimmunotherapy (RIT) with labeled tumor-associated monoclonal antibodies (MAbs) is a promising concept in oncology, which essentially consists of biological targeting of ionising radiation to tumors. Some encouraging clinical results have been achieved with RIT. However, there are severe problems associated with both understanding the mechanisms and predicting the effectiveness of RIT. This paper reviews the results of some major clinical trials, especially in malignant lymphomas and in some solid tumors. Furthermore, problems with RIT are described such as the significance of dose inhomogeneity and dose-rate effects, the appropriate dose calculation method, the toxicity of RIT and the development of HAMAs. It is suggested that newer technologies including chimeric antibodies, multiple-step targeting protocols, bone marrow transplantation, parallel application of external radiation, heat or bioreductive drugs will enable RIT to make an essential contribution to strategies for combating cancer. (orig.)

  17. Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies.

    Science.gov (United States)

    Kawashima, Hidekazu

    2014-01-01

    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 (90)Y-ibritumomab tiuxetan (Zevalin) and (131)I-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.

  18. 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.

  19. Experimental radioimmunotherapy with I-131-antibody against a differentiation antigen

    International Nuclear Information System (INIS)

    Badger, C.C.; Krohn, K.A.; Bernstein, I.D.

    1985-01-01

    The authors have previously shown that I-131-labeled antibodies (Ab) against the Thyl.l antigen can care AKR/Cu (Thyl.2+) mice bearing the AKR/J (Thy 1l.1+) SL2 T-cell lymphoma. The authors have now extended these studies to therapy with I-131-anti-Thyl.1 of SL2 lymphoma in AKR/J mice where Ab reacts with both tumor and normal cells. A 25 μg bolus was rapidly cleared from serum by binding to spleen cells (75% with Tl/2 <60 min.) and only low concentrations of Ab(<2% ID/gm) were present in tumor after infusion. Therapy of AKR/J mice bearing established s.c. lymphoma nodules with 1500 μCi I-131-anti-Thyl.1 resulted in complete regression of the nodule in 6/6 animals although tumor eventually regrew and all animals died of metastatic lymphoma. In contrast, I-131-irrelevant Ab given to produce the same amount of whole body radiation (750 μCi) did not affect tumor growth. These studies suggest that radiolabeled-AB against differentiation antigens may be useful for therapy in spite of binding to normal cell populations

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

    International Nuclear Information System (INIS)

    Dahle, Jostein; Krogh, Cecilie; Melhus, Katrine B.; Borrebaek, Jorgen; Larsen, Roy H.; Kvinnsland, Yngve

    2009-01-01

    Purpose: To determine whether the low-dose-rate α-particle-emitting radioimmunoconjugate 227 Th-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 227 Th-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 227 Th-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 227 Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with 227 Th-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 227 Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 10 5 to 10 7 cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy α-particle radiation from 227 Th-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 227 Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

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

    International Nuclear Information System (INIS)

    Fischer, M.; Behr, T.; Gruenwald, F.; Knapp, W.H.; Truemper, L.; Schilling, C. von

    2004-01-01

    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.)

  2. [Guideline for radioimmunotherapy of rituximab relapsed or refractory CD20(+) follicular B-cell non-Hodgkin's lymphoma].

    Science.gov (United States)

    Fischer, M; Behr, T; Grünwald, F; Knapp, W H; Trümper, L; von Schilling, C

    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.

  3. 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 Joop

    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...

  4. Radioimmunotherapy of fungal diseases: the therapeutic potential of cytocidal radiation delivered by antibody targeting fungal cell surface antigens

    OpenAIRE

    Joshua D Nosanchuk; Ekaterina eDadachova

    2012-01-01

    Radioimmunotherapy is the targeted delivery of cytocidal radiation to cells via specific antibody. Although mature for the treatment of cancer, RIT of infectious diseases is in pre-clinical development. However, as there is an obvious and urgent need for novel approaches to treat infectious diseases, RIT can provide us with a powerful approach to combat serious diseases, including invasive fungal infections. For example, RIT has proven more effective than standard amphotericin B for the treat...

  5. Radioimmunoscintigraphy and radioimmunotherapy with monoclonal antibodies (19-9/anti-CEA and OC 125)

    International Nuclear Information System (INIS)

    Baum, R.P.; Maul, F.D.; Senekowitsch, R.

    1986-01-01

    131 I labelled F (ab') 2 fragments of monoclonal antibodies to tumor-associated antigens (Ca 19-9/DEA and CA 125; specific activity: 55-111 MBq, mean injected activity 61 MBq) were administered to 116 patients for the radioimmunodetection of different malignant tumors (mainly colorectal (19-9/anti-CEA) and ovarian carcinomas (OC 125). Using planar scintigraphy and the second tracer isocontour technique (STIT) sensitivity was 83% and specificity 90% (n = 92 pts.) for the radioimmuno-cocktail 19-9/anti-CEA. In all patients examined with OC 125 retrospectively (n = 17 pts.) immunoscintigraphy was found to be positive. Up to now we have performed three radioimmunotherapies (once with 131 I-19-9/anti-CEA, 2.33 GBq (63mCi); twice with 131 I-OC 125, 3.70 GBq (100 mCi) and 4.63GBq (125 mCi) resulting in radiation doses to the tumor of about 20 Gy. Diagnostic application of radiolabelled monoclonal antibodies is encouraging. For therapeutic use many problems remain to be solved. (Author)

  6. 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...

  7. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis

    NARCIS (Netherlands)

    Isaacs, John D.; Cohen, Stanley B.; Emery, Paul; Tak, Paul P.; Wang, Jianmei; Lei, Guiyuan; Williams, Sarah; Lal, Preeti; Read, Simon J.

    2013-01-01

    Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients. To carry out a meta-analysis of trials from the rituximab

  8. The Pharmacogenomic Association of Fc gamma Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

    NARCIS (Netherlands)

    Cartin-Ceba, Rodrigo; Indrakanti, Divya; Specks, Ulrich; Stone, John H.; Hoffman, Gary S.; Kallenberg, Cees G. M.; Langford, Carol A.; Merkel, Peter A.; Spiera, Robert F.; Monach, Paul A.; St. Clair, E. William; Seo, Philip; Tchao, Nadia K.; Ytterberg, Steven R.; Brunetta, Paul G.; Song, Huijuan; Birmingham, Dan; Rovin, Brad H.; Grp, RAVE-Immune Tolerance Network Res

    Objective The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide

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

    International Nuclear Information System (INIS)

    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-CD40

  10. Comparative analysis of bispecific antibody and streptavidin-targeted radioimmunotherapy for B cell cancers

    Science.gov (United States)

    Green, Damian J.; Frayo, Shani L.; Lin, Yukang; Hamlin, Donald K.; Fisher, Darrell R.; Frost, Sofia H.L.; Kenoyer, Aimee L.; Hylarides, Mark D.; Gopal, Ajay K.; Gooley, Theodore A.; Orozco, Johnnie J.; Till, Brian G.; O’Steen, Shyril; Orcutt, Kelly D.; Wilbur, D. Scott; Wittrup, K. Dane; Press, Oliver W.

    2016-01-01

    Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7) with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hrs. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared to 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (p<0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (p<0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression and superior efficacy. PMID:27590740

  11. Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Thurlings, R. M.; Teng, O.; Vos, K.; Gerlag, D. M.; Aarden, L.; Stapel, S. O.; van Laar, J. M.; Tak, P. P.; Wolbink, G. J.

    2010-01-01

    To analyse whether persistence of synovial B lineage cells and lack of clinical response to rituximab treatment in patients with rheumatoid arthritis (RA) are associated with low rituximab serum levels and anti-rituximab antibody (ARA) formation. Fifty-eight patients with RA were treated with

  12. Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Thurlings, R.M.; Teng, O.; Vos, K.; Gerlag, D.M.; Aarden, L.; Stapel, S.O.; van Laar, J.M.; Tak, P.P.; Wolbink, G.J.

    2010-01-01

    Objectives: To analyse whether persistence of synovial B lineage cells and lack of clinical response to rituximab treatment in patients with rheumatoid arthritis (RA) are associated with low rituximab serum levels and anti-rituximab antibody (ARA) formation. Methods: Fifty-eight patients with RA

  13. Targeting angiogenesis for radioimmunotherapy with a {sup 177}Lu-labeled antibody

    Energy Technology Data Exchange (ETDEWEB)

    Ehlerding, Emily B.; Hernandez, Reinier [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); Lacognata, Saige; Jiang, Dawei [University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); Ferreira, Carolina A. [University of Wisconsin - Madison, Department of Biomedical Engineering, Madison, WI (United States); Goel, Shreya [University of Wisconsin - Madison, Department of Materials Science and Engineering, Madison, WI (United States); Jeffery, Justin J. [University of Wisconsin - Madison, Small Animal Imaging Facility, Madison, WI (United States); Theuer, Charles P. [TRACON Pharmaceuticals, Inc., San Diego, CA (United States); Cai, Weibo [University of Wisconsin - Madison, Department of Medical Physics, Madison, WI (United States); University of Wisconsin - Madison, Department of Radiology, Madison, WI (United States); University of Wisconsin - Madison, Department of Biomedical Engineering, Madison, WI (United States); University of Wisconsin - Madison, Department of Materials Science and Engineering, Madison, WI (United States)

    2018-01-15

    Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy. The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with {sup 177}Lu (t{sub 1/2} 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: {sup 177}Lu only, TRC105 only, {sup 177}Lu-DTPA-IgG (a nonspecific antibody), {sup 177}Lu-DTPA-TRC105 low-dose, and {sup 177}Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of {sup 177}Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose {sup 177}Lu-DTPA-TRC105. Biodistribution studies indicated steady uptake of {sup 177}Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses. {sup 177}Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a

  14. The use of monoclonal antibody (Rituximab in the treatment of type II mixed cryoglobulinemia

    Directory of Open Access Journals (Sweden)

    Thiago Carlos Gonçalves Rego

    Full Text Available Anti-CD20 monoclonal antibody has been successfully used to treat several self-immune diseases. The authors report the case of a 71 year-old female patient under the use of pegylated form of interferon á associated with ribavirin for the treatment of hepatitis C, who, after concluding the therapeutic program - negative Polymerase Chain Reaction (PCR - developed a severe cutaneous vasculitis, receiving the diagnostic of type II mixed cryoglobulinemia. Four sessions of plasmapheresis were prescribed along the period of 11 days, with no result. The choice made was to administer anti-CD 20 monoclonal antibody (rituximab, 375 mg/m², per week, during four consecutive weeks. One could observe fast recovery from the purpura, as well as total remission of urticaria.

  15. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD)

    NARCIS (Netherlands)

    Oertel, SHK; Verschuuren, E; Reinke, P; Zeidler, K; Papp-Vary, M; Babel, N; Trappe, RU; Jonas, S; Hummel, M; Anagnostopoulos, [No Value; Dorken, B; Riess, HB

    2005-01-01

    Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April

  16. 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.

  17. Bone marrow dosimetry using blood-based models for 131i-anti-cd20 rituximab radioimmunotherapy of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Kwon, J. H.; Kim, H. G.; Choi, T. H.

    2005-01-01

    Accurate estimations of radiation absorbed dose are essential part of evaluating the risks and benefits associated with radiotherapy. Determination of red marrow dose is important because myelotoxicity is often dose limiting in radioimmunotherapy. The aim of this study is to set up the procedures of dosimetry with activities in the blood and whole-body and to estimate the dose of patients according to MIRD schema. Therapy activities of 131I (136, 185, 200 mCi) were administrated to patients (n=3). Blood activity concentrations and whole-body images by gamma camera were collected from patients with non-Hodgkin's lymphoma (5min, 6h, 24h, 48h, 72h, 2week). Two kinds of patient specific approaches based on Sgouros bone marrow dosimetry methodology were considered to estimate bone marrow dose. The mean effective half-life in blood and whole-body were 25.2h and 27.1h respectively and the mean absorbed dose to bone marrow was 0.48Gy (0.22∼0.93Gy). The dominant contribution of dose was found to be from bone marrow self-dose (over 60%). The procedures of dosimetry with blood and gamma camera image were established. These enable to estimate the radioimmunotherapy patient's dose retrospectively. Some parts of the procedures need to be elaborated to obtain more accurate dose in the near future

  18. 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

    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....... The rats suffered from reversible myelotoxicity after treatment. CONCLUSIONS: Sequential administration of 177Lu-BR96 and 211At-BR96 resulted in tolerable toxicity providing halogen blocking but did not enhance the therapeutic effect....

  19. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.

    Science.gov (United States)

    Herter, Sylvia; Herting, Frank; Mundigl, Olaf; Waldhauer, Inja; Weinzierl, Tina; Fauti, Tanja; Muth, Gunter; Ziegler-Landesberger, Doris; Van Puijenbroek, Erwin; Lang, Sabine; Duong, Minh Ngoc; Reslan, Lina; Gerdes, Christian A; Friess, Thomas; Baer, Ute; Burtscher, Helmut; Weidner, Michael; Dumontet, Charles; Umana, Pablo; Niederfellner, Gerhard; Bacac, Marina; Klein, Christian

    2013-10-01

    We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation. ©2013 AACR.

  20. Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody.

    Directory of Open Access Journals (Sweden)

    Mark T Winkler

    Full Text Available Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH. We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.

  1. Radioimmunotherapy with an antibody to HPV16 E6 oncoprotein is effective in experimental cervical tumor expressing low levels of E6

    Science.gov (United States)

    Jiang, Zewei; Wang, Xing Guo; Einstein, Mark H; Goldberg, Gary L; Casadevall, Arturo

    2010-01-01

    Purpose HPV16 is associated with ∼50% of all cervical cancers worldwide. The E6 and E7 genes of oncogenic HPV types, such as HPV16, are necessary for the HPV transforming function and tumorogenesis making them ideal targets for novel treatments. Radioimmunotherapy employs systemically administered radiolabeled monoclonal antibodies (mAbs) that bind to tumor-associated antigens. Previously we demonstrated in mice that radioimmunotherapy targeting viral antigens with mAb to HPV16 E6 suppressed CasKi cervical tumors expressing high levels of E6 (∼600 copies of HPV per cell). However, that study opened the question whether radioimmunotherapy can suppress the growth of cervical tumors with low E6 and E7 expression, such as may be seen in patients. Experimental Design We evaluated the expression of E6 in patients' tumors and in the SiHa cell line expressing low levels of E6 and E7 (1–2 copies of HPV per cell) and found them comparable. We initiated SiHa tumors in nude mice, radiolabeled C1P5 mAb to E6 with a beta-emitter 188-Rhenium (188Re) and treated tumor-bearing mice with: (1) 200 µCi 188Re-C1P5 alone; (2) proteasome inhibitor MG132 alone; (3) MG132 followed by 200 µCi 188Re-C1P5; (4) unlabeled C1P5; (5) 200 µCi 188Re-18B7 (isotype-matching control mAb); (6) no treatment. 188Re-C1P5 alone and in combination with MG-132 significantly retarded tumor growth compared to all control groups. Conclusions Our data demonstrate the possibility to suppress tumor growth by targeting viral antigens even in cervical tumors with low E6 expression and provide additional evidence for the potential usefulness of radioimmunotherapy targeting HPV-related antigens in the clinic. PMID:20861673

  2. Efficacy and safety of anti-CD20 antibody rituximab for patients with refractory systemic lupus erythematosus.

    Science.gov (United States)

    Iwata, S; Saito, K; Hirata, S; Ohkubo, N; Nakayamada, S; Nakano, K; Hanami, K; Kubo, S; Miyagawa, I; Yoshikawa, M; Miyazaki, Y; Yoshinari, H; Tanaka, Y

    2018-04-01

    Objective We examined the efficacy and safety of rituximab in patients with refractory systemic lupus erythematosus (SLE). Methods The study enrolled 63 SLE patients who were treated with rituximab between 2002 and 2015. The participants underwent a battery of tests before treatment and at one year. Treatment ranged from two to four times at 500 or 1000 mg. Results Baseline characteristics were males:females = 6:57, age 33.9 years, and disease duration 87.2 months. The primary endpoint: The rate of major clinical response (MCR) was 60% while the partial clinical response (PCR) was 25%. Thirty of 36 (83%) patients with lupus nephritis (WHO II: 2, III: 5, IV: 22, V: 4, IV+V: 2, not assessed: 1) and 22 of 24 patients (92%) with neuropsychiatric SLE, who could be followed at one year, showed changes from BILAG A or B score to C or D score at one year. Multivariate analysis identified high anti-dsDNA antibody and shorter disease duration as significant determinants of MCR at one year. Repeat examination was conducted at five years. Primary failure was recorded in 8.8% and secondary failure in 32.4% (time to relapse: 24.4 months). Rituximab was well tolerated although 65 adverse events, mostly infections, were recorded within one year. Conclusion Rituximab is potentially efficacious for the treatment of patients with refractory SLE.

  3. Rituximab and Monitoring Strategies for Late Antibody-Mediated Rejection After Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Sandesh Parajuli, MD

    2017-12-01

    Conclusion. Treatment of late ABMR with steroids/IVIG ± rituximab was effective in reducing DSA and microcirculation inflammation. The addition of rituximab was associated with better graft survival. Follow-up biopsies could be considered in the management of acute rejection to monitor the effect of therapy. Randomized studies on the best therapeutic options for ABMR are needed.

  4. The anti-CD20 antibody rituximab reduces the Th17 cell response

    NARCIS (Netherlands)

    Veerdonk, F.L. van de; Lauwerys, B.; Marijnissen, R.J.; Timmermans, K.; Padova, F.E. Di; Koenders, M.M.J.F.; Gutierrez-Roelens, I.; Durez, P.; Netea, M.G.; Meer, J.W. van der; Berg, W.B. van den; Joosten, L.A.B.

    2011-01-01

    OBJECTIVE: Rituximab has been shown to be successful in the treatment of rheumatoid arthritis (RA), and this unexpected finding indicates that B cells have an important role in this disease. The present study was undertaken to investigate the mechanism of action of rituximab in RA. METHODS: Twelve

  5. Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT {sup registered})

    Energy Technology Data Exchange (ETDEWEB)

    Urbano, Nicoletta; Papi, Stefano; Paganelli, Giovanni; Chinol, Marco [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Ginanneschi, Mauro [University of Florence and CNR-ICOM, Polo Scientifico, Laboratory of Peptides and Proteins, Chemistry and Biology, Sesto Fiorentino (Italy); De Santis, Rita; Pace, Silvia; Lindstedt, Ragnar; Ferrari, Liliana [Sigma Tau SpA R and D, Pomezia, Rome (Italy); Choi, Sun Ju [Korea Atomic Energy Research Institute, Taejeon (Korea)

    2007-01-15

    A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT {sup registered}) application. Preclinical and clinical results are described. {sup 90}Y and {sup 177}Lu 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 {sup 90}Y or {sup 177}Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both {sup 90}Y- and {sup 177}Lu-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 {proportional_to}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 {proportional_to}12 mGy/MBq. These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials. (orig.)

  6. 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

  7. Intraperitoneal radioimmunotherapy for ovarian cancer: pharmacokinetics, toxicity, and efficacy of I-131 labeled monoclonal antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, J.S.; Hird, V.; Snook, D.; Sullivan, M.; Hooker, G.; Courtenay-Luck, N.; Sivolapenko, G.; Griffiths, M.; Myers, M.J.; Lambert, H.E.

    1989-02-01

    Thirty-six patients with ovarian cancer were treated with intraperitoneal I-131 labeled monoclonal antibodies to tumor associated antigens. The activity of I-131 administered was increased from 20 mCi to 158 mCi and the pharmacokinetics and toxicity evaluated. Five patients who had developed HAMA (Human Antimouse Antibodies) were retreated, and the pharmacokinetics and toxicity of the first and second treatment compared. Patients receiving their first therapy (HAMA negative), had a maximum of 25% (range 19.8-39.8%) of the injected activity in their circulation. This was accompanied by severe marrow suppression at I-131 activities over 120 mCi. The 5 HAMA positive patients had only 5% injected activity in the systemic circulation (range 3.8-6%), with rapid urinary excretion and neglible marrow suppression. In 31 patients with assessable disease there were no responses in 8 patients with gross disease (nodules greater than 2 cms), partial responses in 2 out of 15 patients with nodules less than 2 cms, and complete responses in 3 out of 6 patients with microscopic disease. The non specific radiation dose to the peritoneal cavity was estimated to be less than 500 cGy by lithium fluoride TLD, and could not be expected to account for the responses seen.

  8. 99mTc-rituximab radiolabelled by photo-activation: a new non-Hodgkin's lymphoma imaging agent

    International Nuclear Information System (INIS)

    Gmeiner Stopar, T.; Fettich, J.; Hojker, S.; Mlinaric-Rascan, I.; Mather, S.J.

    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 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 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 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 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 99m Tc-rituximab being internalised over 4 h at 37 C. Our results demonstrate that 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. 99m Tc-rituximab will be further explored as an imaging agent applicable in NHL for the purposes mentioned above. (orig.)

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

    International Nuclear Information System (INIS)

    Cheung, Nai-Kong

    2003-01-01

    because 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 131 I-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

  10. Improvement of Radioimmunotherapy Using Pretargeting

    OpenAIRE

    Frampas, Eric; Rousseau, Caroline; Bodet-Milin, Caroline; Barbet, Jacques; Chatal, Jean-Francois; Kraeber-Bod?r?, Fran?oise

    2013-01-01

    During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled 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 r...

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

    Energy Technology Data Exchange (ETDEWEB)

    Kozak, R.W.; Raubitschek, A.; Mirzadeh, S.; Brechbiel, M.W.; Junghaus, R.; Gansow, O.A.; Waldmann, T.A. (Center for Biologics Evaluation and Research, FDA, Bethesda, MD (USA))

    1989-05-15

    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.

  12. International standards for monoclonal antibodies to support pre- and post-marketing product consistency: Evaluation of a candidate international standard for the bioactivities of rituximab.

    Science.gov (United States)

    Prior, Sandra; Hufton, Simon E; Fox, Bernard; Dougall, Thomas; Rigsby, Peter; Bristow, Adrian

    2018-01-01

    The intrinsic complexity and heterogeneity of therapeutic monoclonal antibodies is built into the biosimilarity paradigm where critical quality attributes are controlled in exhaustive comparability studies with the reference medicinal product. The long-term success of biosimilars will depend on reassuring healthcare professionals and patients of consistent product quality, safety and efficacy. With this aim, the World Health Organization has endorsed the need for public bioactivity standards for therapeutic monoclonal antibodies in support of current controls. We have developed a candidate international potency standard for rituximab that was evaluated in a multi-center collaborative study using participants' own qualified Fc-effector function and cell-based binding bioassays. Dose-response curve model parameters were shown to reflect similar behavior amongst rituximab preparations, albeit with some differences in potency. In the absence of a common reference standard, potency estimates were in poor agreement amongst laboratories, but the use of the candidate preparation significantly reduced this variability. Our results suggest that the candidate rituximab standard can support bioassay performance and improve data harmonization, which when implemented will promote consistency of rituximab products over their life-cycles. This data provides the first scientific evidence that a classical standardization exercise allowing traceability of bioassay data to an international standard is also applicable to rituximab. However, we submit that this new type of international standard needs to be used appropriately and its role not to be mistaken with that of the reference medicinal product.

  13. Optimization of 90 Y-antiCD20 preparation for radioimmunotherapy

    Directory of Open Access Journals (Sweden)

    Nazila Gholipour

    2013-01-01

    Full Text Available Context: The advent of monoclonal antibodies such as Rituximab, in recent years, has brought about decisive progress in the treatment of aggressive and indolent non-Hodgkin′s lymphoma. Aims: A further tried and tested improvement to the unmodified antibody has been its coupling to the beta-emitters Y-90. The optimization of 90 Y-antiCD20 radioimmunoconjugate production and quality control methods for future clinical studies in the country was targeted in this work. Materials and Methods: The antibody was labeled with 90 Y-yttrium chloride (185 MBq after conjugation with freshly prepared ccDTPA. Y-90 chloride was obtained by thermal neutron flux (4 × 10 13 n/cm 2 /s of a natural Y 2 O 3 sample, dissolved in acidic media. Radiolabeling was completed in 24 h by the addition of DTPA-Rituximab conjugate at room temperature. Statistical Analysis Used: All values were expressed as mean ± standard deviation (mean ± SD, and the data were compared using Student′s t-test. Statistical significance was defined as P < 0.05. Results: Radiochemical purity of 96% was obtained by using ITLC method for the final radioimmunoconjugate (specific activity = 440-480 MBq/mg. The final isotonic 90 Y-Rituximab complex was checked by gel electrophoresis for protein integrity retention. Biodistribution studies in normal rats were carried out to determine the radioimmunoconjugate distribution up to 72 h. Conclusion: The results showed that 90 Y-DTPA-Rituximab could be considered for further evaluation in animals and possibly in humans as a radiopharmaceutical for use in radioimmunotherapy against non-Hodgkin′s lymphomas. Because of the importance of developing anti-lymphoma B agents in nuclear medicine for country use, an optimized radiolabeling method has been introduced.

  14. Radioimmunotherapy of cancer: Historical perspectives and prospects for the future

    International Nuclear Information System (INIS)

    Beierwaltes, W.H.; Khazaeli, M.B.

    1983-01-01

    The authors offer the historical perspectives and prospects for the future for radioimmunotherapy of cancer. The first radioimmunotherapy treatments, the development of human chorionic gonadotropin (hCG) hormone as a tumor specific antigen and the use of monoclonal antibodies are described

  15. Preliminary Experience with Yttrium-90-labelled Rituximab (Chimeric Anti CD-20 Antibody) in Patients with Relapsed and Refractory B Cell Non-Hodgkins Lymphoma.

    Science.gov (United States)

    Thakral, Parul; Singla, Suhas; Vashist, Atul; Yadav, Madhav P; Gupta, Santosh K; Tyagi, Jaya S; Sharma, Atul; Bal, Chandra S; Snehlata, EmptyYN Y; Malhotra, Arun

    2016-01-01

    The aim of the study is to evaluate the therapeutic efficacy and safety of Yttrium- 90 radiolabelled chimeric anti CD20 antibody-Rituximab in the treatment of patients with relapsed/ refractory B cell Non-Hodgkins Lymphoma (NHL). Twenty patients with relapsed/refractory CD20+ NHL in progressive state were included in the study. These patients had undergone a median of 2 (range 2-5) prior standard chemotherapy ± immunotherapy regimens. All the patients received rituximab 250 mg/m2 on days 1 and 8, and either 14 MBq/kg (0.4 mCi/kg) or 11 MBq/kg (0.3 mCi/kg) of Y-90 Rituximab on day 8 (maximum dose, 32 mCi) depending upon their platelet count. The patients were observed for systemic toxicity and response for at least 12 weeks after therapy. No acute adverse effects were observed after the administration of 90Y-Rituximab. Overall response rate (ORR) was 45% of which complete response (CR) was observed in 2 patients, stable disease in 1 patient and partial response in 6 patients. The therapy was well tolerated with grade IV thrombocytopenia, neutropenia and anemia observed in 3, 4 and 2 patients respectively. 90Y-Rituximab therapy is safe and well tolerated in high risk extensively pretreated NHL patients. Toxicity is primarily hematologic, transient and reversible.

  16. Rituximab in Minimal Change Disease

    Directory of Open Access Journals (Sweden)

    Nima Madanchi

    2017-03-01

    Full Text Available Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD. MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.

  17. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma.

    Science.gov (United States)

    Mahé, M A; Fumoleau, P; Fabbro, M; Guastalla, J P; Faurous, P; Chauvot, P; Chetanoud, L; Classe, J M; Rouanet, P; Chatal, J F

    1999-10-01

    Standard treatment of advanced ovarian cancer is a combination of surgery and chemotherapy. Additional therapies using the i.p. route are considered as a potential means of improving the locoregional control rate. This Phase II study evaluated the efficacy of i.p. radioimmunotherapy (RIT) in patients with minimal residual ovarian adenocarcinoma after primary treatment with surgery and chemotherapy. Between February 1995 and March 1996, six patients with residual macroscopic (<5 mm) or microscopic disease as demonstrated by laparotomy and multiple biopsies received i.p. RIT. All had initial stage III epithelial carcinoma and were treated with debulking surgery and one line (four patients) or two lines (two patients) of chemotherapy. RIT was performed with 60 mg of OC 125 F(ab')2 monoclonal antibody labeled with 4.44 GBq (120 mCi) of 131I injected 5-10 days after the surgical procedure. Systematic laparoscopy or laparotomy with multiple biopsies performed 3 months after RIT in five patients (clinical progression was seen in one patient) showed no change in three patients and progression in two patients. Toxicity was mainly hematological, with grade III neutropenia and thrombocytopenia in two patients. Human antimouse antibody production was demonstrated in all six patients. This study showed little therapeutic benefit from i.p. RIT in patients with residual ovarian carcinoma.

  18. Combination of rituximab with blinatumomab (MT103/MEDI-538), a T cell-engaging CD19-/CD3-bispecific antibody, for highly efficient lysis of human B lymphoma cells.

    Science.gov (United States)

    d'Argouges, Sandrine; Wissing, Sandra; Brandl, Christian; Prang, Nadja; Lutterbuese, Ralf; Kozhich, Alex; Suzich, Joann; Locher, Mathias; Kiener, Peter; Kufer, Peter; Hofmeister, Robert; Baeuerle, Patrick A; Bargou, Ralf C

    2009-03-01

    We have compared the cytotoxic activity of rituximab with that of blinatumomab (MT103/MEDI-538), a single-chain CD19-/CD3-bispecific antibody engaging human T cells. Blinatumomab consistently led to a higher degree of lysis of human lymphoma lines than rituximab, and was active at much lower concentration. The cytotoxicity mediated by blinatumomab and rituximab both caused a potent activation of pro-caspases 3 and 7 in target cells, a key event in induction of granzyme-mediated apoptotic cell death. Combination of rituximab with blinatumomab was found to greatly enhance the activity of rituximab, in particular at low effector-to-target cell ratios and at low antibody concentration.

  19. Consolidation of first remission using radioimmunotherapy with yttrium-90-ibritumomab-tiuxetan in adult patients with Burkitt lymphoma.

    Science.gov (United States)

    Koechli, Valentin; Klaeser, Bernd; Banz, Yara; Mueller, Beatrice U; Pabst, Thomas

    2015-03-01

    The addition of anti-CD20 antibodies to high intensity polychemotherapy regimens has improved response and survival rates in newly diagnosed patients with Burkitt lymphoma (BL). However, the role of additional anti-CD20 directed radioimmunotherapy for consolidation of first remission (CR1) has not been reported so far in BL patients receiving rituximab during first-line treatment. We compared five BL patients receiving Y-90-IT radioimmunotherapy consolidation in CR1 to 22 consecutive BL patients without consolidation. We observed that Y-90-IT treatment was associated with clinically relevant myelosuppression. After a median follow-up of 50 months, none of the patients with Y-90-IT treatment relapsed, and no patient died. In contrast, one patient (4.5%) in the non-Y-90-IT group relapsed (50 months-PFS 95.5%; p=0.6336), and one patient died (50 months-OS 95.5%; p=0.6171). In conclusion, our data suggest that survival rates are excellent and equal in rituximab pretreated BL patients with or without Y-90-IT consolidation in first remission. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study.

    Directory of Open Access Journals (Sweden)

    Øystein Fluge

    Full Text Available Chronic fatigue syndrome (CFS is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.In this double-blind, placebo-controlled phase II study (NCT00848692, 30 CFS patients were randomised to either Rituximab 500 mg/m(2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67% in the Rituximab group and in two out of 15 patients (13% in the Placebo group (p = 0.003. Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44. Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed, with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact

  1. [Radioimmunotherapy in the treatment of cancers].

    Science.gov (United States)

    Mahé, M; Chatal, J F

    1994-09-01

    Radioimmunotherapy is a special form of internal radiotherapy which uses radiolabeled monoclonal antibodies. Until now, best results were achieved in refractory lymphomas and in ovarian cancer with minimal tumor residues. Several approaches are now under investigation to enhance tumor uptake and to improve hematologic tolerance. Recent advances in radiobiology are helpful to select future indications of this new method of treatment.

  2. 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

  3. Radiolabeling parameters of 177Lu-DOTA-RITUXIMAB

    International Nuclear Information System (INIS)

    Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de

    2013-01-01

    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 177 LuCl 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)

  4. 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)

  5. Yttrium-90 for cancer radioimmunotherapy

    International Nuclear Information System (INIS)

    Hupf, H.B.; Wanek, P.M.; Barbosa, B.; Poggenburg, J.K.

    1989-01-01

    An ideal radiopharmaceutical for cancer therapy must provide a sufficient radiation dose to destroy all the viable malignant cells while sparing normal cells of critical body organs. The strategy implies a radionuclide with high linear energy transfer, a moderate range in tissue and a high equilibrium dose constant be delivered specifically to target cells. Yttrium-90 coupled with tumor-cell-specific antibody approaches the ideal product necessary for radioimmunotherapy. Yttrium-90 is separated from its fission by-product parent Sr-90, purified and aseptically coupled with an antibody conjugate to prepare a therapy radiopharmaceutical. The same antibody conjugate is labeled with In-111 and used after injection for estimating tumor targeting and therapy planning. A dedicated robotic facility has been constructed for safe handling of the large quantities of radioactive materials used. Several Phase 1 clinical protocols using the Y-90 and In-111 antibody labeled matched pair have been initiated, providing excellent safety results and several tumor remissions

  6. Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131I-labeled bivalent hapten in a phase I optimization clinical trial.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Ferrer, Ludovic; Faivre-Chauvet, Alain; Campion, Loïc; Vuillez, Jean-Philippe; Devillers, Anne; Chang, Chien-Hsing; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2006-02-01

    Safety, targeting, and antitumor efficacy of pretargeted radioimmunotherapy using anti-carcinoembryonic antigen (CEA) hMN-14 x m734 bispecific antibody (BsmAb) and 131I-di-diethylenetriamine pentaacetic acid (DTPA)-indium hapten were evaluated in a phase I study performed on patients with CEA-expressing tumors. Twenty-two patients with nonmedullary thyroid carcinoma (non-MTC) (group I, 13 patients) or medullary thyroid carcinoma (MTC) (group II, 9 patients) were enrolled. These patients received a 75 mg/m2 (11 patients) or 40 mg/m2 (11 patients) dose of BsmAb and escalating activities of (131)I-di-DTPA-indium 5 d later. Toxicity and tumor response were assessed in 20 patients who received a therapeutic (>2.2 GBq) hapten dose of radioactivity. The percentage of lesions detected by immunoscintigraphy after injection of the therapeutic dose of hapten was 70% on an anatomic-site basis. High bone uptake was relatively frequent. A transient grade I or II hepatic toxicity was observed in 5 patients (45%) injected with 75 mg/m2 of BsmAb and in 1 patient (11%) injected with 40 mg/m2. No other nonhematologic toxicity was observed. With 75 mg/m2 of BsmAb, hematologic toxicity was high: 5 cases of grade III or IV leukopenia (45%) and 5 cases of grade III or IV thrombopenia (45%). With a 40 mg/m2 dose of BsmAb, hematologic toxicity was reduced significantly: 3 cases of grade III or IV leukopenia (33%) and 1 case of grade III or IV thrombopenia (11%) (P = 0.02). Toxicity was significantly higher in MTC patients than in non-MTC patients (P = 0.019). Nine cases of tumor stabilization of 3 mo to more than 12 mo were observed (45%), 6 in the MTC group and 3 in the non-MTC group. The rate of disease stabilization was significantly higher with 75 mg/m2 of BsmAb (64%) than with 40 mg/m2 (22%) (P = 0.04). Human antimouse antibody elevation was observed in 1 patient (8%) and human antihuman antibody in 4 (33%). A BsmAb dose of 40 mg/m2 and a 5-d interval appeared to be a better dose

  7. 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

  8. Improved radioimmunotherapy of hematologic malignancies

    International Nuclear Information System (INIS)

    Press, O.W.

    1992-01-01

    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 ( 131 Iodine, 111 Indium, 90 Yttrium, 99m Technetium, 186 Rhenium); and to examine the utility of radioimmunoconjugates targeting oncogene products for the radioimmunotherapy and radioimmunoscintigraphy of cancer

  9. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Poepperl, G.; Gildehaus, F.J.; Hahn, K.; Tatsch, K. [Klinik und Poliklinik fuer Nuklearmedizin, Klinikum Grosshadern, Muenchen (Germany); Goetz, C.; Reulen, H.J. [Klinik und Poliklinik fuer Neurochirurgie, Klinikum Grosshadern, Muenchen (Germany); Yousry, T.A. [Inst. fuer Neuroradiologie der LMU Muenchen, Klinikum Grosshadern, Muenchen (Germany)

    2002-06-01

    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 {sup 131}labelled 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

  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)

    Press, O.W.

    1996-01-01

    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. Choice of radionuclides for radioimmunotherapy

    International Nuclear Information System (INIS)

    DeNardo, S.J.; Jungerman, J.A.; DeNardo, G.L.; Lagunas-Solar, M.C.; Cole, W.C.; Meares, C.F.

    1985-01-01

    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

  15. Radioimmunotherapy is an effective adjuvant treatment after cytoreductive surgery of experimental colonic peritoneal carcinomatosis.

    NARCIS (Netherlands)

    Koppe, M.J.; Hendriks, T.; Boerman, O.C.; Oyen, W.J.G.; Bleichrodt, R.P.

    2006-01-01

    Because tumor targeting with radiolabeled monoclonal antibodies is more efficient in small lesions, radioimmunotherapy is considered most suitable for minimal or microscopic residual disease. The aim of the present studies was to assess the efficacy of adjuvant radiommunotherapy using radiolabeled

  16. 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

  17. Radioimmunotherapy in treatment of malignancies. La radio-immunotherapie dans le traitement des cancers

    Energy Technology Data Exchange (ETDEWEB)

    Mahe, M.; Chatal, J.F. (Centre Hospitalier Universitaire, 44 - Nantes (France))

    1994-01-01

    Radioimmunotherapy is a special form of internal radiotherapy which uses radiolabeled monoclonal antibodies. Until now, best results were achieved in refractory lymphomas and in ovarian cancer with minimal tumor residues. Several approaches are now under investigation to enhance tumor uptake and to improve hematologic tolerance. Recent advances in radiobiology are helpful to select future indications of this new method of treatment. (authors). 92 refs., 7 tabs.

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

    International Nuclear Information System (INIS)

    Divgi, C.

    2001-01-01

    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)

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

    DEFF Research Database (Denmark)

    Elgqvist, Jörgen; Andersson, Håkan; Haglund, Elin

    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....

  20. 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.

  1. Improvement of radioimmunotherapy using pretargeting.

    Science.gov (United States)

    Frampas, Eric; Rousseau, Caroline; Bodet-Milin, Caroline; Barbet, Jacques; Chatal, Jean-Francois; Kraeber-Bodéré, Françoise

    2013-01-01

    During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled 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.

  2. Immunoscintigraphy and radioimmunotherapy of transplanted pancreatic carcinoma

    International Nuclear Information System (INIS)

    Klapdor, R.; Greten, H.; Saccavini, J.C.; Dietel, M.

    1985-01-01

    The immunoscintigraphic results in 12 human pancreatic carcinomas established on nude mice (Nu-Nu-Balb-C) are reported. 131 I-labeled monoclonal antibodies against CA 19-9, CEA and CA 125 were used. The result show that pancreatic carcinomas are detectable with the antibodies applied here. The quality of the scintigraphic detection depends, among other factors, on the antibody affinity to the tumor, the localization and the size of the tumor. Preliminary results of the studies on radioimmunotherapy of pancreatic cancer with 131 I-anti-CA 19-9 indicate that effective absorbed doses in the tumor may be achieved via intravenous application only in cases with a rather high expression of the tumor antigen. But direct instillation into the tumor enables therapeutic radiation doses to the tumor even with moderate affinity and a low whole-body burden. (orig./MG) [de

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

    International Nuclear Information System (INIS)

    Schomäcker, Klaus; Fischer, Thomas

    2010-01-01

    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

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Fares Al-Ejeh

    Full Text Available 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.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.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-targeted ionizing radiation induces additional cycles of tumor cell death

  6. [Radioimmunotherapy of malignant diseases. Value and prospects].

    Science.gov (United States)

    Mahé, M A; Chatal, J F

    1995-01-07

    Radioimmunotherapy is based on the use of radioactive agents (iodine 131, yttrium 90...), murine-derived monoclonal antibodies and specific tumour-related membrane antigens. This new treatment modality was applied in 800 patients with different types of malignant tumours which had not responded to traditional therapy. Among the haematologic tumours, the most promising results were obtained in B phenotype non-Hodgkin lymphoma. More modest results were obtained for solid tumours although good results were observed after intraperitoneal administration in patients with cancer of the ovary. The main side effects are acute reversible anaphylactic shock, haematologic toxicity and development of anti-murine human antibodies. Several methods are currently under study to increase irradiation dose delivered at the tumoural site since less than 1% of the injected radioactive dose is absorbed by tumoural cells. Several clinical studies are to be conducted in France, particularly for malignant non-Hodgkin lymphoma and cancer of the ovary.

  7. Comparison of radioimmunotherapy and external beam radiotherapy in colon cancer xenografts

    International Nuclear Information System (INIS)

    Buras, R.R.; Wong, J.F.C.; Kuhn, J.A.; Beatty, B.G.; Williams, L.E.; Beatty, J.D.; Wanek, P.M.

    1993-01-01

    Radioimmunotherapy and external beam radiotherapy were compared in a nude mouse human colon cancer model. Radioimmunotherapy was delivered by intraperitoneal injection of 90 Y-labeled anticarcinoembryonic antigen monoclonal antibody (anti-CEA MAB). Single fraction external beam radiotherapy was delivered using a 60 Co teletherapy unit. Control groups received saline, unlabeled anit-CEA monoclonal antibody and labeled nonspecific monoclonal antibody. Tumor growth suppression was expressed as delay to reach 2g compared to saline controls. Unlabeled anti-CEA monoclonal antibody and labeled nonspecific monoclonal antibody had no effect. External beam radiotherapy of 300, 600, 1000 and 2000 cGy produced growth delays of 3, 12, 17, and 22 days, respectively. Radioimmunotherapy with 120 μCi, 175 μCi, and 225 μCi resulted in growth delays of 20, 34, and 36 days. Estimated absorbed tumor dose was 1750 cGy in the 120 μCi group. Similar comparisons were done with the more radioresistant WiDr human colon carcinoma cell line. External beam radiotherapy doses of 400, 800, 1200, and 1600 cGy resulted in growth delays of 6, 21, 36 and 48 days, respectively. Radioimmunotherapy of 120 μCi and 175 μCi resulted in growth delays of 9 and 19 days, respectively. The 120 μCi dose delivered an estimated absorbed tumor dose of 1080 cGy to WiDr tumors. In summary, for the radiosensitive LS174T line, radioimmunotherapy produced biologic effects that were comparable to a similar dose of single fraction external beam radiotherapy. For the more radioresistant WiDr tumor, radioimmunotherapy produced a biologic effect which was less than a similar dose of single fraction external beam radiotherapy. These studies suggest that a tumor's response to radioimmunotherapy relative to that of external beam radiotherapy is, in part, dependent on tumor radiosensitivity and repair capacity. 23 refs., 5 figs. 4 tabs

  8. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome

    Science.gov (United States)

    Lunde, Sigrid; Kristoffersen, Einar K.; Sapkota, Dipak; Risa, Kristin; Dahl, Olav; Bruland, Ove; Mella, Olav; Fluge, Øystein

    2016-01-01

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6–9.5 g/L, IgA 1.8–1.5 g/L, and IgM 0.97–0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B

  9. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development

    NARCIS (Netherlands)

    Klink, D. T.; van Elburg, R. M.; Schreurs, M. W. J.; van Well, G. T. J.

    2008-01-01

    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

  10. Pretargeting with the affinity enhancement system for radioimmunotherapy.

    Science.gov (United States)

    Barbet, J; Kraeber-Bodéré, F; Vuillez, J P; Gautherot, E; Rouvier, E; Chatal, J F

    1999-06-01

    The pretargeting 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 AES 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.

  11. Radioimmunotherapy of small cell lung carcinoma with the two-step method using a bispecific anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid (DTPA) antibody and iodine-131 Di-DTPA hapten: results of a phase I/II trial.

    Science.gov (United States)

    Vuillez, J P; Kraeber-Bodéré, F; Moro, D; Bardiès, M; Douillard, J Y; Gautherot, E; Rouvier, E; Barbet, J; Garban, F; Moreau, P; Chatal, J F

    1999-10-01

    As small cell lung carcinoma (SCLC) is frequently a widespread disease at diagnosis, highly radiosensitive and often only partially responsive to chemotherapy, radioimmunotherapy (RIT) would appear to be a promising technique for treatment. We report the preliminary results of a Phase I/II trial of RIT in SCLC using a two-step method and a myeloablative protocol with circulating stem cells transplantation. Fourteen patients with proved SCLC relapse after chemotherapy were treated with RIT. They were first injected i.v. with a bispecific (anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid) monoclonal antibody (20-80 mg in 100 ml of saline solution) and then 4 days later with di-(In-diethylenetriaminepentaacetic acid)-tyrosyl-lysine hapten labeled with 1.48-6.66 GBq (40-180 mCi) of I-131 and diluted in 100 ml of saline solution. In patients receiving 150 mCi or more, circulating stem cells were harvested before treatment and reinfused 10-15 days later. Treatment response was evaluated by CT and biochemical data during the month before and 1, 3, 6, and 12 months after treatment. All patients received the scheduled dose without immediate adverse reactions to bispecific antibody or 1-131 hapten. Toxicity was mainly hematological, with two cases of grade 2 leukopenia and three cases of grade 3 or 4 thrombopenia. Body scanning 8 days after injection of the radiolabeled hapten generally showed good uptake at the tumor sites. Estimated tumor dose was 2.6-32.2 cGy/mCi. Among the 12 patients evaluated to date, we have observed 9 progressions, 2 partial responses (one almost complete for 3 months), and 1 stabilization of more than 24 months. Efficiency and toxicity were dose-related. The maximal tolerable dose without hematological rescue was 150 mCi. These preliminary results are encouraging, and dose escalation is currently continuing to reach 300 mCi. RIT should prove to be an interesting therapeutic method for SCLC, although repeated injections and

  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. Radioimmunotherapy: Development of an effective approach

    International Nuclear Information System (INIS)

    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

  14. 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.

  15. Mechanisms of cell sensitization to alpha radioimmunotherapy by doxorubicin or paclitaxel in multiple myeloma cell lines.

    Science.gov (United States)

    Supiot, Stephane; Gouard, Sebastien; Charrier, Josiane; Apostolidis, Christos; Chatal, Jean-Francois; Barbet, Jacques; Davodeau, François; Cherel, Michel

    2005-10-01

    The purpose of this study was to analyze different mechanisms (cell cycle synchronization, DNA damage, and apoptosis) that might underlie potential synergy between chemotherapy (paclitaxel or doxorubicin) and radioimmunotherapy with alpha radionuclides. Three multiple myeloma cell lines (LP1, RMI 8226, and U266) were treated with 213Bi-radiolabeled B-B4, a monoclonal antibody that recognizes syndecan-1 (CD138) 24 hours after paclitaxel (1 nmol/L) or doxorubicin (10 nmol/L) treatment. Cell survival was assessed using a clonogenic survival assay. Cell cycle modifications were assessed by propidium iodide staining and DNA strand breaks by the comet assay. Level of apoptosis was determined by Apo 2.7 staining. Radiation enhancement ratio showed that paclitaxel and doxorubicin were synergistic with alpha radioimmunotherapy. After a 24-hour incubation, paclitaxel and doxorubicin arrested all cell lines in the G2-M phase of the cell cycle. Doxorubicin combined with alpha radioimmunotherapy increased tail DNA in the RPMI 8226 cell line but not the LP1 or U266 cell lines compared with doxorubicin alone or alpha radioimmunotherapy alone. Neither doxorubicin nor paclitaxel combined with alpha radioimmunotherapy increased the level of apoptosis induced by either drug alone or alpha radioimmunotherapy alone. Both cell cycle arrest in the G2-M phase and an increase in DNA double-strand breaks could lead to radiosensitization of cells by doxorubicin or paclitaxel, but apoptosis would not be involved in radiosensitization mechanisms.

  16. Radioimmunotherapy for malignant diseases. Current contributions and future options; Radioimmunotherapie des affections malignes. Interet et perspectives

    Energy Technology Data Exchange (ETDEWEB)

    Mahe, M.A.; Chatal, J.F. [Centre Regional de Lutte Contre le Cancer Rene-Gauducheau, 44 - Nantes (France)

    1995-01-01

    Radioimmunotherapy is based on the use of radioactive agents (iodine 131, yttrium 90), murine-derived monoclonal antibodies and specific tumour-related membrane antigens. This new treatment modality was applied in 800 patients with different types of malignant tumours which had not responded to traditional therapy. Among the haematologic tumours, the most promising results were obtained in B phenotype non-Hodgkin lymphoma. More modest results were obtained for solid tumours although good results were observed after intraperitoneal administration in patients with cancer of the ovary. The main side effects are acute reversible anaphylactic shock, haematologic toxicity and development of anti-murine human antibodies. Several methods are currently under study to increase irradiation dose delivered at the tumoural site since less than 1% of the injected radioactive dose is absorbed by tumoural cells. Several clinical studies are to be conducted in France, particularly for malignant non-Hodgkin lymphoma and cancer of the ovary. (authors). 31 refs.

  17. Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial.

    Science.gov (United States)

    Kraeber-Bodéré, F; Bardet, S; Hoefnagel, C A; Vieira, M R; Vuillez, J P; Murat, A; Ferreira, T C; Bardiès, M; Ferrer, L; Resche, I; Gautherot, E; Rouvier, E; Barbet, J; Chatal, J F

    1999-10-01

    The toxicity and therapeutic efficacy of escalating doses of anti-carcinoembryonic antigen x anti-N alpha-(diethylenetriamine-N,N,N',N''-tetraacetic acid)-In bispecific monoclonal antibody (F6-734) and iodine 131-labeled bivalent hapten were determined in a Phase I/II trial. A total of 26 patients with recurrences of medullary thyroid cancer documented by imaging and a rise in serum thyrocalcitonin were enrolled. Twenty to 50 mg of F6-734 and 40-100 mCi of 131I-hapten were injected 4 days apart. Quantitative scintigraphy was performed after the second injection for dosimetry estimations in eight cases. Clinical, biological, and morphological follow-up was carried out for 1 year after treatment. The mean percentage of injected activity per gram of tumor at the time of maximum uptake was 0.08% (range, 0.003-0.26%). The tumor biological half-life ranged from 3 to 95 days, and tumor doses ranged from 2.91 to 184 cGy/mCi. The estimated tumor-to-nontumor dose ratios were 43.8 x 53.4, 29.6 x 35.3, 10.9 x 13.6, and 8.4 x 10.0 for total body, red marrow, liver, and kidney, respectively. Grade III/IV hematological toxicity was observed in seven patients, most of them with bone metastases. Among the 17 evaluable patients, 4 pain reliefs, 5 minor tumor responses, and 4 biological responses with decrease of thyrocalcitonin were observed. Nine patients developed human anti-mouse antibody. Dose-limiting toxicity was hematological, and maximum tolerated activity was 48 mCi/m2 in this group of patients, most of whom had suspected bone marrow involvement. The therapeutic responses observed in patients mainly with a small tumor burden are encouraging for the performance of a Phase II trial with minimal residual disease.

  18. Fulminante, rituximab-resistente, mucocutane pemphigus vulgaris

    NARCIS (Netherlands)

    Gostyński, A.; Ammatuna, E.; Huls, G.; Wouthuyzen-Bakker, M.; Jonkman, M. F.; Horváth, B.

    2017-01-01

    Pemphigus vulgaris is an autoimmune disease mediated by auto-antibodies against desmoglein 1 and 3. First line treatment for pemphigus consists of systemic corticosteroids and anti-CD20 therapy (rituximab) to eliminate B-cells. Since 2005, more than 100 patients with pemphigus have been treated with

  19. Radio-immunotherapy of solid tumors; La radio-immunotherapie des tumeurs solides

    Energy Technology Data Exchange (ETDEWEB)

    Chatal, J.F.; Faivre Chauvet, A.; Bardies, M.; Kraeber-Bodere, F.; Barbet, J. [Federation Inter-hospitaliere de Medecine Nucleaire, INSERM U 463, 44 - Nantes (France)

    2001-11-01

    A convincing efficacy of radio-immunotherapy of solid tumors has not been documented yet in clinical studies. Consequently, a methodological optimization is needed within the scope in increasing absorbed doses delivered to tumor targets by amplifying cumulative tumor activity and in the same time in reducing absorbed doses delivered normal organs. Multi-step pre-targeting techniques allow to approach these goals. The most developed technique is based on the high affinity for biotin. In a first step an anti-tumor antibody coupled to avidin or biodin is injected. In a second step, 24 hours later, the circulating residual immuno-conjugate is bound to a molecular complex and eliminated through the reticulo endothelial system of the liver ('chase'phase). A third step, a few hours later, consists in injecting biotin coupled to DOTA chelating agent and labeled with yttrium 90. This small molecule rapidly diffuses to tumor targets and binds to pre-localized immuno-conjugate. Another technique, designed and developed in France, is based on antigen-antibody affinity. In a first step an anti-tumor / anti-hapten bi-specific antibody is injected and, in a second step, a few days later, the small hapten molecule is radiolabeled with I-131 and injected. It diffuses rapidly to the tumor targets and binds to the anti-hapten arm of the pre-localized bi-specific antibody. An alternative way to increase radio-immunotherapy efficacy consists in combining this low-dose rate irradiation to radiosensitizing molecules within the scope of an additive or supra additive effect which has previously documented. (author)

  20. 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

  1. Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargeting of Iodine-131-labeled hapten in a phase I radioimmunotherapy trial.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Faivre-Chauvet, Alain; Ferrer, Ludovic; Vuillez, Jean-Philippe; Brard, Pierre-Yves; Rousseau, Caroline; Resche, Isabelle; Devillers, Anne; Laffont, Sophie; Bardiès, Manuel; Chang, Ken; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2003-09-01

    Pharmacokinetics and dosimetry of hMN-14 x m734 bispecific monoclonal antibody (BsMAb) and (131)I-labeled di-diethylenetriaminepentaacetic acid-indium ((131)I-hapten) were studied to optimize pretargeted radioimmunotherapy. Thirty-five patients with carcinoembryonic antigen-expressing tumors were included. In a first group of 12 patients, (131)I-trace-labeled BsMAb doses were escalated from 10 to 100 mg/m(2), and 3.7 GBq of (131)I-hapten were administered 7 days later. In a second group, 12 patients received 75 mg/m(2) BsMAb and 2.6-4.2 GBq of (131)I-hapten 5 days later. The BsMAb dose was then reduced to 40 mg/m(2), and 10 patients received 1.9-5.5 GBq of (131)I-hapten. Blood samples were collected. Biodistribution was monitored by quantitative scintigraphy. Directly labeled BsMAb pharmacokinetics was described by two exponentials: half-lives were 8.1 h (2.0-18.1 h) and 48.2 h (22.8-79.4 h); blood clearance was 123 ml/h (64-195 ml/h). With a 7-day interval, 10 or 30 mg/m(2) BsMAb resulted in fast elimination and very low tumor uptake of hapten, whereas 50 or 100 mg/m(2) resulted in favorable tumor accretion. With 75 mg/m(2) BsMAb and a 5-day interval, hapten clearance was 152 ml/h (81-298 ml/h). Calculated radiation dose to tumor was 3.9 Gy/GBq (0.4-22.4 Gy/GBq) for the hapten, compared with 2.0 Gy/GBq (0.3-3.8 Gy/GBq) for the BsMAb, but hematological toxicity prevented dose escalation. Reduction of the BsMAb dose to 40 mg/m(2) accelerated hapten clearance to 492 ml/h (113-2544 ml/h) and reduced hematological toxicity without compromising tumor uptake [5.2 Gy/GBq (0.5-12.6 Gy/GBq)]. Optimized BsMAb doses and time interval will allow for the administration of higher, tumoricidal, activity doses.

  2. Current status and perspectives in alpha radioimmunotherapy.

    Science.gov (United States)

    Chérel, M; Davodeau, F; Kraeber-Bodéré, F; Chatal, J F

    2006-12-01

    Systemic administration of radiolabeled antibody directed against tumor antigens in radioimmunotherapy (RIT) enables to specifically target the cancer cells and to destroy them. So far, this strategy has proven its efficiency in the treatment of some hematological cancers with antibodies labeled with beta emitting radionuclides. In the last 2 decades, availability of short half life alpha emitters prompted to consider their use in RIT. Contrary to beta particles, alpha particles have a short path length and display a high lineic energy transfer. Those physical characteristics open new fields of clinical applications complementary to beta-RIT. To date, alpha-RIT is still at a preclinical stage of development: the radiolabeling methods need to be optimized to ensure in vivo stability of the radiopharmaceuticals. Some radionuclides have complex decay schemes with daughters emitting further alpha particles whose toxicity needs to be investigated. The modalities of administration of radiolabeled antibodies in animal models require also to be improved for delivering higher doses to tumor targets. A comprehensive analysis of the specific events occurring at cell or tissue level in response to alpha irradiation would be of great interest in order to define the best therapeutic association for residual disease or consolidation treatments. This approach has been proven to be efficient in increasing antitumor response either by using high doses with organ protection (kidney, bone marrow) or by a synergistic effect between alpha-RIT and associated treatments, such as chemotherapy.

  3. Rituximab and chemotherapy in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Sonet, Anne; Bosly, André

    2009-06-01

    Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as 'younger' or 'older': 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era.

  4. Dosimetry and quantitative radionuclide imaging in radioimmunotherapy: Final report, July 15, 1992-July 14, 1996

    International Nuclear Information System (INIS)

    Leichner, P.K.

    1996-09-01

    Brief summaries of the principal accomplishments of this project on the development of quantitative SPECT for high energy photons (87Y, 19F) and stability testing of 87Y-labeled antibodies in the nude mouse model, development of an unified approach to photon and beta particle dosimetry, quantitative SPECT for nonuniform attenuation, and development of patient-specific dosimetry in radioimmunotherapy

  5. Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

    Science.gov (United States)

    Fayad, Luis; Offner, Fritz; Smith, Mitchell R.; Verhoef, Gregor; Johnson, Peter; Kaufman, Jonathan L.; Rohatiner, Ama; Advani, Anjali; Foran, James; Hess, Georg; Coiffier, Bertrand; Czuczman, Myron; Giné, Eva; Durrant, Simon; Kneissl, Michelle; Luu, Kenneth T.; Hua, Steven Y.; Boni, Joseph; Vandendries, Erik; Dang, Nam H.

    2013-01-01

    Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m2) was confirmed to be the same as that for single-agent INO (1.8 mg/m2). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. Conclusion R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20+/CD22+ B-cell NHL. PMID:23295790

  6. EXPERIENCE OF TREATMENT WITH RITUXIMAB IN PATIENT WITH JUVENILE POLYARTERITIS

    Directory of Open Access Journals (Sweden)

    E.I. Alexeeva

    2011-01-01

    Full Text Available The article presents a case report of severe course of nodular polyarteritis. The disease was highly active, aggressive, and refractory to treatment with corticosteroids and cyclophosphamide combined with plasmapheresis and drugs for microcirculation improvement. The treatment with chimerical anti-CD20 monoclonal antibodiesrituximab — was successful. Symptoms of intoxication and tromboangiatic syndrome decreased in 4 weeks. Disease was stopped up to 16th week. The case report demonstrates high efficacy of rituximab: patient with severe nodular polyarteritis remains clinical and laboratory remission during 52 weeks.Key words: children, nodular polyarteritis, rituximab.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2011; 10 (2: 193–200

  7. Rituximab for childhood refractory nephrotic syndrome.

    Science.gov (United States)

    Iijima, Kazumoto

    2011-10-01

    Several therapies including immunosuppressive agents have been shown to be effective and safe for frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS) and steroid-resistant nephrotic syndrome in children. It is evident, however, that a substantial number of children are still refractory to treatment despite these therapies. Rituximab is a chimeric monoclonal antibody, which inhibits CD20-mediated B-cell proliferation and differentiation. It was first introduced for the treatment of B-cell non-Hodgkin's lymphoma and was subsequently administered to patients with autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, or immunocomplex glomerulonephritis. Recently, a number of case reports and non-controlled clinical trials have suggested that rituximab may be effective for children with refractory nephrotic syndrome. Controlled prospective trials, however, are required to establish the value of rituximab in refractory nephrotic syndrome. The purpose of the present study was therefore to evaluate the efficacy and safety of rituximab in childhood-onset refractory nephrotic syndrome. The Research Group of Childhood-onset Refractory Nephrotic Syndrome (RCRNS) conducted a randomized, double-blind, placebo-controlled, multi-center clinical trial (RCRNS-01) and an open-label, multi-center, pharmacokinetic clinical trial (RCRNS-02). These two trials were investigator-initiated, registration-directed clinical trials designed to apply Ministry of Health, Labour and Welfare approval for the use of rituximab for childhood-onset refractory FRNS/SDNS in Japan. RCRNS-01 could be the first study to clarify whether rituximab is effective and safe for childhood-onset refractory FRNS/SDNS. © 2011 The Author. Pediatrics International © 2011 Japan Pediatric Society.

  8. Radioimmunotherapy: Development of an effective approach

    Energy Technology Data Exchange (ETDEWEB)

    DeNardo, S.J.

    1991-01-01

    We plan to extend our success in treating B cell malignancies with {sup 131}I labeled Lym-1 by a major effort in therapy with {sup 67}Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the {sup 111}In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the {sup 111}In-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{prime},N{double prime}, N{prime}{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 {sup 67}Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry.

  9. Radioimmunotherapy of solid cancers. A review

    International Nuclear Information System (INIS)

    Kairemo, K.J.A.

    1996-01-01

    Depending on radionuclide characteristics, radioimmunotherapy (RIT) relies on radioactivity to destroy cells distant from immunotargeted cells. Therefore, even heterogeneous tumors (for antigen recognition) can be treated, because not all cells have to be targeted. Substantial complete response rates have been reported in patients with non-Hodgkin's lymphoma. Much more modest results have been reported for patients iwth bulky solid tumors, e.g. adenocarcinomas. The radiation doses delivered by targeting antibodies are generally too low to achieve major therapeutic responses. Dose escalation is limited by myelotoxicity, and higher doses need to be delivered to neoplasmas less radiosensitive than lymphomas. Various trials for both systematic and regional RIT have been reported on. Intraperitoneal adminostration has been applied for colorectal and ovarian carcinomas. Our own results indicate that, e.g., intraperitoneal pseudomyxoma can be treated with RIT. Myelotoxicity can be reduced by anti-antibody-enhancement, 2- and 3-step strategies, bispecific monoclonal antibodies (MABs), and extracorporeal immunoadsorption. The radionuclide has to be selected properly for each purpose; it can be a β-emitter, e.g. I-131, Y-90, Re-188, Re-186, Lu-177 or Sm-153, an α-emitter At-211 or Bi-212 or an Auger-emitter, e.g. I-125, I-123. One major problem with RIT, besides slow penetration rate into tumor tissue and low tumor-to-normal tissue ratio, is the HAMA response, which can be partly avoided by the use of humanized MAbs and immunosuppression. However, RIT will be, because of all the recent developments, an important form of cancer management. (orig.)

  10. Radioimmunotherapy: Development of an effective approach

    International Nuclear Information System (INIS)

    DeNardo, S.J.

    1991-01-01

    We plan to extend our success in treating B cell malignancies with 131 I labeled Lym-1 by a major effort in therapy with 67 Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the 111 In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the 111 In-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 67 Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry

  11. Rituximab for nephrotic syndrome in children.

    Science.gov (United States)

    Iijima, Kazumoto; Sako, Mayumi; Nozu, Kandai

    2017-04-01

    Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. At least 20 % of children with this syndrome show frequent relapses and/or steroid dependence during or after immunosuppressive therapies, a condition defined as complicated frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). Approximately 1-3 % of children with idiopathic nephrotic syndrome are resistant to steroids and all immunosuppressive agents, a condition defined as refractory steroid-resistant nephrotic syndrome (SRNS); these SRNS children have a high risk of end-stage renal failure. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective for patients with complicated FRNS/SDNS and refractory SRNS. This review describes the recent results of rituximab treatment applied to pediatric nephrotic syndrome, as well as those of our recent study, a multicenter, double-blind, randomized, placebo-controlled trial of rituximab for childhood-onset complicated FRNS/SDNS (RCRNS01). The overall efficacy and safety of rituximab for this disease are discussed.

  12. 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

  13. Criteria for the selection of radionuclides for tumor radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, S.C.; Mausner, L.F.; Mease, R.C.

    1991-01-01

    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.

  14. Radioimmunotherapy for malignant diseases. Current contributions and future options

    International Nuclear Information System (INIS)

    Mahe, M.A.; Chatal, J.F.

    1995-01-01

    Radioimmunotherapy is based on the use of radioactive agents (iodine 131, yttrium 90), murine-derived monoclonal antibodies and specific tumour-related membrane antigens. This new treatment modality was applied in 800 patients with different types of malignant tumours which had not responded to traditional therapy. Among the haematologic tumours, the most promising results were obtained in B phenotype non-Hodgkin lymphoma. More modest results were obtained for solid tumours although good results were observed after intraperitoneal administration in patients with cancer of the ovary. The main side effects are acute reversible anaphylactic shock, haematologic toxicity and development of anti-murine human antibodies. Several methods are currently under study to increase irradiation dose delivered at the tumoural site since less than 1% of the injected radioactive dose is absorbed by tumoural cells. Several clinical studies are to be conducted in France, particularly for malignant non-Hodgkin lymphoma and cancer of the ovary. (authors). 31 refs

  15. Radionuclide therapy of cancer with radiolabeled antibodies.

    NARCIS (Netherlands)

    Boerman, O.C.; Koppe, M.J.; Postema, E.J.; Corstens, F.H.M.; Oyen, W.J.G.

    2007-01-01

    Radioimmunotherapy (RIT) using radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens has evolved from an appealing concept to one of the standard treatment options for patients with non-Hodgkin's lymphoma (NHL). Inefficient localization of radiolabeled MAbs to

  16. Neurophysiological and clinical responses to rituximab in patients with anti-MAG polyneuropathy.

    Science.gov (United States)

    Zara, Gabriella; Zambello, Renato; Ermani, M

    2011-12-01

    Rituximab treatment has shown clinical improvement in anti-myelin associated glycoprotein (MAG) polyneuropathy. We analyzed scores of clinical scales and the most sensitive electrophysiological parameters before and after immunomodulating treatment with rituximab in a group of patients affected by anti-MAG demyelinating polyneuropathy. Clinical scores, the percentage of CD20 B-lymphocytes, anti-MAG antibody titers and electrophysiological data in 7 patients with anti-MAG polyneuropathy were analyzed. The patients were examined before a cycle with rituximab, 6, 12 and 24 months after the end of the treatment. Two patients were treated with rituximab additional cycles and re-evaluated 48 months after the first treatment. There were no evident correlation between anti-MAG serum antibody titers or clinical scales and electrodiagnostic data. Significant decrease in the proportion of CD20 B-lymphocytes was observed. Significant anti-MAG antibodies titers reduction was detected after re-treatment. At follow-up, pinprik sensation and two point discrimination presented a significant improvement compared with the score before treatment. In our patients, rituximab did not improve any electrophysiological data. No correlation with anti-MAG serum antibodies course was found. With rituximab only pin sensibility improved. Rituximab re-treatment significantly reduces anti-MAG serum antibodies titers but improves only small fibers sensibility. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  17. Radioimmunotherapy

    Science.gov (United States)

    ... page is reviewed regularly by a physician with expertise in the medical area presented and is further reviewed by committees from the American College of Radiology (ACR) and the Radiological Society of North ... with expertise in several radiologic areas. Outside links: For the ...

  18. Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience.

    Science.gov (United States)

    Jade, Jui Dilip; Bansi, Srishti; Singhal, Bhim

    2017-01-01

    Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease, with recurrent attacks of severe bilateral optic neuritis and longitudinally extensive transverse myelitis. Aggressive immunosuppression is essential to prevent clinical relapses and permanent disability. Rituximab, a monoclonal antibody to CD20, has been found effective in several reports and small uncontrolled studies. There is a paucity of data regarding its use in Indian patients. The aim of this study was to report the results of rituximab treatment in NMO spectrum disorders (NMOSDs) in the Indian scenario. This study is a retrospective, observational study including 13 NMOSD patients treated with rituximab. After initial therapy in the acute episode with IV methylprednisolone and if needed plasma exchange, therapy was initiated as a cycle of intravenous rituximab, two doses 2 weeks apart of 1 g each. Subsequent cycles were advised at intervals of every 6 months. The primary outcome measure was annualized relapse rate (ARR), defined as a number of clinical attacks per year. Clinical adverse events were recorded throughout the study. In the study, mean ARR reduced from 2.61 to 0.09 after therapy ( P = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted. The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated.

  19. Rituximab for peripheral ulcerative keratitis with wegener granulomatosis.

    Science.gov (United States)

    Huerva, Valentín; Sanchez, María Carmen; Traveset, Alicia; Jurjo, Carmen; Ruiz, Agustín

    2010-06-01

    To demonstrate the effectiveness of Rituximab in the management of peripheral ulcerative keratitis (PUK) associated with Wegener granulomatosis (WG). A 50-year-old female with WG, confirmed by skin biopsy and positive anti-neutrophil cytoplasmic antibodies 3 years prior, was presented with a corneoscleral granulomatous mass that affected the superior limbus and with vasculitic PUK in the right eye. The mass was treated daily with oral prednisone (1 mg.kg-1.d-1) in conjunction with weekly maintenance treatment of 10 mg of methotrexate. After 2 months of treatment, the volume of the nodular granulomatous lesion decreased. However, the PUK and corneal thinning persisted, which presented a risk for corneal perforation. Subsequently, two 1000-mg infusions of rituximab were administered at weekly intervals. One week after the first administration of rituximab, we observed persistence of corneal thinning, flattening of the nodular lesion, and disappearance of the necrotic foci. After the second rituximab treatment, the patient exhibited no signs of corneal perforation and we further observed total epithelialization of the PUK. No systemic side effects were seen. After 2 months, no nodular lesion was observed, although conjunctival epithelialization from the previous PUK remained. Weekly methotrexate and 10 mg of prednisone per day were maintained. Rituximab seems to offer therapeutic promise in the treatment of refractory PUK associated with WG. Rituximab may be the elective treatment for severe anterior ocular inflammation associated with risk for corneal perforation, as a result of WG.

  20. Cancer radioimmunotherapy with alpha-emitting nuclides

    Energy Technology Data Exchange (ETDEWEB)

    Couturier, Olivier [INSERM U 601, Nantes (France); Place Alexis Ricordeau, Department of Nuclear Medicine, Nantes, Cedex (France); Supiot, Stephane; Degraef-Mougin, Marie; Faivre-Chauvet, Alain; Carlier, Thomas; Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel [INSERM U 601, Nantes (France)

    2005-04-01

    In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with {beta}-emitters for the treatment of refractory cases. The development of novel RIT with {alpha}-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of {alpha}-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with {alpha}-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of {alpha}-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an {alpha}-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with {alpha}-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of {alpha}-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies. (orig.)

  1. Cancer radioimmunotherapy with alpha-emitting nuclides.

    Science.gov (United States)

    Couturier, Olivier; Supiot, Stéphane; Degraef-Mougin, Marie; Faivre-Chauvet, Alain; Carlier, Thomas; Chatal, Jean-François; Davodeau, François; Cherel, Michel

    2005-05-01

    In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

  2. Cancer radioimmunotherapy with alpha-emitting nuclides

    International Nuclear Information System (INIS)

    Couturier, Olivier; Supiot, Stephane; Degraef-Mougin, Marie; Faivre-Chauvet, Alain; Carlier, Thomas; Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel

    2005-01-01

    In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with β-emitters for the treatment of refractory cases. The development of novel RIT with α-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of α-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with α-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of α-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an α-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with α-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of α-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies. (orig.)

  3. 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...

  4. Treatment of Graves' disease with rituximab specifically reduces the production of thyroid stimulating autoantibodies

    DEFF Research Database (Denmark)

    El Fassi, Daniel; Banga, J Paul; Gilbert, Jacqueline A

    2008-01-01

    Treatment of Graves' disease (GD) with the B-lymphocyte depleting agent rituximab in addition to standard methimazole-therapy prolongs remission. Paradoxically, it does not mediate a reduction in thyrotropin receptor antibody (TRAb) levels over that of methimazole monotherapy. Using a bioassay...... methimazole alone (p=0.04 between groups). The overall levels of TRAbs decreased by around 15% in both groups. Within one year of follow-up, rituximab therapy mediated specific decreases in thyroid-peroxidase antibody- and IgM levels, whereas IgG levels were unaffected. The data indicate that rituximab...

  5. Expanded use of rituximab in the management of non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Dennis A Eichenauer

    2009-07-01

    Full Text Available Dennis A Eichenauer1, Andreas Engert1, Holger Schulz21First Department of Internal Medicine, University Hospital Cologne, Cologne, Germany; 2pioh – Praxis Internistischer Onkologie und Häematologie Kölnerstr. g, Frechen, GermanyAbstract: Rituximab is a chimeric monoclonal antibody targeting the B cell antigen CD20. Since its first approval for clinical use in 1997, rituximab has become an inherent part of the treatment of CD20-positive lymphoma. In previously untreated non-Hodgkin lymphoma (NHL conventional chemotherapy supplemented by rituximab (R-chemotherapy was shown to be more effective than chemotherapy alone. This holds true for indolent as well as aggressive NHL. Rituximab was also shown to be beneficial when used as maintenance therapy or part of salvage and re-induction regimens in relapsed NHL. Administration of rituximab is generally well tolerated. The most common side effects including fever, urticaria and bronchospasm are mostly mild, treatable and restricted to the infusion period. Thus, rituximab can usually be administered in an outpatient setting. Due to its favorable effect/side effect ratio, clinical trials are currently evaluating a possible role for rituximab in several other diseases such as Hodgkin lymphoma (HL and non-malignant autoimmune disorders. This review aims at giving an overview of the pharmacological properties of rituximab and summarizing key publications and recent literature on its use in NHL.Keywords: rituximab, non-Hodgkin lymphoma, immunochemotherapy

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    . Immunosuppressive medication (mycophenolate and prednisolone) was administered to 3 patients at the time of rituximab therapy. Three patients had previously been treated with anti-tumour-necrosis-factor-alpha antibodies, and one of these patients had also received cyclophosphamide as treatment for orbital...

  7. 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...

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

    Science.gov (United States)

    Fischer, M; Grünwald, F; Knapp, W H; Trümper, L; von Schilling, C; Dreyling, M

    2009-01-01

    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, radioimmunotherapy under consideration of the development of the disease.

  9. Criteria for the selection of nuclides for radioimmunotherapy

    International Nuclear Information System (INIS)

    Adelstein, S.J.; Kassis, A.I.

    1986-01-01

    This report describes many factors that need to be considered if radioimmunotherapy is to become a commonplace reality. For beta-emitting radionuclides, two physical features of importance are half-life and energy, with the latter determining the range. These features must be matched to the pharmacokinetics of the carrier and the distribution of the radionuclide, both macroscopically and microscopically. Alpha-particle emitters could be considered for cells that are readily accessible to the labeled antibody and for populations that uniformly and constantly display the targeted antigen or idiotype, e.g., trafficking cells such as T or B lymphocytes. For cells that concentrate the radioactive label, the use of low-energy electrons should be examined. If the radionuclide is translocated to the nucleus, the Auger effect can be particularly lethal because of the high LET-like biological response. 15 refs., 3 figs., 2 tabs

  10. 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.

  11. 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

  12. Rituximab in systemic lupus erythematosus and lupus nephritis.

    Science.gov (United States)

    Beckwith, Hannah; Lightstone, Liz

    2014-01-01

    Treatment options for systemic lupus erythematosus (SLE) and lupus nephritis (LN) have high associated morbidity and mortality. Side effects, particularly from long-term corticosteroid usage, limit patient adherence, with subsequent impacts on treatment efficacy. In addition, a subset of patients with SLE/LN fails to respond to current standard immunotherapy. There is an urgent need to develop steroid-sparing treatment regimens as well as novel therapies for the management of refractory disease. Rituximab is a chimeric mouse/human monoclonal antibody directed against the B cell CD20 receptor. It has been used in the treatment of non-Hodgkin's lymphoma for over 30 years and has an excellent safety profile. Recent work has demonstrated a role for B cell depletion therapy in the management of autoimmune disease, and the efficacy of rituximab in many observational studies in SLE and LN has been noted. Unfortunately, two large randomised controlled trials evaluating rituximab for the treatment of renal and non-renal lupus failed to meet their primary endpoints. Reasons for this have been discussed extensively within the medical community with a general consensus that trial design (steroid use, trial size and endpoints used) was the principal reason for the failures. Despite the lack of trial evidence, clinical experience means many physicians firmly believe in the value of rituximab in SLE/LN treatment and have continued to use it in their clinical practice. Recent work has demonstrated the efficacy of rituximab as a steroid-sparing agent and as an alternative therapeutic option for refractory SLE/LN. There are two further rituximab randomised controlled trials planned/started in LN – one using a steroid-minimising regimen with rituximab for induction and one evaluating rituximab for LN refractory to 6 months standard of care treatment. Rituximab remains a problematic drug in lupus and LN – it is a biologically plausible agent with a huge amount of supportive

  13. 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

  14. Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab')2.

    Science.gov (United States)

    Elgqvist, Jörgen; Andersson, Håkan; Bernhardt, Peter; Bäck, Tom; Claesson, Ingela; Hultborn, Ragnar; Jensen, Holger; Johansson, Bengt R; Lindegren, Sture; Olsson, Marita; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars

    2006-11-15

    To elucidate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the alpha-particle emitter Astatine-211 (211At) labeled to the mAb MX35 F(ab')2. Animals were inoculated intraperitoneally with approximately 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab')2 (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab')2 (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq (211)At-MX35 F(ab')2, respectively, the specific energy to irradiated cell nuclei varying between approximately 2 and approximately 400 Gy. As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is approximately 100 kBq (211)At-MX35 F(ab')2. MCP was most consistent with the TFF when assuming a diffusion depth of 30 mum of the mAbs in the tumors.

  15. Myeloablative radioimmunotherapy in conditioning prior to haematological stem cell transplantation: closing the gap between benefit and toxicity?

    Energy Technology Data Exchange (ETDEWEB)

    Buchmann, Inga; Haberkorn, Uwe [University of Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); University of Luebeck, Luebeck (Germany); Meyer, Ralf G. [University of Mainz, Department of Medicine 3, Mainz (Germany); Mier, Walter [University of Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany)

    2009-03-15

    High-dose radio-/chemotherapy in the context of autologous and allogeneic haematopoietic stem cell transplantation is a double-edged sword. The requirement for dose intensification is linked to an increase in toxicity to noninvolved organs. Particularly for older patients and patients with comorbidities, efficient but toxicity-reduced schemes are needed. Myeloablative radioimmunotherapy is a targeted, internal radiotherapy that uses radiolabelled monoclonal antibodies (mAb) with affinity to the bone marrow. It involves the administration of high radiation doses (up to 30 Gy) to the bone marrow and spleen but without exposing radiosensitive organs to doses higher than 1-7 Gy. Added to conventional or intensity-reduced conditioning, myeloablative radioimmunotherapy may achieve a pronounced antileukaemic effect with tolerable toxicities. A rational and individual design of the ideal nuclide-antibody combination optimizes therapy. The anti-CD33, anti-CD45 and anti-CD66 mAbs appear to be ideal tracers so far. The {beta}-emitter {sup 90}Y is coupled by DTPA and is the best nuclide for myeloablation. Approval trials for DTPA anti-CD66 mAb are underway in Europe, and in the near future these therapies may become applicable in practice. This review gives an overview of current myeloablative conditioning radioimmunotherapy. We discuss the selection of the optimal radioimmunoconjugate and discuss how radioimmunotherapy might be optimized in the future by individualization of therapy protocols. We also highlight the potential advantages of combination therapies. (orig.)

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

    International Nuclear Information System (INIS)

    Perera Pintado, Alejandro; Leyva Montaña, René; Prats Capote, Anaís; Góngora Bravo, Magdiel; Alberti Ramírez, Alejandro; León, Mariela; Hernández González, Ignacio; Dorvignit, Denise

    2016-01-01

    the implementation of the radioimmunotherapy with this type of 90 Y-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 90 Y. (author)

  17. Rituximab in lupus nephritis: A non-systematic review.

    Science.gov (United States)

    Zurita Gavilanes, Luis; Costa Valarezo, Aldo

    2016-01-01

    Lupus nephritis (LN) is a common and severe complication in patients with lupus. Current therapy is based on immunosuppressive drugs and glucocorticoids. Recently, rituximab has been proposed as an alternative treatment for LN. Rituximab is a monoclonal antibody directed against the CD20 antigen receptor on B cells. The aim of this review is to summarize all the available information about rituximab in LN. Eleven studies were found; three of them were observational studies (2 prospective and 1 retrospective) and eight were clinical trials (7 open-label studies and only 1 randomized controlled trial [RCT]). The evidence is insufficient to establish the role of rituximab in the treatment of LN. Results from the only RCT, which were negative, suggest a clinical benefit in black people. Further studies must confirm this hypothesis. Controlled clinical trials involving adaptive randomization are required to establish the real benefit of rituximab in LN. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  18. Improving testing for hepatitis B before treatment with rituximab.

    Science.gov (United States)

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

    2016-10-01

    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. 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. 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.

  19. Socioeconomic inequality in the use of rituximab therapy among non-Hodgkin lymphoma patients in Chinese public hospitals.

    Science.gov (United States)

    Yu-Wen, Huang; Mei-Bian, Zhang; Xiang, Xu; Xiao-Hua, Xu; Quan, Zhou; Le, Jian

    2014-03-01

    Rituximab is a patient-paid effective monoclonal-antibody drug for non-Hodgkin lymphoma (NHL). Little is known in China, a country with unequal distribution of wealth and medical insurance systems, about the impact of socioeconomic status (SES) on selecting rituximab therapy in NHL patients. A total of 328 NHL inpatients in 2 public hospitals in Hangzhou were recruited and divided into 2 equal groups: with rituximab therapy and with no rituximab therapy group. Selection and frequency of rituximab therapy increased with duration of education and in urban citizens (P inequality in provision of rituximab therapy among Chinese NHL patients, and this was associated with differences in SES status. Effective measures are suggested to ameliorate the inequality issue.

  20. Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event.

    Science.gov (United States)

    Berger, Joseph R; Malik, Vineeta; Lacey, Stuart; Brunetta, Paul; Lehane, Patricia B

    2018-03-05

    This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000-50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time.

  1. Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention.

    Science.gov (United States)

    Stolz, Claudia; Schuler, Martin

    2009-06-01

    The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible.

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

    International Nuclear Information System (INIS)

    Jandl, Thomas; Revskaya, Ekaterina; Jiang, Zewei; Harris, Matthew; Dorokhova, Olena; Tsukrov, Dina; Casadevall, Arturo; Dadachova, Ekaterina

    2013-01-01

    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( 188 Re)-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 188 Re-6D2 antibody, saline, unlabeled 6D2 antibody or 188 Re-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

  3. A pretargeting system for tumor PET imaging and radioimmunotherapy.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2015-01-01

    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.

  4. 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.

  5. Rituximab in a child with autoimmune thrombotic thrombocytopenic purpura refractory to plasma exchange.

    Science.gov (United States)

    Narayanan, Parameswaran; Jayaraman, Aparna; Rustagi, Rashi S; Mahadevan, S; Parameswaran, Sreejith

    2012-07-01

    A nine-year-old girl presented with headache, purpura and mild left hemiparesis. Laboratory evaluation revealed thrombotic microangiopathy with ADAMTS13 deficiency, with auto-antibodies to ADAMTS13. She was treated with plasma exchange and steroids, following which she improved transiently, relapsing within 2 months. The relapse was refractory to conventional therapy and rituximab was tried. She had good response to rituximab and has been in remission for the past 12 months. Rituximab may be a promising option for children with acquired TTP refractory to plasma exchange and steroids.

  6. Current role of rituximab in systemic lupus erythematosus.

    Science.gov (United States)

    Mok, Chi Chiu

    2015-02-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by periods of flares and remission, resulting in organ damage over time caused by persistent disease activity and treatment-related complications. Conventional therapies are not ideal in terms of efficacy and safety. Novel biological therapies are being developed to enhance therapeutic efficacy, minimize disease exacerbation and reduce toxicities. As dysregulation of B cells is the hallmark of SLE, B-cell targeted therapies are the focus of recent clinical research. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been used with success in recalcitrant lupus manifestations. However, randomized controlled trials have failed to reveal its benefit in renal and non-renal SLE when combined with conventional immunosuppressive protocols. Although heterogeneity of SLE manifestations, pitfalls in study design and the limitations of the assessment tools for various clinical end points may have contributed to the discouraging results, rituximab remains an option in patients who are refractory or intolerant to conventional therapies. Recently, a regimen consisting of rituximab and mycophenolate mofetil without oral corticosteroids was reported to be effective in lupus nephritis. While the efficacy of this regimen has to be confirmed, future controlled trials should focus on the efficacy of rituximab in refractory lupus manifestations and its synergistic effect with other immunosuppressive agents such as cyclophosphamide. In short-term randomized controlled trials, a non-significant increase in serious adverse events was observed in SLE patients treated with rituximab. Long-term safety data of rituximab in SLE, in particular the incidence of hypogammaglobulinemia and serious/opportunistic infections, have to be continuously surveyed. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  7. Current perspective on rituximab in rheumatic diseases

    Directory of Open Access Journals (Sweden)

    Schioppo T

    2017-10-01

    Full Text Available Tommaso Schioppo, Francesca Ingegnoli Department of Clinical Sciences and Community Health, Division of Rheumatology, ASST Pini, Università degli Studi di Milano, Milano, Italy Abstract: The steadily increasing knowledge regarding pathogenetic mechanisms in ­autoimmune rheumatic diseases has paved the way to different therapeutic approaches. In particular, the market entry of biologics has dramatically modified the natural history of rheumatic chronic inflammatory diseases with a meaningful impact on patients’ quality of life. Among the wide spectrum of available biological treatments, rituximab (RTX, first used in the treatment of non-Hodgkin’s lymphoma, was later approved for rheumatoid arthritis and anti-neutrophil cytoplasmic antibodies-associated vasculitis. Nowadays, in rheumatology, RTX is also used with off-label indications in patients with systemic sclerosis, Sjögren’s syndrome and systemic lupus erythematosus. RTX is a monoclonal antibody directed to CD20 molecules expressed on the surfaces of pre-B and mature B lymphocytes. It acts by causing apoptosis of these cells with antibody- and complement-dependent cytotoxicity. As inflammatory responses to cell-associated immune complexes are key elements in the pathogenesis of several autoimmune rheumatic diseases, such an approach might be effective in these patients. In fact, RTX, by promoting the rapid and long-term depletion of circulating and lymphoid tissue-associated B cells, leads to a lower recruitment of these effector cells at sites of immune complex deposition, thus reducing inflammation and tissue damage. RTX is of the most interest to rheumatologists as it represents an important additional therapeutic approach. Thus, the advent in clinical practice of approved RTX biosimilars, such as CT-P10, may be of help in improving treatment access as well as in reducing costs. Keywords: rituximab, rheumatoid arthritis, ANCA-associated vasculitis, systemic sclerosis, Sj

  8. 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

  9. 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)

  10. 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.

  11. Iodine-131-labeled MAb F(ab')2 fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice

    International Nuclear Information System (INIS)

    Buchegger, F.; Pelegrin, A.; Delaloye, B.; Bischof-Delaloye, A.; Mach, J.P.

    1990-01-01

    During one week, beginning 18 days after transplantation, nude mice bearing human colon carcinoma ranging from 115 to 943 mm3 (mean 335 mm3) were treated by repeated intravenous injections of either iodine-131-( 131 I) labeled intact antibodies or 131 I-labeled corresponding F(ab')2 fragments of a pool of four monoclonal antibodies (MAbs) directed against distinct epitopes of carcinoembryonic antigen (CEA). Complete tumor remission was observed in 8 of 10 mice after therapy with F(ab')2 and 6 of the animals survived 10 mo in good health. In contrast, after treatment with intact MAbs, tumors relapsed in 7 of 8 mice after remission periods of 1 to 3.5 mo despite the fact that body weight loss and depression of peripheral white blood cells, symptoms of radiation toxicity, and the calculated radiation doses for liver, spleen, bone, and blood were increased or equal in these animals as compared to mice treated with F(ab')2

  12. EXPERIENCE OF RITUXIMAB APPLICATION ON A PATIENT, SUFFERING FROM JUVENILE RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    E.I. Alexeeva

    2006-01-01

    Full Text Available The article describes the run of the severe systemic juvenile rheumatoid arthritis, which is resistant to the standard antirheumatic therapy. The disease was characterized by such systemic implications of the disease, as: fever, rash, pericarditis, lymphadenopathy, hepatomegaly accompanied by the generalized joint syndrome and high laboratory indices of activity. Introduction of rituximab into the treatment scheme allowed the researchers to decrease the general activity of the disease, arrest the systemic implications, improve functional status of the joints, and normalize the laboratory indices of activity. The effect duration was 5 months and 4 months after the first and second course of treatment by rituximab accordingly. The treatment results prove the perspective of rituximab application with in the complex therapy for the patients, suffering from juvenile rheumatoid arthritis. However, it is necessary to conduct further research to identify the location of antibodies to cd 20+ within the therapy scheme of this disease. Key words: children, treatment, rituximab, juvenile rheumatoid arthritis.

  13. Radioimmunotherapy: Development of an effective approach. Annual report, 1991

    Energy Technology Data Exchange (ETDEWEB)

    DeNardo, S.J.

    1991-12-31

    We plan to extend our success in treating B cell malignancies with {sup 131}I labeled Lym-1 by a major effort in therapy with {sup 67}Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the {sup 111}In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the {sup 111}In-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{prime},N{double_prime}, N{prime}{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 {sup 67}Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry.

  14. Radiolabeling and targeting of lipidic nanocapsules for applications in radioimmunotherapy.

    Science.gov (United States)

    Jestin, E; Mougin-Degraef, M; Faivre-Chauvet, A; Remaud-Le Saëc, P; Hindre, F; Benoit, J P; Chatal, J F; Barbet, J; Gestin, J F

    2007-03-01

    Radioimmunotherapy is limited in some cases by the low radioactive doses delivered to tumor cells by antibodies or pretargeted haptens. In order to increase this dose, lipidic nanocapsules (LNC) with a hydrophobic core are proposed as radionuclide vectors that could be targeted to cancer cells by a bispecific anti-tumor x anti-hapten antibody after incorporation of different haptens in the nanocapsule membrane. To bind different radionuclides to the nanocapsules, several bifunctional chelating agents (BCA) were used to form stable complexes with the radionuclides. Some of them are hydrophilic for LNC shell while others are lipophilic to radiolabel the core. Poly(ethylene glycols) (PEG) were used to increase the residence time in blood. Since PEG can modify haptens recognition by the bispecific antibody and radiolabeling efficiency, haptens, BCA or Bolton-Hunter reagent (BH) were attached to the PEG extremity to optimize accessibility. Specific constructs (DSPE-PEG-haptens, DSPE-PEG-BCA, and DSPE-PEG-BH) were synthesized to develop these new radiolabeled vector formulations. Large amounts of PEG have been introduced by a postinsertion method without important change in nanocapsule size and properties. The nanocapsule core was radiolabeled with a lipophilic [(99m)Tc]SSS complex. Serum stability studies showed that this (99m)Tc-labeling method was efficient for at least 20 h. Concerning the nanocapsule surface, several methods have been performed for (111)In-labeling by using DSPE-PEG-DTPA and for (125)I-labeling with DSPE-PEG-BH. The nanocapsules labeling feasibility with a variety of radionuclides and their stability were demonstrated in this paper.

  15. Stress-induced molecules MICA as potential target for radioimmunotherapy of cancer

    Science.gov (United States)

    Abakushina, E. V.; Anokhin, Yu N.; Abakushin, D. N.; Kaprin, A. D.

    2017-01-01

    Improving the treatment of cancer, increasing their effectiveness and safety is the main objective in the medicine. Molecular nuclear medicine plays an important role in the therapy of cancer. Radioimmunotherapy (RIT) involves the use of antibodies conjugated with therapeutic radionuclides. More often for RIT use the radiolabeled monoclonal antibodies against tumor-associated antigens. Encouraging results have been achieved with this technology in the management of hematologic malignancies. On the contrary, solid tumors have been less responsive. Despite these encouraging results, new potential target for radioimmunodetection and RIT should be found. It was found to increase the level of tumor-associated molecules MICA in the serum of cancer patients. Use of anti-MICA monoclonal antibodies capable a specifically attach to cancer cell via NKG2D ligands and destroy it, is a very promising direction, both therapeutic and diagnostic standpoint.

  16. Incidence and clinical characteristics of hepatitis B virus reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for rheumatoid arthritis.

    Science.gov (United States)

    Tien, Ya-Chih; Yen, Hsu-Heng; Chiu, Ying-Ming

    2017-01-01

    To analyse the incidence, clinical characteristics, and prognosis of patients with rheumatoid arthritis (RA) and hepatitis B virus (HBV) surface antigen negative/core antibody positive serostatus (HBsAg-/HBcAb+), who underwent rituximab therapy and developed HBV reactivation. Medical records of RA patients with different HBV serostatus who received rituximab from January 2000 through January 2015 were reviewed. Case notes of four HBsAg-/HBcAb+ patients with RA who had HBV reactivation during treatment with rituximab were excerpted and summarised. We also searched the Medline (PubMed) database to identify published reports of other HBsAg-/HBcAb+ RA patients who likewise developed HBV reactivation during rituximab treatment. The study cohort comprised 54 RA patients who received rituximab, of whom 44 (81.5%) were HBsAg-/HBcAb+ whilst receiving rituximab. Four HBsAg-/HBcAb+ patients had HBV reactivations during rituximab therapy; thus, the incidence of HBV reactivation in the HBsAg-/HBcAb+ group was 9.1%. The literature search discovered another three cases, making a total of at least seven known rituximab-treated HBsAg-/HBcAb+ RA patients who have developed HBV reactivation. The mean duration from the first rituximab infusion to HBV reactivation was 25.4±4.6 months; no fatalities occurred. Approximately 9% of Taiwanese RA patients with HBsAg-/HBcAb+ serostatus had HBV reactivation around 2 years after starting regular rituximab therapy; they all had a relatively good prognosis.

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

    DEFF Research Database (Denmark)

    Elgqvist, Jörgen; Andersson, Håkan; Jensen, Holger

    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....... Nude mice were intraperitoneally inoculated with ~1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later 6 groups of animals were given 400 kBq (211)At-MX35 F(ab')(2) as a single or as a repeated treatment of up to 6 times (n = 18 in each group). The fractionated treatments were given every...... seventh day. Control animals were treated with unlabeled MX35 F(ab')(2) (n = 12). Eight weeks posttreatment the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. Results. The tumor-free fractions (TFFs) of the animals, defined as the fraction of animals...

  18. Radioimmunotherapy: a long story of more than thirty years

    International Nuclear Information System (INIS)

    Chatal, J.F.

    2013-01-01

    This article shows that radioimmunotherapy (RIT) was invented more than 30 years ago and at its beginning (between 1993 and 1997) results were quite modest: over a population of 300 patients and with all pathological indications being considered, the clinical effectiveness reached 2% of complete and partial responses and 3% of minor responses. The main cause of these poor results was the very large tumor burden in the majority of the patients which is now commonly recognized as not favorable for RIT efficiency. Consequently, in the clinical studies performed between 1997 and 2002, patients with smaller tumors were considered, higher activities were injected sometimes with stem cell rescue and, in a few studies RIT was associated with chemotherapy and especially with Taxol. The results of such studies, showed a significant clinical efficacy improvement. In the beginning of the 2000 years the situation of RIT has been rapidly progressing. Two radiolabeled antibodies (Bexxar and Zevalin) have been approved for the treatment of radiosensitive non-Hodgkin's lymphoma, thus illustrating the fact that RIT has come of age as a new therapeutic modality. Since then new technological approaches have been developed and clinically validated

  19. Rituximab as a therapeutic option for patients with advanced melanoma.

    Science.gov (United States)

    Winkler, Julia K; Schiller, Matthias; Bender, Carolin; Enk, Alexander H; Hassel, Jessica C

    2018-03-07

    Treatment of metastatic melanoma remains challenging, despite a variety of new and promising immunotherapeutic and targeted approaches to therapy. New treatment options are still needed to improve long-term tumour control. We present a case series of seven patients with metastatic melanoma who were treated individually with the anti-CD20 antibody rituximab between July 2014 and July 2015. Two of the patients were treated in an adjuvant setting. All patients had already received a variety of treatments. During an induction phase, the administration of four cycles of weekly rituximab 375 mg/m 2 body surface area was planned. After imaging, patients with stable disease continued therapy with rituximab 375 mg/m 2 body surface area every 4 weeks up to a maximum of 24 weeks. Two patients experienced grade 2 infusion reactions during the first infusion. Otherwise, treatment was well tolerated and there were no grade 3 or 4 side effects. Staging after the induction phase showed stable disease in five patients, and two patients had progressive disease. Median progression-free survival was 6.3 months (95% CI 4.97-7.53), median overall survival was 14.7 months (95% CI 4.52-24.94), and one patient was still alive in December 2016. In conclusion, rituximab might be a therapeutic option for metastatic melanoma. However, further studies on rituximab among larger patient cohorts are warranted. Evaluation of therapy in an adjuvant setting or in combination with other systemic treatment might, therefore, be of particular interest.

  20. Large Granular Lymphocytic Leukemia: A Report of Response to Rituximab

    Directory of Open Access Journals (Sweden)

    Uroosa Ibrahim

    2017-01-01

    Full Text Available Large granular lymphocytic (LGL leukemia is a rare form of low grade leukemia characterized by large cytotoxic T cells or natural killer cells on morphological examination. Immunosuppressive therapy is employed as first-line therapy. Treatment options in refractory cases include the anti-CD52 antibody alemtuzumab and purine analogues. We report a rare case that responded to the anti-CD20 monoclonal antibody rituximab. A 77-year-old female presented with complaints of fatigue, fever, and chills of 3 months’ duration. A CBC showed that pancytopenia with an absolute neutrophil count (ANC was 0. Peripheral blood flow cytometry detected increased number of T cell large granular lymphocytes and T cell receptor rearrangement study detected a clonal T cell population. Bone marrow biopsy showed peripheral T cell lymphoma, most consistent with T-large granulocytic leukemia. The patient was treated with prednisone and oral cyclophosphamide for four months with no response. Thereafter, she received four weekly infusions of rituximab with improvement in her blood counts. A response to rituximab in refractory cases such as ours has been reported and may guide us towards exploring other immune-based therapeutics in this rare disease.

  1. Anti-angiogenic therapy and radioimmunotherapy in colon cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Kinuya, Seigo; Yokoyama, Kunihiko; Michigishi, Takatoshi; Tonami, Norihisa [Dept. of Nuclear Medicine, Kanazawa Univ. (Japan); Kawashima, Atsuhiro [Dept. of Pathology (I), Kanazawa Univ. School of Medicine, Kanazawa, Ishikawa (Japan); Kudo, Miho; Kasahara, Yoshihito [Dept. of Pediatrics, Kanazawa University School of Medicine, Kanazawa, Ishikawa (Japan); Watanabe, Naoto [Dept. of Radiology, Toyama Medical and Pharmaceutical University, Toyama (Japan); Shuke, Noriyuki [Dept. of Radiology, Asahikawa Medical College, Asahikawa (Japan); Bunko, Hisashi [Medical Informatics, Kanazawa University Hospital, Kanazawa (Japan)

    2001-09-01

    Angiogenesis is critical to the growth and metastatic process of malignant tumors. An endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), displays anti-angiogenic and anti-tumorigenic effects. The purpose of this investigation was to determine whether exogenously administered 2-ME would enhance the efficacy of radioimmunotherapy (RIT). Experimental RIT with 4.63 MBq of {sup 131}I-A7, an IgG1 anti-colorectal monoclonal antibody, was conducted in mice xenografted with LS180 human colon cancer cells. 2-ME suspended in 0.5% carboxymethylcellulose was administered daily at a dose of 75 mg/kg per day. 2-ME administration suppressed tumor growth and improved the efficacy of RIT in comparison to RIT alone. Tumor volumes on day 13, expressed as a ratio relative to the initial volume, were 12.7{+-}2.95 in the nontreated control, 4.73{+-}0.89 with 2-ME, 3.05{+-}0.37 with RIT and 0.97{+-}0.20 with RIT+2-ME. Immunohistochemistry of tumor sections stained with an antibody against factor VIII demonstrated a decrease in microvessel number within tumors treated with 2-ME (7.9{+-}0.8/200 x field) as compared with that in control tumors (29.9{+-}2.5). Cell proliferation assay at increasing concentrations of 2-ME showed direct cytotoxicity of 2-ME in vitro at 5 {mu}M and greater. In conclusion, 2-ME enhanced the efficacy of RIT with {sup 131}I-A7 via inhibition of angiogenesis within the xenografts. The direct cytotoxicity of 2-ME appears to have contributed to this improvement. Anti-angiogenic therapy may prolong the dormancy of microscopic metastases while RIT may exterminate this population of cells. Therefore, the combined treatment may improve the therapeutic outcome of patients with disseminated cancer. (orig.)

  2. [Review of the current use of rituximab during 4 years in a French university hospital].

    Science.gov (United States)

    Reynaud, Q; Killian, M; Robles, A; Mounsef, F; Camdessanché, J-P; Mariat, C; Cathébras, P

    2015-12-01

    Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently, it has also been used in the treatment of several autoimmune diseases. We conducted a retrospective analysis of patients treated at least once with rituximab between 2010 and 2013 in a French university hospital, to provide a panoramic view of rituximab use including FDA or off-labels uses, its efficacy and safety. Eighty-seven patients were included with 20 different indications: cryoglobulinemic vasculitis (16%) and anti-PLA2R idiopathic membranous nephropathy (13%) were the most frequent. Rituximab use was off-labels in 50% of cases. Eleven percent of patients experienced severe adverse events, mostly infections. After rituximab, 17% of patients were in complete response (CR), 41% in partial response (PR), and 39% non-responding (NR). Relapse was observed in 65% (33/51) of responding patients. Further investigation with randomized controlled trials will provide more insight into the specifics of the role of RTX in the overall management of each disease. Identifying clear objectives and strict outcome measures, associated with long term clinical and biological follow-up would help deciding when, how and in which therapeutic regimen will rituximab most benefit a disease or a patient. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  3. 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.

  4. 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

  5. Lupus nephritis, pregnancy and rituximab

    Directory of Open Access Journals (Sweden)

    Enrique Dorado

    2017-04-01

    Full Text Available La nefritis lúpica (NL proliferativa es una de las complicaciones más graves del LES. La respuesta terapéutica con los esquemas clásicos no existe en el 20 al 70% de los casos, siendo la amplitud de dicho rango explicada por variaciones étnicas, falta de consenso en la definición de remisión, diferencias en los tiempos de tratamiento, seguimiento y en la clase de NL. En presencia de NL recidivante o refractaria los tratamientos y el nivel de evidencia sobre su eficacia son más limitados. Rituximab es un anticuerpo monoclonal quimérico (ratón-humano dirigido contra el antígeno CD 20 localizado en la superficie celular de los linfocitos B. Estos participan en la patogénesis del LES a partir de su maduración en células plasmáticas, producción de anticuerpos, secreción de citoquinas proinflamatorias, presentación de autoantígenos a las células T y en la activación de células T. La administración de rituximab genera un rápido y sostenido descenso de los linfocitos B CD 20+ circulantes y una reducción de los títulos de auto-anticuerpos. Se reportó una disminución significativa en los niveles de antiDNA a partir de la semana 14 y de los niveles de IgM, sin compromiso de IgG ni de IgA. Se detectó droga activa en sangre periférica luego de la semana 24 de la última infusión. La depleción de linfocitos B se puede mantener por 6 meses, su reconstitución es heterogénea y puede tardar más de un año. Esta linfopenia selectiva tendría un valor predictivo de respuesta terapéutica, la remisión clínica prolongada tendría asociación con repoblación incompleta de células B de memoria varios años luego del tratamiento. En estudios observacionales realizados en pacientes con NL refractaria se reportó respuesta terapéutica con rituximab entre 67-77 % luego de 6 a 12 meses de seguimiento. Sin embargo los resultados del estudio Lupus Nephritis Assesment with Rituximab (LUNAR, randomizado controlado, a doble ciego

  6. Does immunoscintigraphy serve clinical needs effectively? Is there a future for radioimmunotherapy?

    International Nuclear Information System (INIS)

    Chata, J.F.; Peltier, P.; Bardies, M.; Chetanneau, A.; Thedrez, P.; Faivre-Chauvet, A.; Gestin, J.F.

    1992-01-01

    Since 1980, immunoscintigraphy has been performed in thousands of patients, and its clinical value has been demonstrated for selective indications in malignant (early detection of recurrences of colorectal and ovarian carcinomas) and non-malignant (cardiovascular and inflammatory) pathology. However, many clinicians are not yet very convinced of its efficiency. Opinions range between favourable interest and marked scepticism. The causes of this inconclusive verdict include an often moderate target-to-background ratio in images, the immunogenicity of injected murine antibodies and the fact that a true benefit for the patient has not yet been clearly demonstrated in large series of patients. Future prospects could significantly improve this and involve the reduction of non-specific activity in normal tissues (to improve disease target contrast and thus make image interpretation easier) and the decreased immunogenicity of injected immunoconjugates (to permit repetition of examinations). Radioimmunotherapy, an innovative and promising approach, is still limited by numerous problems. The results of clinical studies are still inconclusive, being encouraging only for specific indications. In the future, pre-targetting techniques should allow the rapid elimination of radioactivity from normal tissues, resulting in a significant increase in tumour-to-normal tissue ratios. Progress is also required in the choice of radionuclides and labelling techniques and in methods for dosimetric estimations. The clinical indications of radioimmunotherapy after systemic injection will concern mainly radiosensitive tumours such as lymphomas, small-cell lung cancers and neuroblastomas. After endocavitary injection, radioimmunotherapy could prove efficient in the treatment of micrometastases of ovarian carcinomas. For all indications, this new approach should be combined with other therapeutic modalities. (orig.)

  7. 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)

    Akanji, Akinkunmi Ganiyu

    2006-01-01

    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

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

    International Nuclear Information System (INIS)

    Akanji, Akinkunmi Ganiyu

    2012-01-01

    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®). 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

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

    DEFF Research Database (Denmark)

    Birgens, Henrik; 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 ritu...

  10. Treatment of posttransplant lymphoproliferatieve disease with rituximab : The remission, the relapse, and the complication

    NARCIS (Netherlands)

    Verschuuren, EAM; Stevens, SJC; Van Imhoff, GW; Middeldorp, JM; De Boer, C; Koeter, G; The, TH; Van Der Bij, W

    2002-01-01

    Background. Rituximab, a humanized anti-CD20 monoclonal antibody, is a promising new tool for the treatment of posttransplant lymphoproliferative disease (PTLD), especially for patients transplanted with rejection prone transplants of vital organs, such as patients after lung transplantation. Thus

  11. 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)

    Akanji, Akinkunmi Ganiyu

    2006-01-01

    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 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

  12. Rituximab in the treatment of refractory lupus nephritis with vasculitis

    Directory of Open Access Journals (Sweden)

    Huseyin Kadikoy

    2012-01-01

    Full Text Available Dysfunction of the B lymphocyte, an important component of adaptive immunity, is thought to be important in the pathogenesis of lupus nephritis (LN. There are several novel strategies emerging including B-cell depletion by the monoclonal antibodies to B-cell markers, rituximab. We describe an unusual clinical response of a 22-year-old Hispanic woman with class IV LN with vasculitis while on dialysis to cyclophosphamide (CY and adjunct rituximab. The patient had a history of class III/V LN and was treated with nine months of CY and maintenance therapy with mycophenolate mofetil (MMF for three years. While on MMF, the patient deve-loped class IV LN with vasculitis leading to end-stage renal disease (ESRD. While the patient was on peritoneal dialysis, the patient was treated with two doses of rituximab and six doses of intravenous CY. The patient responded to this regimen and recovered kidney function within four months. The kidney function remained stable nine months after discontinuing peritoneal dialysis.

  13. Refractory myasthenia gravis - clinical profile, comorbidities and response to rituximab.

    Science.gov (United States)

    Sudulagunta, Sreenivasa Rao; Sepehrar, Mona; Sodalagunta, Mahesh Babu; Settikere Nataraju, Aravinda; Bangalore Raja, Shiva Kumar; Sathyanarayana, Deepak; Gummadi, Siddharth; Burra, Hemanth Kumar

    2016-01-01

    Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications. Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27-53 years. In our study 25 patients (32.89%) belonged to the age group of 21-30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA 1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% ( p =3.3x10 -8 ) to 94.6% ( p =2.2x10 -14 ) after the third cycle of rituximab treatment. Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA 1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low.

  14. Combination radioimmunotherapy approaches and quantification of immuno-PET

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Su [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2016-06-15

    Monoclonal antibodies (mAbs), which play a prominent role in cancer therapy, can interact with specific antigens on cancer cells, thereby enhancing the patient' immune response via various mechanisms, or mAbs can act against cell growth factors and, thereby, arrest the proliferation of tumor cells. Radionuclide-labeled mAbs, which are used in radioimmunotherapy (RIT), are effective for cancer treatment because tumor associated-mAbs linked to cytotoxic radionuclides can selectively bind to tumor antigens and release targeted cytotoxic radiation. Immunological positron emission tomography (immuno-PET), which is the combination of PET with mAb, is an attractive option for improving tumor detection and mAb quantification. However, RIT remains a challenge because of the limited delivery of mAb into tumors. The transport and uptake of mAb into tumors is slow and heterogeneous. The tumor microenvironment contributed to the limited delivery of the mAb. During the delivery process of mAb to tumor, mechanical drug resistance such as collagen distribution or physiological drug resistance such as high intestinal pressure or absence of lymphatic vessel would be the limited factor of mAb delivery to the tumor at a potentially lethal mAb concentration. When α-emitter-labeled mAbs were used, deeper penetration of α-emitter-labeled mAb inside tumors was more important because of the short range of the α emitter. Therefore, combination therapy strategies aimed at improving mAb tumor penetration and accumulation would be beneficial for maximizing their therapeutic efficacy against solid tumors.

  15. Combination radioimmunotherapy approaches and quantification of immuno-PET

    International Nuclear Information System (INIS)

    Kim, Jin Su

    2016-01-01

    Monoclonal antibodies (mAbs), which play a prominent role in cancer therapy, can interact with specific antigens on cancer cells, thereby enhancing the patient' immune response via various mechanisms, or mAbs can act against cell growth factors and, thereby, arrest the proliferation of tumor cells. Radionuclide-labeled mAbs, which are used in radioimmunotherapy (RIT), are effective for cancer treatment because tumor associated-mAbs linked to cytotoxic radionuclides can selectively bind to tumor antigens and release targeted cytotoxic radiation. Immunological positron emission tomography (immuno-PET), which is the combination of PET with mAb, is an attractive option for improving tumor detection and mAb quantification. However, RIT remains a challenge because of the limited delivery of mAb into tumors. The transport and uptake of mAb into tumors is slow and heterogeneous. The tumor microenvironment contributed to the limited delivery of the mAb. During the delivery process of mAb to tumor, mechanical drug resistance such as collagen distribution or physiological drug resistance such as high intestinal pressure or absence of lymphatic vessel would be the limited factor of mAb delivery to the tumor at a potentially lethal mAb concentration. When α-emitter-labeled mAbs were used, deeper penetration of α-emitter-labeled mAb inside tumors was more important because of the short range of the α emitter. Therefore, combination therapy strategies aimed at improving mAb tumor penetration and accumulation would be beneficial for maximizing their therapeutic efficacy against solid tumors

  16. Pretargeted radioimmunotherapy (pRAIT) in medullary thyroid cancer (MTC).

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Salaun, Pierre-Yves; Ansquer, Catherine; Drui, Delphine; Mirallié, Eric; Faivre-Chauvet, Alain; Barbet, Jacques; Goldenberg, David M; Chatal, Jean-François

    2012-06-01

    Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models. Moreover, two phase I/II clinical trials assessing anti-CEA × anti-DTPA-indium BsMAb (murine F6x734 and chimeric hMN14x734) with (131)I-di-DTPA-indium showed encouraging therapeutic results in progressive, metastatic, MTC patients, with an improved survival in intermediate- and high-risk (pre-pRAIT Ct DT, <2 years) patients, as compared to contemporaneous untreated patients (median overall survival, 110 months vs 61 months; P < 0.030). pRAIT efficacy has been recently confirmed in a prospective multicenter phase II study assessing hMN14x734 and (131)I-di-DTPA-indium in rapidly progressive MTC patients. New pRAIT compounds are now available with fully humanized, recombinant, trivalent BsMAb (anti-CEA TF2) and histamine-succinyl-glutamine (HSG) peptides. The HSG peptide allows easy and stable labeling with different radiometals, such as (177)Lu or (90)Y beta-emitters having favorable physical features for pRAIT or (68)Ga and (18)F positron-emitters, allowing the development of a highly sensitive and specific immuno-positron emission tomography method in MTC or other CEA-positive tumors.

  17. 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.

  18. Role of rituximab in first-line treatment of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Jeffrey Bryan

    2010-12-01

    Full Text Available Jeffrey Bryan, Gautam BorthakurDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: Chronic lymphocytic leukemia (CLL is a biologically heterogeneous illness that primarily afflicts the elderly. For many decades, the initial therapy for most patients requiring treatment was limited to single-agent alkylator therapy. Within the last two decades, we have seen remarkable progress in understanding the biology of CLL and the development of more effective treatment strategies that have employed monoclonal antibodies, such as rituximab (anti-CD20. Furthermore, recognition of the synergy between fludarabine, cyclophosphamide, and rituximab (FCR prompted investigators to explore the clinical activity of FCR in Phase II and III trials in patients with relapsed/refractory or previously untreated CLL. On the basis of these findings, the US Food and Drug Administration (FDA recently approved rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed/refractory or previously untreated CD20-postive CLL. Recent data from a randomized Phase III trial has confirmed improved overall survival with FCR in patients with previously untreated CLL. However, FCR is not for everyone. More tolerable regimens using rituximab for the elderly and less fit patients are being pursued in clinical trials. Recent Phase II trials have explored potentially less myelosuppressive approaches by using lower doses of fludarabine and cyclophosphamide, replacing fludarabine with pentostatin, and combining rituximab with chlorambucil. Furthermore new biomarkers predictive of early disease progression have prompted investigators to explore the benefits of early treatment with rituximab combined with other agents. In addition to the proven utility of rituximab as a frontline agent for CLL, rituximab has a favorable toxicity profile both as a single agent and in combination with chemotherapy. The

  19. Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome.

    Science.gov (United States)

    Sato, Mai; Ito, Shuichi; Ogura, Masao; Kamei, Koichi; Miyairi, Isao; Miyata, Ippei; Higuchi, Masataka; Matsuoka, Kentaro

    2013-01-01

    Rituximab, an anti-CD20 antibody that targets B cells, is a promising agent against steroid-dependent and steroid-resistant nephrotic syndrome in children. We report a 3-year-old boy who presented with atypical Pneumocystis jiroveci pneumonia (PCP) following administration of rituximab for refractory nephrotic syndrome. He had received cyclosporine and daily prednisolone for over 1 year. Following rituximab therapy, a hazy shadow was observed on his chest X-ray. Chest-computed tomography revealed multiple nodular lesions in bilateral lungs, although his clinical symptoms were subtle. PCR analysis demonstrated the presence of Pneumocystis DNA in his bronchoalveolar lavage. Lung wedge resection of the nodular lesion exhibited granulomas containing a few cysts of P. jiroveci that primarily consisted of T cells and histiocytes and lacked B cells. A deficiency of B cells following rituximab treatment suggests a dramatic effect on the immune response and, therefore, could result in granulomatous PCP. Nodular granulomatous lesions of PCP comprise an emerging concept previously reported in adults with hematological disease, bone marrow transplant, or treatment with rituximab. We report the first pediatric case of nodular PCP. Granulomatous PCP can be life-threatening. Moreover, bronchoalveolar lavage often fails to demonstrate the presence of P. jiroveci DNA. Wedge biopsy is warranted for definitive diagnosis. Our patient fully recovered with sulfamethoxazole/trimethoprim treatment because of early detection. The indication of rituximab for refractory nephrotic syndrome has increased recently. Therefore, recognition of the risk of atypical PCP is important. Our findings suggest that PCP prophylaxis should be considered following rituximab therapy.

  20. Infusion reactions associated with rituximab treatment for childhood-onset complicated nephrotic syndrome.

    Science.gov (United States)

    Kamei, Koichi; Ogura, Masao; Sato, Mai; Ito, Shuichi; Ishikura, Kenji

    2018-02-09

    Infusion reaction (IR) is defined as an adverse event within 24 h after monoclonal antibody infusion. In non-Hodgkin lymphoma, IR incidence following rituximab treatment is high (77-80%), but there are no data in complicated nephrotic syndrome. Records of rituximab infusions in patients with complicated nephrotic syndrome between February 2006 and December 2014 at the National Center for Child Health and Development were reviewed. Rituximab was administered at doses of 375 mg/m 2 . The severity of IR was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. For 309 rituximab infusions in 159 patients (male, 110; median age, 12 years), IR was observed in 165 infusions (53.4%). Respiratory symptoms were most common (66% of all events). Ninety-five percent of the IR was observed within 3 h after rituximab infusion initiation. Sixty-eight percent of the events were classified as grade 1 and others classified as grade 2. Only 18% required medical intervention. CD20 cell count in patients with IR was significantly higher than in patients without IR. Incidence of IR was similar in subsequent rituximab treatment after B-cell recovery. Patients who experienced IR at first rituximab treatment were more likely to experience recurrent IR with subsequent treatments compared to those not having IR at initial treatment (odds ratio 3.64; p nephrotic syndrome, respiratory symptoms were the major type of IR, mostly observed within 3 h of infusion. Incidence of IR was lower and its severity milder in patients with complicated nephrotic syndrome than those with lymphoma.

  1. Hepatitis B screening before rituximab therapy: a multicentre South Australian study of adherence.

    Science.gov (United States)

    Hall, Samuel Al; Shaikh, Abdul; KailinTeh; Tantiongco, Mahsa; Coghlan, Douglas; Karapetis, Chris S; Chinnaratha, Mohammad A; Woodman, Richard; Muller, Kate R; Wigg, Alan J

    2018-01-18

    Background and Aims International guidelines recommend screening for Hepatitis B virus (HBV) infection prior to administration of rituximab, due to high risk of HBV reactivation in at risk patients. The aim of this study was to determine; (1) adherence to the South Australian (SA) protocol for HBV screening, (2) HBV prevalence in patients receiving rituximab, and (3) outcomes of patients at risk of HBV reactivation. All patients commenced on rituximab at the 6 major SA public hospitals during a 12-month period were included in the study. Adherence was assessed by documentation of both hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) prior to initiation of rituximab. Patients were observed for a minimum of 6 months following rituximab initiation. 438 patients were included in the study. The main indication for rituximab therapy was haematological malignancy (76.0%). 209 (47.7%) failed to receive appropriate HBV screening, 86 (19.6%) had neither HBsAg nor HBcAb performed, and 119 (27.2%) had only HBsAg performed. The identified prevalence of at risk cases (either HBsAg or HBcAb positive) within the study population was 4.6% (20/438 cases). One case of HBV reactivation was identified but none led to acute liver failure, transplantation or death. Poor adherence to HBV screening protocols suggests the need for targeted clinician education and system redesign. While the rate of reactivation was low, the prevalence of at risk patients in this population was high and justifies further initiatives to increase adherence rates to HBV screening pre-rituximab. This article is protected by copyright. All rights reserved.

  2. Rituximab administration in a patient with pemphigus vulgaris following reactivation of occult hepatitis B virus infection.

    Science.gov (United States)

    Tavakolpour, Soheil; Soori, Tahereh; Noormohammadpour, Pedram; Balighi, Kamran; Mahmoudi, Hamidreza; Daneshpazhooh, Maryam

    2017-06-20

    Immunosuppressive drugs are the milestone of treatment of autoimmune diseases, but they can lead to serious complications, including hepatitis B virus reactivation in HBV carriers as well as in patients with occult HBV infection (OBI). A 36-year-old man with OBI was diagnosed with pemphigus vulgaris. He was prescribed prednisolone and his hepatitis B surface antigen turned positive. Viral replication was successfully controlled by lamivudine and adefovir. Mycophenolate mofetil and intravenous immunoglobulin  were not effective in controlling the pemphigus vulgaris. The patient received rituximab 500 mg weekly for four weeks and went into remission without any adverse effect. He safely received another course of rituximab after a relapse one year later. In conclusion, testing for hepatitis B core antibody should be considered mandatory, in addition to HBsAg, for the screening of pemphigus patients to detect rare cases of OBI before starting therapy. Furthermore, rituximab may in some cases be safely used in HBV carriers using antivirals concomitantly.

  3. 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 .

  4. Rituximab in the treatment of primary cutaneous B-cell lymphoma: a review.

    Science.gov (United States)

    Fernández-Guarino, M; Ortiz-Romero, P L; Fernández-Misa, R; Montalbán, C

    2014-06-01

    Rituximab is a chimeric mouse-human antibody that targets the CD20 antigen, which is found in both normal and neoplastic B cells. In recent years, it has been increasingly used to treat cutaneous B-cell lymphoma and is now considered an alternative to classic treatment (radiotherapy and surgery) of 2 types of indolent lymphoma, namely, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma. Rituximab is also administered as an alternative to polychemotherapy in the treatment of primary cutaneous large B-cell lymphoma, leg type. Its use as an alternative drug led to it being administered intralesionally, with beneficial effects. In the present article, we review the literature published on the use of rituximab to treat primary cutaneous B-cell lymphoma. Copyright © 2012 Elsevier España, S.L. and AEDV. All rights reserved.

  5. Rituximab in autoimmune hematologic diseases: not just a matter of B cells.

    Science.gov (United States)

    Stasi, Roberto

    2010-04-01

    Rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen, has been investigated extensively in autoimmune disorders. Following the encouraging results in immune thrombocytopenia (ITP), the use of this agent was explored in other autoimmune hematologic diseases, most notably autoimmune hemolytic anemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), characterized by the presence of pathogenetic autoantibodies. Although randomized clinical trials are lacking, the cumulative data would suggest that rituximab has a beneficial role in their treatment. Response to B-cell-depleting therapy is actually associated with a significant decrease of circulating autoantibodies. However, several lines of evidence indicate that the T-cell compartment may also be modulated by these interventions. The doses and the duration of rituximab treatment in patients with autoimmune diseases are still unclear. The incidence of severe side effects is low but not insignificant. In particular, the risk of systemic infections and viral reactivation is a major concern.

  6. Rituximab for non-Hodgkin's lymphoma: a story of rapid success in translation.

    Science.gov (United States)

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

    2014-02-01

    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 medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation. © 2013 Wiley Periodicals, Inc.

  7. Rituximab for Non‐Hodgkin's Lymphoma: A Story of Rapid Success in Translation

    Science.gov (United States)

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

    2013-01-01

    Abstract 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 medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation. PMID:24528902

  8. Interleukin-21 enhances rituximab activity in a cynomolgus monkey model of B cell depletion and in mouse B cell lymphoma models.

    Directory of Open Access Journals (Sweden)

    Cecile M Krejsa

    Full Text Available Rituximab, a monoclonal antibody targeting CD20 on B cells, is currently used to treat many subtypes of B cell lymphomas. However, treatment is not curative and response rates are variable. Recombinant interleukin-21 (rIL-21 is a cytokine that enhances immune effector function and affects both primary and transformed B cell differentiation. We hypothesized that the combination of rIL-21 plus rituximab would be a more efficacious treatment for B cell malignancies than rituximab alone. We cultured human and cynomolgus monkey NK cells with rIL-21 and found that their activity was increased and proteins associated with antibody dependent cytotoxicity were up-regulated. Studies in cynomolgus monkeys modeled the effects of rIL-21 on rituximab activity against CD20 B cells. In these studies, rIL-21 activated innate immune effectors, increased ADCC and mobilized B cells into peripheral blood. When rIL-21 was combined with rituximab, deeper and more durable B cell depletion was observed. In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma. Therefore, our results do suggest that the therapeutic efficacy of rituximab may be improved when used in combination with rIL-21.

  9. Enfermedad pulmonar intersticial asociada a rituximab

    Directory of Open Access Journals (Sweden)

    Marcelo Fernández Casares

    2013-08-01

    Full Text Available La introducción en la práctica clínica del anticuerpo anti-CD20 rituximab ha mejorado sustancialmente el pronóstico de diversas enfermedades autoinmunes y hematológicas. Con el incremento de su uso ha aumentado el registro de efectos adversos, entre ellos la toxicidad pulmonar. Una de sus complicaciones más serias es la enfermedad pulmonar intersticial, entidad potencialmente fatal que debe ser considerada en pacientes que han recibido rituximab y presentan disnea, fiebre y tos sin clara evidencia de infección. Presentamos un caso de enfermedad pulmonar intersticial asociada a rituximab.

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

    International Nuclear Information System (INIS)

    Le Du, A.

    2011-01-01

    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)

  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. Rituximab for severe refractory pediatric Wegener granulomatosis.

    Science.gov (United States)

    Patel, Aarat M; Lehman, Thomas J A

    2008-10-01

    We describe a case of pediatric Wegener granulomatosis initially treated with cyclophosphamide and oral corticosteroids resulting in remission for 5 years. Of note in this case is relapse with severe pulmonary disease treated with multiple regimens, all unsuccessful. Patient achieved remission with rituximab infusion therapy. This demonstrates how rituximab may be beneficial for childhood-onset Wegener granulomatosis unresponsive to conventional therapy. The case is followed by a review of the current treatment options.

  14. 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.

  15. Rituximab for troublesome cases of childhood nephrotic syndrome.

    Science.gov (United States)

    Safdar, Osama Y; Aboualhameael, Adila; Kari, Jameela A

    2014-11-08

    Nephrotic syndrome (NS) is the most common glomerular disease of childhood. Steroid-dependent and steroid-resistant nephrotic syndrome present challenges in their pharmaceutical management; patients may need several immunosuppressive medication for optimum control, each of which medication has its own safety profile. Rituximab (RTX) is a monoclonal antibody that targets B cells and has been used successfully for management of lymphoma and rheumatoid arthritis. Recent clinical studies showed that rituximab may be an efficacious and safe alternative for the treatment of complicated nephrotic syndrome. In this review article, we aim to review the efficacy and safety of RTX therapy in nephrotic syndrome. We reviewed the literature pertaining to this topic by searching for relevant studies on PubMed and Medline using specific keywords. The initial search yielded 452 articles. These articles were then examined to ensure their relevance to the topic of research. We focused on multicenter randomized controlled trials with relatively large numbers of patients. A total of 29 articles were finally identified and will be summarized in this review. The majority of clinical studies of RTX in complicated pediatric NS showed that rituximab is effective in approximately 80% of patients with steroid-dependent NS, as it decreases the number of relapses and steroid dosage. However, RTX is less effective at achieving remission in steroid-resistant NS. RTX use was generally safe, and most side effects were transient and infusion-related. More randomized, double-blinded clinical studies are needed to assess the role of RTX in children with nephrotic syndrome.

  16. Microangiopathic antiphospholipid antibody syndrome due to anti-phosphatidylserine/prothrombin complex IgM antibody.

    Science.gov (United States)

    Senda, Yumi; Ohta, Kazuhide; Yokoyama, Tadafumi; Shimizu, Masaki; Furuichi, Kengo; Wada, Takashi; Yachie, Akihiro

    2017-03-01

    Herein we describe a case of microangiopathic antiphospholipid syndrome (MAPS) due to anti-phosphatidylserine/prothrombin complex (aPS/PT) IgM antibody successfully treated with rituximab. A significant correlation was observed between the clinical course and the aPS/PT IgM antibody titer, which can rise earlier before the appearance of clinical symptoms. Rituximab can be safely and effectively used for MAPS. Although detection of only aPS/PT IgM antibody is rare, aPS/PT IgM antibody might be associated with the pathogenesis of MAPS and might be a useful marker of disease activity. © 2017 Japan Pediatric Society.

  17. Radioimmunotherapy. Dose calculation and radionuclides used in treatment; Radioimmunoterapia. Hoidon radionuklidit ja annoslaskenta

    Energy Technology Data Exchange (ETDEWEB)

    Savolainen, S. [Helsinki Univ. (Finland). Dept. of Physics; Kairemo, K. [Helsinki Univ. (Finland). Dept. of Clinical Chemistry; Liewendahl, K. [Helsinki Univ. Central Hospital (Finland). Dept. of Isotopes; Rannikko, S. [Finnish Centre for Radiation and Nuclear Safety, Helsinki (Finland)

    1995-10-01

    In radioimmunotherapy (RIT) monoclonal antibodies to cancer-associated antigens can be utilized for the transport of therapeutic radioisotopes to cancer cells. Intravenous administration of radiolabelled antibody is a potentially curative form of therapy in hematological amignancies as circulating antibodies have easy access to tumour sites. Intravenous RIT is less effective in the treatment of solid tumours because of the low fractional uptake of the injected dose, particularly in the central parts of tumours. In solid tumours more promising results have been achieved by local RIT applications. The choice of radiation - {alpha}, {beta} or {gamma} - will depend of the characteristics of the tumour. The importance of radiation delivered by Auger electrons has been largely underestimated in the past, but recent research has resulted in a remarkable reassessment of this issue significantly influencing the selection of radioisotopes for RIT. Research is now being focused on the therapeutic aspects of different isotopes and microdosimetric problems. There are now good prospects of RIT becoming an important form of cancer treatment before year 2000. (orig.) (78 refs., 3 figs., 1 tab.).

  18. Interest of a treatment combined by radioimmunotherapy and Avastin 1 in a murine model of thyroid medullary carcinoma; Interet d'un traitement combine par radioimmunotherapie et Avastin1 dans un modele murin de carcinome medullaire de la thyroide

    Energy Technology Data Exchange (ETDEWEB)

    Salaun, P.Y.; Bodet-Milin, C.; Paris, F.; Frampas, E.; Sai Maurel, C.; Faivre Chauvet, A.; Barbet, J.; Kraeber Bodere, F. [Unite Inserm U892, Brest, (France)

    2009-05-15

    The objective of this study was to evaluate the efficiency and the toxicity of the association radioimmunotherapy and bevacizumab on a murine model grafted by the human line T.T. of thyroid medullar cancer. After results it appears that in pretreatment, bevacizumab (Avastin) improves the efficiency of radioimmunotherapy without increasing the toxicity face the radioimmunotherapy alone. (N.C.)

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    To study the efficacy of rituximab therapy for the treatment of orbital inflammation in patients with Wegener's granulomatosis (WG).......To study the efficacy of rituximab therapy for the treatment of orbital inflammation in patients with Wegener's granulomatosis (WG)....

  1. Repeated Courses of Rituximab in Chronic ITP: Three Different Regimens

    Science.gov (United States)

    Hasan, Aisha; Michel, Marc; Patel, Vivek; Stasi, Roberto; Cunningham-Rundles, Susanna; Leonard, John; Bussel, James

    2009-01-01

    This study investigated responses to re-treatment with rituximab in chronic ITP patients. Treatment with rituximab in chronic ITP patients induces long-lasting responses in approximately 30% of patients but even these patients may relapse. Twenty patients who had achieved a response to rituximab and relapsed were re-treated with rituximab (375 mg/m2 × 4); this data was analyzed retrospectively. Subsequently, 16 patients were prospectively randomized to receive rituximab with CVP (R-CVP) or double dose rituximab (DDR). Re- treatment with standard dose rituximab demonstrated responses similar to initial rituximab treatment in 15 of 20 patients. Neither of the 2 more intensive regimens (R-CVP, DDR) induced responses in any patient who had previously failed to respond to rituximab nor induced substantially longer-lasting responses among previous responders. No additional toxicity was noted with the DDR regimen, whereas R-CVP was not well tolerated. These results suggest that re-treatment with standard dose rituximab induces similar responses in 75% of previously responding patients and is well tolerated. Neither combining rituximab with CVP nor doubling the dose of rituximab increased the response rate. PMID:19731307

  2. A new radiotherapy approach: the radioimmunotherapy

    International Nuclear Information System (INIS)

    Kraeber-Bodere, F.; Chatal, J.F.; Ansquer, C.; Faivre-Chauvet, A.

    2003-01-01

    To irradiate a tumor in preserving as possible the healthy tissues, that the aim of the radio immuno therapy. This new form of treatment whom efficiency is modulated in function of the choice of antibody, radionuclide, and target, knows success against some types of lymphomas. (N.C.)

  3. Future therapies for pemphigus vulgaris: Rituximab and beyond.

    Science.gov (United States)

    Huang, Amy; Madan, Raman K; Levitt, Jacob

    2016-04-01

    The conventional treatment for patients with pemphigus vulgaris (PV) centers on global immunosuppression, such as the use of steroids and other immunosuppressive drugs, to decrease titers of antidesmoglein autoantibodies responsible for the acantholytic blisters. Global immunosuppressants, however, cause serious side effects. The emergence of anti-CD20 biologic medications, such as rituximab, as an adjunct to conventional therapy has shifted the focus to targeted destruction of autoimmune B cells. Next-generation biologic medications with improved modes of delivery, pharmacology, and side effect profiles are constantly being developed, adding to the diversity of options for PV treatment. We review promising monoclonal antibodies, including veltuzumab, obinutuzumab (GA-101), ofatumumab, ocaratuzumab (AME-133v), PRO131921, and belimumab. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  4. Radio-immunotherapy of non Hodgkin lymphomas: Experience from Lille; Radio-immunotherapie des lymphomes non hodgkiniens, experience lilloise

    Energy Technology Data Exchange (ETDEWEB)

    Huglo, D.; Morschhauser, F.; Steinling, M. [Lille Univ. Nord de France, UPRESS EA 1049, 59 (France); Huglo, D.; Prangere, T.; Robu, D.; Malek, E.; Petyt, G.; Steinling, M. [CHU de Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Hopital Huriez, 59 - Lille (France); Huglo, D. [Inserm U703, 59 - Lille (France); Morschhauser, F.; Robu, D. [CHU de Lille, Service des maladies du sang, Hopital Huriez, 59 - Lille (France)

    2009-08-15

    From an experience of radio-immunotherapy of non Hodgkin lymphomas from March 2002 to December 2008 (near 7 years), corresponding to 160 treatments, an analysis of indications has been done: clinical research trials, authorized indications from A.M.M. or medically justified. Some elements which could be problematic are pointed: coordination between the regional Haematology departments and our Nuclear Medicine department, radio labelling and radioprotection. (authors)

  5. Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Trahair, Toby N; Wainstein, Brynn; Manton, Nicholas; Bourne, Anthony J; Ziegler, John B; Rice, Michael; Russell, Susan J

    2008-02-01

    Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT. (c) 2007 Wiley-Liss, Inc.

  6. Dermatomyositis with Rapidly Progressive Interstitial Lung Disease Treated with Rituximab: A Report of 3 Cases in Japan.

    Science.gov (United States)

    Tokunaga, Kenichiro; Hagino, Noboru

    2017-01-01

    We performed a retrospective chart review of three patients with hypomyopathic dermatomyositis and rapidly progressive interstitial lung disease. The patients were Japanese women of 71, 69, and 65 years of age. Two patients were anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive and 1 was anti-aminoacyl-tRNA synthetase (anti-ARS) antibody-positive. Their respiratory statuses deteriorated despite the administration of glucocorticoid, calcineurin inhibitors, and intravenous cyclophosphamide therapy. We subsequently administered rituximab. The anti-ARS antibody-positive patient survived, while 2 anti-MDA5 antibody-positive patients died.

  7. Identification of Fc Gamma Receptor Glycoforms That Produce Differential Binding Kinetics for Rituximab.

    Science.gov (United States)

    Hayes, Jerrard M; Frostell, Asa; Karlsson, Robert; Müller, Steffen; Martín, Silvia Míllan; Pauers, Martin; Reuss, Franziska; Cosgrave, Eoin F; Anneren, Cecilia; Davey, Gavin P; Rudd, Pauline M

    2017-10-01

    Fc gamma receptors (FcγR) bind the Fc region of antibodies and therefore play a prominent role in antibody-dependent cell-based immune responses such as ADCC, CDC and ADCP. The immune effector cell activity is directly linked to a productive molecular engagement of FcγRs where both the protein and glycan moiety of antibody and receptor can affect the interaction and in the present study we focus on the role of the FcγR glycans in this interaction. We provide a complete description of the glycan composition of Chinese hamster ovary (CHO) expressed human Fcγ receptors RI (CD64), RIIa Arg131/His131 (CD32a), RIIb (CD32b) and RIIIa Phe158/Val158 (CD16a) and analyze the role of the glycans in the binding mechanism with IgG. The interactions of the monoclonal antibody rituximab with each FcγR were characterized and we discuss the CHO-FcγRIIIa Phe158/Val158 and CHO-FcγRI interactions and compare them to the equivalent interactions with human (HEK293) and murine (NS0) produced receptors. Our results reveal clear differences in the binding profiles of rituximab, which we attribute in each case to the differences in host cell-dependent FcγR glycosylation. The glycan profiles of CHO expressed FcγRI and FcγRIIIa Phe158/Val158 were compared with the glycan profiles of the receptors expressed in NS0 and HEK293 cells and we show that the glycan type and abundance differs significantly between the receptors and that these glycan differences lead to the observed differences in the respective FcγR binding patterns with rituximab. Oligomannose structures are prevalent on FcγRI from each source and likely contribute to the high affinity rituximab interaction through a stabilization effect. On FcγRI and FcγRIIIa large and sialylated glycans have a negative impact on rituximab binding, likely through destabilization of the interaction. In conclusion, the data show that the IgG1-FcγR binding kinetics differ depending on the glycosylation of the FcγR and further support a

  8. Rituximab Administration and Reactivation of HBV

    Directory of Open Access Journals (Sweden)

    Yutaka Tsutsumi

    2010-01-01

    Full Text Available Rituximab is a drug used for the treatment of B-cell non-Hodgkin's lymphoma, and its range of use has expanded to the treatment of collagen diseases such as idiopathic thrombocytopenic purpura and rheumatoid arthritis. One serious complication of rituximab use is the reactivation of dormant hepatitis B virus, and prevention of this phenomenon has become an urgent issue. This paper provides a general outline of the problem through an analysis of patient cases that we and other groups have experienced to date.

  9. Successful Treatment of a Bullous Pemphigoid Patient with Rituximab Who Was Refractory to Corticosteroid and Omalizumab Treatments

    Directory of Open Access Journals (Sweden)

    Aslı Bilgiç Temel

    2017-02-01

    Full Text Available Omalizumab is a humanized monoclonal antibody which is an FDA-approved treatment of severe allergic asthma and inhibits IgE binding to FcεRI. According to increasing evidence of IgE inhibition, omalizumab was suggested as a therapeutic approach for bullous pemphigoid (BP. Rituximab has been reported to be effective in various autoimmune diseases, including autoimmune bullous dermatoses. A specific protocol for the use of rituximab to treat BP patients is not yet available. There are only small case series and case reports about the efficacy and safety of rituximab in BP. Here we present a young BP patient who responded well to rituximab therapy and was refractory to conventional and omalizumab therapies although he had elevated IgE levels and eosinophilia. Our case supports the knowledge about the effectiveness and safety of rituximab not only in pemphigus but also in BP. On the other hand, although it did not work in our case, omalizumab may be a potentially effective agent in some carefully selected patients with certain subtypes of BP.

  10. 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.

  11. 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

  12. Impact of rituximab therapy on response to tetanus toxoid vaccination in kidney-transplant patients.

    Science.gov (United States)

    Puissant-Lubrano, Benedicte; Rostaing, Lionel; Kamar, Nassim; Abbal, Michel; Fort, Marylise; Blancher, Antoine

    2010-03-01

    Rituximab is used after kidney transplant to prevention or treat kidney-allograft rejection. However, the impact of rituximab on the ability of patients to respond to tetanus toxoid vaccination has not yet been studied. The response to tetanus toxoid vaccination was analyzed in 39 kidney transplant recipients immunosuppressed by corticoids, antiproliferative agents, and/or calcineurin inhibitors. Thirteen patients had previously received rituximab (group 1), 26 patients had not (group 2). Response to control bacterial antigens and immunologic parameters (lymphocyte count, B-cell subsets, serum immunoglobulin level) were analyzed before and at 1 month after vaccination. Thirty healthy blood donors were used as controls for the before-vaccination immunologic parameters. Before vaccination, neither patient group differed from controls in serum levels of immunoglobulins and antibodies against bacterial antigens, but they did display lower levels of CD4 T cells and B cells compared with controls. Responders to the tetanus toxoid vaccination were slightly fewer in group 1 (4/13) than in group 2 (16/26), but the intensity of the anti-tetanus toxoid response was not significantly different between these 2 groups. None of the parameters studied at the time of vaccination (anti-tetanus toxoid level, peripheral B or CD4 T-cell count, memory B-cell subsets, treatment with rituximab, time since transplant) were associated with an ability to respond to vaccination. The ability to respond to vaccination and graft outcomes were not correlated in each patient group. Rituximab impaired the secondary immune response after tetanus toxoid vaccination, but did not abolish it in all patients.

  13. Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis.

    Science.gov (United States)

    van Daalen, Emma E; Rizzo, Raffaella; Kronbichler, Andreas; Wolterbeek, Ron; Bruijn, Jan A; Jayne, David R; Bajema, Ingeborg M; Rahmattulla, Chinar

    2017-06-01

    Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with cyclophosphamide have an increased malignancy risk compared with the general population. We investigated whether treatment with rituximab instead of cyclophosphamide has decreased the malignancy risk in patients with AAV. The study included patients with AAV treated at a tertiary vasculitis referral centre between 2000 and 2014. The malignancy incidence in these patients was compared with the incidence in the general population by calculating standardised incidence ratios (SIRs), adjusted for sex, age and calendar year. Malignancy incidence was compared between rituximab-treated and cyclophosphamide-treated patients. Of the 323 included patients, 33 developed a total of 45 malignancies during a mean follow-up of 5.6 years. This represented a 1.89-fold increased (95% CI 1.38 to 2.53) malignancy risk, and a non-significantly increased risk if non-melanoma skin cancer was excluded (SIR, 1.09; 95% CI 0.67 to 1.69). The risk of non-melanoma skin cancer was 4.58-fold increased (95% CI 2.96 to 6.76). Cyclophosphamide-treated patients had an increased malignancy risk compared with the general population (SIR, 3.10; 95% CI 2.06 to 4.48). In contrast, rituximab-treated patients had a malignancy risk similar to the general population (SIR, 0.67; 95% CI 0.08 to 2.43). The malignancy risk in cyclophosphamide-treated patients was 4.61-fold higher (95% CI 1.16 to 39.98) than in rituximab-treated patients. The malignancy risk in patients with AAV was lower in rituximab-treated patients than in cyclophosphamide-treated patients. Notably, rituximab treatment was not associated with an increased malignancy risk compared with the general population. Rituximab could therefore be a safe alternative to cyclophosphamide in the treatment of AAV. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. Analytical similarity assessment of rituximab biosimilar CT-P10 to reference medicinal product.

    Science.gov (United States)

    Lee, Kyoung Hoon; Lee, Jihun; Bae, Jin Soo; Kim, Yeon Jung; Kang, Hyun Ah; Kim, Sung Hwan; Lee, So Jung; Lim, Ki Jung; Lee, Jung Woo; Jung, Soon Kwan; Chang, Shin Jae

    2018-02-22

    CT-P10 (TruximaTM) was recently approved as the world's first rituximab biosimilar product in the European Union (EU) and South Korea. To demonstrate biosimilarity of CT-P10 with the reference medicinal product (RMP), extensive 3-way similarity assessment has been conducted between CT-P10, EU-Rituximab and US-Rituximab, focusing on the physicochemical and biological quality attributes. A multitude of state-of-the-art analyses revealed that CT-P10 has identical primary and higher order structures compared to the original product. Purity/impurity profiles of CT-P10 measured by the levels of aggregates, fragments, non-glycosylated form and process-related impurities were also found to be comparable with those of RMPs. In terms of the post-translational modification, CT-P10 contains slightly less N-terminal pyro-glutamate variant, which has been known not to affect product efficacy or safety. Oligosaccharide profiling has revealed that, although CT-P10 contains the same conserved glycan species and relative proportion with the RMPs, the content of total afucosylated glycan in CT-P10 was slightly higher than in EU- or US-Rituximab. Nevertheless, the effect of the observed level of afucosylation in CT-P10 drug product on Fc receptor binding affinity or antibody-dependent cell-mediated cytotoxicity was found to be negligible based on the spiking study with highly afucosylated sample. Arrays of biological assays representative of known and putative mechanisms of action for rituximab have shown that biological activities of CT-P10 are within the quality range of RMPs. Recent results of clinical studies have further confirmed that the CT-P10 exhibits equivalent clinical efficacy and safety profiles compared to EU- and US-Rituximab. The current 3-way similarity assessment together with clinical study results confidently demonstrate that CT-P10 is highly similar with EU- and US-Rituximab in terms of physicochemical properties, biological activities, efficacy, and safety for

  15. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

    Directory of Open Access Journals (Sweden)

    Maximilian Richter

    2016-01-01

    Full Text Available Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs. The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with

  16. Glomerular filtration rate after alpha-radioimmunotherapy with 211At-MX35-F(ab')2: a long-term study of renal function in nude mice

    DEFF Research Database (Denmark)

    Back, T.; Haraldsson, B.; Hultborn, R

    2009-01-01

    Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, (211)At, were studied in nude mice by serial measurements...... of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals...

  17. 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.

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

    Science.gov (United States)

    Akram, Qasim; 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.

  19. 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.

  20. Immunotherapy with rituximab in follicular lymphomas.

    Science.gov (United States)

    Saguna, Carmen; Mut, Ileana Delia; Lupu, Anca Roxana; Tevet, Mihaela; Bumbea, Horia; Dragan, Cornel

    2011-04-01

    Non-Hodgkin Lymphomas (NHL) represent a recent and fascinating domain of hemato-oncology, in which remarkable progress has been made. The conventional treatments of indolent lymphomas do not extend the survival rate, nor do they cure. Recent directions are centered on using several new drugs that are capable of overcoming the mechanisms that are resistant to recovery. The initiation of immunotherapy (Rituximab in 1997) seems to have changed the natural evolution of follicular lymphomas (FL). It is possible that resistance to healing in follicular lymphomas may be neutralized with Rituximab by suppressing STAT-1 positive macrophages that are present in the cellular microenvironment.Thereinafter, the re-evaluation of recent models of prognostic and therapeutic paradigmas that were used in FL became compulsory.The purpose of the paper is to compare the evolution of patients with follicular lymphoma and the period of response, according to the treatments. The study group consisted of the 71 patients diagnosed with follicular lymphoma, out of a total of 767 malignant lymphatic proliferations with B cells, for a period of 7 years (2002-2008), at the Hematology Department, Hospital Coltea, Bucharest and Hematology Department, Universitary Hospital, BucharestResults and conclusions: Combining chemotherapy with Rituximab had better results compared to the same chemotherapy, administered alone, both in induction and in case of relapse. The overall response rate in our study group was 74.7%, out of which 42.3% complete remissions. The overall response rate was 84.61% in the Rituximab group, compared to 68.88% in patients without Rituximab.

  1. Complex cell geometry and sources distribution model for Monte Carlo single cell dosimetry with iodine 125 radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Arnaud, F.X. [Université Toulouse III-Paul Sabatier, INPT, LAPLACE, F-31062 Toulouse (France); CNRS, LAPLACE, F-31062 Toulouse (France); Paillas, S. [IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298 (France); INSERM, U1194, Montpellier F-34298 (France); Pouget, J.P [IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298 (France); INSERM, U1194, Montpellier F-34298 (France); Université de Montpelllier, F-34090 Montpellier (France); Institut régional du Cancer de Montpellier, F-34298 Montpellier (France); Incerti, S. [Université Bordeaux, CENBG, UMR 5797, F-33170 Gradignan (France); CNRS, IN2P3, CENBG, UMR 5797, F-33170 Gradignan (France); Bardiès, M. [Inserm, UMR1037 CRCT, F-31000 Toulouse (France); Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse (France); Bordage, M.C., E-mail: marie-claude.bordage@inserm.fr [Université Toulouse III-Paul Sabatier, INPT, LAPLACE, F-31062 Toulouse (France); CNRS, LAPLACE, F-31062 Toulouse (France); Inserm, UMR1037 CRCT, F-31000 Toulouse (France); Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse (France)

    2016-01-01

    In cellular dosimetry, common assumptions consider concentric spheres for nucleus and cell and uniform radionuclides distribution. These approximations do not reflect reality, specially in the situation of radioimmunotherapy with Auger emitters, where very short-ranged electrons induce hyper localised energy deposition. A realistic cellular dosimetric model was generated to give account of the real geometry and activity distribution, for non-internalizing and internalizing antibodies (mAbs) labelled with Auger emitter I-125. The impact of geometry was studied by comparing the real geometry obtained from confocal microscopy for both cell and nucleus with volume equivalent concentric spheres. Non-uniform and uniform source distributions were considered for each mAbs distribution. Comparisons in terms of mean deposited energy per decay, energy deposition spectra and energy-volume histograms were calculated using Geant4. We conclude that realistic models are needed, especially when energy deposition is highly non-homogeneous due to source distribution.

  2. {sup 177}Lu labeling of Herceptin and preclinical validation as a new radiopharmaceutical for radioimmunotherapy of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rasaneh, Samira [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran (Iran, Islamic Republic of); Rajabi, Hossein, E-mail: hrajabi@modares.ac.i [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran (Iran, Islamic Republic of); Babaei, Mohammad Hossein; Daha, Fariba Johari [Department of Radioisotope, Nuclear Science and Technology Research Institute, 14115-331 Tehran (Iran, Islamic Republic of)

    2010-11-15

    Introduction: In the present study, Herceptin was labeled with lutetium-177 via DOTA, and the necessary preclinical quality control tests (in vitro and in vivo) were performed to evaluate its use as a radioimmunotherapy agent. Material and Methods: Herceptin was conjugated to DOTA as a chelator in three different conjugation buffers (ammonium acetate, carbonate and HEPES buffer); each of the resulting conjugates was compared with respect to in vitro characteristics such as number of chelates per antibody, incorporated activity, immunoreactivity and in vitro stability in PBS buffer and blood serum. The biodistribution study and gamma camera imaging were performed in mice bearing breast tumors. To assess the therapeutic effects of {sup 177}Lu-Herceptin, cytotoxicity was investigated for 7 days in a SKBr3 breast cancer cell line. Results: Carbonate buffer was the best conjugation buffer (number of chelates per antibody: 6; incorporated activity: 81%; immunoreactivity: 87%; buffer stability: 86%; serum stability: 81%, after 4 days). The efficient tumor uptake observed in the biodistribution studies was consistent with the gamma camera image results. At a concentration of 4 {mu}g ml{sup -1}, {sup 177}Lu-Herceptin (surviving cells: 5{+-}0.6% of the total cells) of the total cells corresponded to an approximately eightfold increase in cytotoxicity in comparison to unmodified Herceptin (surviving cells: 43{+-}3.9%). Conclusion: The new complex described herein could be considered for further evaluation in animals and potentially in humans as a radiopharmaceutical for use in the radioimmunotherapy of breast cancer. These results may be important for patients who cannot tolerate the therapeutic dosage of Herceptin currently used because of heart problems.

  3. 177Lu labeling of Herceptin and preclinical validation as a new radiopharmaceutical for radioimmunotherapy of breast cancer

    International Nuclear Information System (INIS)

    Rasaneh, Samira; Rajabi, Hossein; Babaei, Mohammad Hossein; Daha, Fariba Johari

    2010-01-01

    Introduction: In the present study, Herceptin was labeled with lutetium-177 via DOTA, and the necessary preclinical quality control tests (in vitro and in vivo) were performed to evaluate its use as a radioimmunotherapy agent. Material and Methods: Herceptin was conjugated to DOTA as a chelator in three different conjugation buffers (ammonium acetate, carbonate and HEPES buffer); each of the resulting conjugates was compared with respect to in vitro characteristics such as number of chelates per antibody, incorporated activity, immunoreactivity and in vitro stability in PBS buffer and blood serum. The biodistribution study and gamma camera imaging were performed in mice bearing breast tumors. To assess the therapeutic effects of 177 Lu-Herceptin, cytotoxicity was investigated for 7 days in a SKBr3 breast cancer cell line. Results: Carbonate buffer was the best conjugation buffer (number of chelates per antibody: 6; incorporated activity: 81%; immunoreactivity: 87%; buffer stability: 86%; serum stability: 81%, after 4 days). The efficient tumor uptake observed in the biodistribution studies was consistent with the gamma camera image results. At a concentration of 4 μg ml -1 , 177 Lu-Herceptin (surviving cells: 5±0.6% of the total cells) of the total cells corresponded to an approximately eightfold increase in cytotoxicity in comparison to unmodified Herceptin (surviving cells: 43±3.9%). Conclusion: The new complex described herein could be considered for further evaluation in animals and potentially in humans as a radiopharmaceutical for use in the radioimmunotherapy of breast cancer. These results may be important for patients who cannot tolerate the therapeutic dosage of Herceptin currently used because of heart problems.

  4. Development of dosimetric approaches to treatment planning for radioimmunotherapy. Annual report 1989--1990

    Energy Technology Data Exchange (ETDEWEB)

    DeNardo, S.J.

    1990-12-31

    The objective of quantitative imaging is to provide pharmacokinetic information for patients that is analogous to that provided by biodistribution studies in mice. Radionuclide images depict the distribution of labeled antibodies in-vivo; thus the amount of radionuclide in a specific organ or site can be estimated by relating the counts detected in a defined region of interest to the total radionuclide content. This pharmacokinetic information can be used to obtain definitive and relevant answers to basic questions of importance for optimizing radioimmunoimaging and radioimmunotherapy and, in addition, can provide a data base from which to calculate the distribution of radiation absorbed doses. The research employs quantitative imaging in evaluating therapies. Quantitative imaging is performed by a certified nuclear medicine technician using the Siemens gamma camera interfaced with the microVAX II. The technician processes the imaging data and obtains pharmacokinetic information from it using programs developed by the authors and others. A large amount of data has been acquired and analyzed on the pharmacokinetics, dosimetry and toxicity of radiolabeled monoclonal therapy. Important dosimetry data on the whole body, marrow and tumor doses are available and all studies are archived so that they can be retrospectively analyzed. Although the radiation absorbed doses delivered to tumor sites were modest, significant biological responses were found.

  5. Preparation and biological evaluation of {sup 177}Lu conjugated PR81 for radioimmunotherapy of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Salouti, Mojtaba, E-mail: saloutim@yahoo.com [Department of Biology, Faculty of Sciences, Zanjan Branch, Islamic Azad University, Zanjan 45156-58145 (Iran, Islamic Republic of); Babaei, Mohammad Hossein [Nuclear Biomolecule Laboratory, Radioisotope Department, Nuclear Science and Technology Research Institute, Tehran 14144-1339 (Iran, Islamic Republic of); Rajabi, Hossein [Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14115-111 (Iran, Islamic Republic of); Rasaee, Mohammad javad [Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14115-111 (Iran, Islamic Republic of)

    2011-08-15

    Aim: PR81 is a monoclonal antibody that binds with high affinity to MUC1 antigen that is over expressed in 80% of breast cancers. In this study, we developed a method for indirect labeling of PR81 with lutetium-177 and performed all preclinical qualifications in production of a biologic agent for radioimmunotherapy of breast cancer. Materials and Methods: The radiochemical purity and in vitro stability of {sup 177}Lu labeled PR81 was determined by instant thin layer chromatography. The immunoreactivity and cell toxicity of the complex were tested on MCF7 cell line. The biodistribution and scintigraphy studies were performed in BALB/c mice with breast tumor. Results: The radiochemical purity was 91.2{+-}3.8% after 2 h. The in vitro stabilities in phosphate buffer and human blood serum were 83.1{+-}3.4% and 76.2{+-}3.6% at 96 h, respectively. The immunoreactivity of the complex was 83.4{+-}2.4%. The cell toxicity study showed that the complex inhibited 85.2{+-}3.4% growth of MCF7 cells at a concentration of 2500 ng/ml after 96 h. The biodistribution and scintigraphy studies showed the accumulation of the complex at the site of tumors with high sensitivity and specificity. Conclusion: The results showed that one may consider {sup 177}Lu-DOTA-PR81 as a potential radiopharmaceutical for therapy of human breast cancer, which needs further investigations.

  6. Development of dosimetric approaches to treatment planning for radioimmunotherapy. DOE annual report

    International Nuclear Information System (INIS)

    1998-01-01

    The objective of quantitative imaging is to Provide pharmacokinetic information for patients that is analogous to that provided by biodistribution studies in mice. Radio nuclide images depict the distribution of labeled antibodies in-vivo; thus the amount of radio nuclide in a specific organ or site can be estimated by relating the counts detected in a defined region of interest to the total radio nuclide content. This pharmacokinetic information can be used to obtain definitive and relevant answers to basic questions of importance for optimizing radioimmunoimaging and radioimmunotherapy and, in addition, can provide a data base from which to calculate the distribution of radiation absorbed doses. The projects supported by this program routinely employ quantitative imaging in evaluating therapies. Quantitative imaging is performed by a certified nuclear medicine technician using the Siemens gamma camera interfaced with the microVAX II. The technician processes the imaging data and obtains pharmacokinetic information from it using programs developed by us and others. During this grant period project staff have acquired and analyzed a large amount of data on the pharmacokinetics, dosimetry and toxicity of radiolabeled monoclonal therapy. Important dosimetry data on the whole body, marrow and tumor doses are available and all studies are archived so that they can be retrospectively analyzed

  7. Development of dosimetric approaches to treatment planning for radioimmunotherapy. DOE annual report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-05-01

    The objective of quantitative imaging is to Provide pharmacokinetic information for patients that is analogous to that provided by biodistribution studies in mice. Radio nuclide images depict the distribution of labeled antibodies in-vivo; thus the amount of radio nuclide in a specific organ or site can be estimated by relating the counts detected in a defined region of interest to the total radio nuclide content. This pharmacokinetic information can be used to obtain definitive and relevant answers to basic questions of importance for optimizing radioimmunoimaging and radioimmunotherapy and, in addition, can provide a data base from which to calculate the distribution of radiation absorbed doses. The projects supported by this program routinely employ quantitative imaging in evaluating therapies. Quantitative imaging is performed by a certified nuclear medicine technician using the Siemens gamma camera interfaced with the microVAX II. The technician processes the imaging data and obtains pharmacokinetic information from it using programs developed by us and others. During this grant period project staff have acquired and analyzed a large amount of data on the pharmacokinetics, dosimetry and toxicity of radiolabeled monoclonal therapy. Important dosimetry data on the whole body, marrow and tumor doses are available and all studies are archived so that they can be retrospectively analyzed.

  8. The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE.

    Science.gov (United States)

    Watson, L; Beresford, M W; Maynes, C; Pilkington, C; Marks, S D; Glackin, Y; Tullus, K

    2015-01-01

    B cells drive antibody formation and T cell activation. This study aimed to describe the clinical indications, efficacy and adverse events (AEs) for the B-cell depleting agent, rituximab, in a large cohort of children with lupus. Prescribing records and the UK JSLE Cohort Study database identified rituximab use. Sixty-three patients received 104 courses of intravenous rituximab over a 10-year period. Patients were aged 12.2 (IQR 9.0-13.9) years at diagnosis and 50 (79%) were female. They had disease for 1.4 (0.2-3.0) years at the time of rituximab. Lupus nephritis was the most common indication (36% of first courses). Clinical biomarkers, 2.5 (1.6-4.3) months after treatment, demonstrated a statistically significant improvement in ESR, C3, C4, creatinine, albumin, haemoglobin, anti-dsDNA titres and urine albumin:creatinine ratio. IgG, IgA and IgM levels decreased (p < 0.01). Oral corticosteroid dose significantly reduced after rituximab (dose before 0.26 (0.09-0.44) mg/kg, after 0.17 (0.09-0.30) mg/kg; p = 0.01)). AEs occurred in 19 (18%) of all courses including; delayed second dose (8%), Ig replacement (2%) and infusion reactions (6%; anaphylaxis 2%). The global BILAG score showed a trend toward improvement (before 4.5 (2.0-9.0), after 3.0 (2.0-5.0); p = 0.16). Rituximab improves disease activity in children with lupus and serious AEs are infrequent. Controlled studies are required. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  9. 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

  10. Bendamustine plus rituximab for chronic cold agglutinin disease

    DEFF Research Database (Denmark)

    Berentsen, Sigbjørn; Randen, Ulla; Oksman, Markku

    2017-01-01

    response (PR). Among 14 patients previously treated with rituximab or fludarabine-rituximab, 7 (50%) responded to bendamustine-rituximab (3 CR and 4 PR). Hemoglobin levels increased by a median of 4.4 g/dL in the complete responders, 3.9 g/dL in those achieving PR, and 3.7 g/dL in the whole cohort. The 10...

  11. Rituximab ameliorated severe hearing loss in Cogan's syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Bacciu Salvatore

    2010-06-01

    Full Text Available Abstract Background Rituximab is a monoclonal antibody inducing depletion of B lymphocytes and presently approved for the treatment of non-Hodgkin's lymphoma and rheumatoid arthritis. Here is the first report of the use of this drug in a case of Cogan's syndrome (CS. Case Presentation a 25-year-old Italian woman was referred with conjunctival hyperaemia, interstitial keratitis, moderate bilateral sensorineural hearing loss accompanied by tinnitus, dizziness, nausea and vertigo, poorly responsive to oral and topical steroidal therapy. Diagnosis of typical CS was made. The administration of a combined immunosuppressive treatment resolved ocular inflammation, dizziness, nausea, and vertigo but gave little results in controlling progressive hearing loss. A noticeable improvement in hearing function was documented by pure tone audiometry after infusion of Rituximab. Discussion in CS, hearing function is often the most difficult parameter to control with therapy. A positive effect of Rituximab on was observed in our case. The drug also allowed to significantly reduce the number of adjuvant immunosuppressive medications.

  12. EFFICACY OF RECURRENT RITUXIMAB TREATMENT IN PATIENT WITH SEVERE REFRACTORY SYSTEMIC JUVENILE RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    E.I. Alexeeva

    2011-01-01

    Full Text Available The article contains clinical case description of a severe systemic juvenile rheumatoid arthritis, that was refractory to classic immunosuppressant therapy. The disease was characterized by such extraarticular manifestations as fever, lymphadenopathy,  hepatosplenomegaly, polyserositis, generalized joint involvement and high activity in lab tests. As a result of severe clinical course of the disease, patients develop bilateral aseptic bone necrosis in coxofemoral joints and coxarthrosis. Against the background of glucocorticosteroid treatment the patient has developed hormone-dependency and hormone resistance. Inclusion into the treatment of anti-CD20 monoclonal antibodies (rituximab has stopped systemic manifestations of the disease, inflammation in the joints, normalized lab activity rates. The positive therapeutic effect allowed to perform surgery due to bilateral coxarthrosis. These results show that rituximab is highly effective in children with systemic juvenile rheumatoid arthritis, that is resistant to classic immunosupressants and glucocorticoides. Key words: children, systemic juvenile rheumatoid arthritis, rituximab, recurrent treatment, prosthetics, hip joint. (Voprosy sovremennoi pediatrii — Current Pediatrics. — 2011; 10 (5: 157–163.

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

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Noriko; Saga, Tsuneo; Sakahara, Harumi; Nakamoto, Yuji; Zhao, Songji; Iida, Yasuhiko; Konishi, Junji [Kyoto Univ. (Japan). Graduate School of Medicine; Kuroki, Masahide; Endo, Keigo

    2000-06-01

    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 {sup 131}I-labeled anti-CEA monoclonal antibody (MAb) (24-38 {mu}g, 11.1 MBq). Mice of the chase group then received an intravenous injection of avidin twice (24 and 30 h, 72-115 {mu}g 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)

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

    International Nuclear Information System (INIS)

    Mcquarrie, S.A.; Xiao, Z.; Mercer, J. R.; Suresh, M. R.

    2001-01-01

    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 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

  15. A new radiotherapy approach: the radioimmunotherapy; Une nouvelle approche de radiotherapie: la radio-immunotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Kraeber-Bodere, F.; Chatal, J.F.; Ansquer, C.; Faivre-Chauvet, A. [Institut National de la Sante et de la Recherche Medicale (INSERM) U463, Institut de Biologie, 44 - Nantes (France)

    2003-11-01

    To irradiate a tumor in preserving as possible the healthy tissues, that the aim of the radio immuno therapy. This new form of treatment whom efficiency is modulated in function of the choice of antibody, radionuclide, and target, knows success against some types of lymphomas. (N.C.)

  16. Refractory myasthenia gravis – clinical profile, comorbidities and response to rituximab

    Science.gov (United States)

    Sudulagunta, Sreenivasa Rao; Sepehrar, Mona; Sodalagunta, Mahesh Babu; Settikere Nataraju, Aravinda; Bangalore Raja, Shiva Kumar; Sathyanarayana, Deepak; Gummadi, Siddharth; Burra, Hemanth Kumar

    2016-01-01

    Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications. Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27–53 years. In our study 25 patients (32.89%) belonged to the age group of 21–30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% (p=3.3x10–8) to 94.6% (p=2.2x10–14) after the third cycle of rituximab treatment. Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low. PMID:27790079

  17. Use of Rituximab in Autoimmune Hemolytic Anemia Associated with Non-Hodgkin Lymphomas

    Science.gov (United States)

    Fozza, Claudio; Longinotti, Maurizio

    2011-01-01

    The association between non-Hodgkin lymphomas and autoimmune disorders is a well-known event. Also autoimmune hemolytic anemia (AHA), although much more frequent in patients with chronic lymphocytic leukemia (CLL), has been described in this group of patients. In recent years, among the more traditional therapeutic options, rituximab, an anti-CD20 monoclonal antibody, has shown interesting results in the treatment of primary AHA. Although this drug has been frequently used for AHA in patients with CLL, much less data are available on its use in NHL patients. However, considering that the main pathogenetic mechanism of AHA in course of lymphoproliferative disorders seems to be an antibody production directly or indirectly mediated by the neoplastic clone, this monoclonal antibody represents an ideal therapeutic approach. In this paper we will briefly describe some biological and clinical features of NHL-patients with AHA. We will then analyze some studies focusing on rituximab in primary AHA, finally reviewing the available literature on the use of this drug in NHL related AHA. PMID:21547266

  18. The hypoxic cytotoxin SR 4233 increases the effectiveness of radioimmunotherapy in mice with human non-Hodgkin's lymphoma xenografts.

    Science.gov (United States)

    Wilder, R B; McGann, J K; Sutherland, W R; Waller, E K; Minchinton, A I; Goris, M L; Knox, S J

    1994-01-01

    To determine if either the hypoxic cell radiosensitizer etanidazole (SR 2508) or the hypoxic cytotoxin SR 4233 could improve the effectiveness of radioimmunotherapy. LC4 (an IgG1 monoclonal antibody directed toward malignant T cells) and MB-1 (an irrelevant isotype-matched control antibody) were injected intraperitoneally into severe combined immunodeficient phenotype mice with human cutaneous T cell lymphoma xenografts in order to determine the distribution of the antibodies in the tumors and normal tissues as a function of time. Computerized-pO2-histography was used to measure the median oxygen tension in the tumors. Tumor-bearing mice were treated with: (a) LC4; (b) 90Y-LC4; (c) 90Y-MB-1; (d) whole body irradiation delivered via an external 137Cs source; (e) etanidazole and 90Y-LC4; (f) SR 4233 and 90Y-LC4; (g) etanidazole; and (h) SR 4233. An additional group of mice received no treatment and served as controls. A tumor growth delay assay was used to assess the effectiveness of the different treatment regimens. LC4 accumulated in the tumors to a significantly greater extent than MB-1 (p LC4 by itself was able to produce a minor decrease in tumor size (control vs. LC4; p = 0.001). 90Y-LC4 produced greater tumor growth delay than LC4 alone (LC4 vs. 90Y-LC4; p = 0.01); however, the Yttrium-90 caused neutropenia and weight loss. The 90Y-labeled tumor-specific and non-specific antibodies both exerted greater tumor growth delay than externally delivered whole body irradiation (p LC4 (90Y-LC4 vs etanidazole and 90Y-LC4, p = 0.13). SR 4233, on the other hand, did enhance the tumor growth delay produced by 90Y-LC4 (90Y-LC4 vs. SR 4233 and 90Y-LC4, p = 0.046). The neutropenia and weight loss caused by 90Y-LC4 were exacerbated slightly (< 10%) by the administration of SR 4233. A first generation hypoxic cytotoxin, SR 4233, was able to enhance the tumor growth delay produced by radioimmunotherapy in severe combined immunodeficient phenotype mice with human cutaneous T cell

  19. Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis

    NARCIS (Netherlands)

    Boumans, Maria J. H.; Thurlings, Rogier M.; Yeo, Lorraine; Scheel-Toellner, Dagmar; Vos, Koen; Gerlag, Danielle M.; Tak, Paul P.

    2012-01-01

    Objectives To examine how rituximab may result in the inhibition of joint destruction in rheumatoid arthritis (RA) patients. Methods Twenty-eight patients with active RA were treated with rituximab. Radiographs of hands and feet before and 1 year after therapy were assessed using the Sharp-van der

  20. Experience with rituximab in patients with rheumatoid arthritis in ...

    African Journals Online (AJOL)

    Background: Rheumatoid Arthritis (RA) is a disease associated with significant morbidity and mortality. Newer therapies include B-cell targeted therapies such as rituximab. Objectives: To study the outcome in RA patients receiving rituximab following resistance to Disease Modifying Anti- Rheumatic Agents (DMARDS) and ...

  1. Combination of anti-retroviral drugs and radioimmunotherapy specifically kills infected cells from HIV infected individuals

    Directory of Open Access Journals (Sweden)

    Dina Tsukrov

    2016-09-01

    Full Text Available Eliminating virally infected cells is an essential component of any HIV eradication strategy. Radioimmunotherapy (RIT, a clinically established method for killing cells using radiolabeled antibodies, was recently applied to target HIV-1 gp41 antigen expressed on the surface of infect-ed cells. Since gp41 expression by infected cells is likely down-regulated in patients on an-tiretroviral therapy (ART, we evaluated the ability of RIT to kill ART-treated infected cells us-ing both in vitro models and lymphocytes isolated from HIV-infected subjects. Human peripheral blood mononuclear cells (PBMCs were infected with HIV and cultured in the presence of two clinically relevant ART combinations. Scatchard analysis of the 2556 human monoclonal anti-body to HIV gp41 binding to the infected and ART-treated cells demonstrated sufficient residual expression of gp41 on the cell surface to warrant subsequent RIT. This is the first time the quantification of gp41 post-ART is being reported. Cells were then treated with Bismuth-213-labeled 2556 antibody. conjugated to the human monoclonal antibody 2556, which binds to HIV gp41. Cell survival was quantified by Trypan blue and residual viremia by p24 ELISA. Cell surface gp41 expression was assessed by Scatchard analysis. The experiments were repeated using PBMCs isolated from blood specimens obtained from 15 HIV-infected individuals: ten on ART and five ART-naive. We found that 213Bi-2556 killed ART-treated infected PBMCs and reduced viral production to undetectable levels. ART and RIT co-treatment was more effective at reducing viral load in vitro than either therapy alone, indicating that gp41 expression under ART was sufficient to allow 213Bi-2556 to deliver cytocidal doses of radiation to infected cells. This study provides proof of concept that 213Bi-2556 may represent an innovative and effective targeting method for killing HIV-infected cells treated with ART, and supports continued development of 213Bi

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

    International Nuclear Information System (INIS)

    Dahle, Jostein; Heyerdahl, Helen; Hjelmerud, Anne Kristine; Larsen, Roy H.; Jonasdottir, Thora J.; Nesland, Jahn M.; Borrebaek, Joergen

    2010-01-01

    The anti-CD20 antibody rituximab labelled with the α-particle-emitting radionuclide 227 Th 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 227 Th-rituximab has been observed. To evaluate possible late side effects of 227 Th-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 227 Th-rituximab and followed for up to 1 year. In addition, nude mice with Raji xenografts treated with various doses of 227 Th-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 227 Th-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 227 Th-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 227 Th-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.)

  3. Nasal, pharyngeal, and laryngeal pemphigus vulgaris successfully treated with rituximab.

    Science.gov (United States)

    Sami, Naveed

    2017-01-01

    Pemphigus vulgaris is a potentially fatal autoimmune blistering disease that can involve the nasopharyngeal and laryngeal tissues. The disease can be recalcitrant to conventional oral treatments, and treatment alternatives are limited. This retrospective study evaluated the efficacy of rituximab as a rescue agent in 5 patients with recalcitrant pemphigus vulgaris involving nasopharyngeal and laryngeal mucosa. All 5 patients were unresponsive to systemic steroids and at least one conventional oral immunosuppressive agent. The patients received rituximab infusions as a rescue agent because of recalcitrant disease. All 5 patients had a complete clinical response to rituximab and could discontinue systemic steroids and reduce the dosage of their initial immunosuppressive agent. No major adverse reactions were observed or reported with rituximab. Rituximab can be used as an effective rescue agent in the treatment of severe pemphigus vulgaris with nasopharyngeal and laryngeal involvement.

  4. [Efficacy and safety of rituximab in the treatment of primary antiphospholipid syndrome: analysis of 24 cases from the bibliography review].

    Science.gov (United States)

    Pons, Isaac; Espinosa, Gerard; Cervera, Ricard

    2015-02-02

    Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) and thrombotic and/or obstetric manifestations. Patients without another associated autoimmune disease are considered to have primary APS. Some patients develop thrombosis recurrence despite anticoagulant treatment and some clinical features do not respond to standard therapy. Rituximab may be an alternative in these cases. We review the published scientific evidence on the use of rituximab in the treatment of primary APS. Description of a case and review of the literature with descriptive analysis of the demographic, clinical, and immunologic features, treatment and outcome of patients. We identified 24 patients (15 women [62.5%]), with a mean age of 37.0 ± 13.4 years. The reasons for the use of rituximab were thrombocytopenia (41.7%), skin involvement (33.3%), neurologic and heart valve involvement (12.5%), hemolytic anemia (8.3%) and pulmonary and renal involvement (4.2%). Lupus anticoagulant was present in 72.7% of the cases, the IgG and IgM isotypes of anticardiolipin antibodies in 75 and 50%, respectively, and the anti-β2GPI (IgG e IgM) antibodies in 80% of patients. Thirteen (54.1%) patients received 2 doses of 1,000 mg of rituximab fortnightly, 10 (41.7%) 4 doses of 375 mg/m(2) weekly and one (4.2%) 8 doses of 375 mg/m(2) weekly. Eleven (45.8%) patients presented a complete clinical response, 7 (29.2%) a partial response and 6 (25%) did not respond to rituximab. Four patients with clinical improvement presented with aPL titer decrease and in one patient, aPL levels did not change. In one patient without clinical response, aPL remained positive. A clinical-immunologic dissociation existed in 2 additional cases. The results obtained suggest a possible potential benefit of rituximab in the treatment of some clinical manifestations of primary APS such as thrombocytopenia, skin and heart valve involvement. Copyright © 2013 Elsevier España, S.L.U. All rights

  5. 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.

  6. Characterization of CD4 T Cell Epitopes of Infliximab and Rituximab Identified from Healthy Donors

    Directory of Open Access Journals (Sweden)

    Moustafa Hamze

    2017-05-01

    Full Text Available The chimeric antibodies anti-CD20 rituximab (Rtx and anti-TNFα infliximab (Ifx induce antidrug antibodies (ADAs in many patients with inflammatory diseases. Because of the key role of CD4 T lymphocytes in the initiation of antibody responses, we localized the CD4 T cell epitopes of Rtx and Ifx. With the perspective to anticipate immunogenicity of therapeutic antibodies, identification of the CD4 T cell epitopes was performed using cells collected in healthy donors. Nine T cell epitopes were identified in the variable chains of both antibodies by deriving CD4 T cell lines raised against either Rtx or Ifx. The T cell epitopes often exhibited a good affinity for human leukocyte antigen (HLA-DR molecules and were part of the peptides identified by MHC-associated peptide proteomics assay from HLA-DR molecules of dendritic cells (DCs loaded with the antibodies. Two-third of the T cell epitopes identified from the healthy donors stimulated peripheral blood mononuclear cells from patients having developed ADAs against Rtx or Ifx and promoted the secretion of a diversity of cytokines. These data emphasize the predictive value of evaluating the T cell repertoire of healthy donors and the composition of peptides bound to HLA-DR of DCs to anticipate and prevent immunogenicity of therapeutic antibodies.

  7. High-dose rituximab does not negatively affect peripheral blood stem cell mobilization kinetics in patients with intermediate-grade non-Hodgkin's lymphoma.

    Science.gov (United States)

    Hosing, Chitra; Saliba, Rima M; Körbling, Martin; Acholonu, Sandra; McMannis, John; Anderlini, Paolo; Giralt, Sergio; De Lima, Marcos; Okoroji, Grace-Julia; Couriel, Daniel R; Champlin, Richard; Khouri, Issa F; Donato, Michele L

    2006-07-01

    Rituximab, an anti-CD20 human-mouse chimeric monoclonal antibody has been shown to improve response rates when it is combined with standard salvage chemotherapy in patients with relapsed or refractory intermediate-grade B-cell non-Hodgkin's lymphoma. A vast majority of these patients subsequently undergo high-dose therapy followed by stem cell transplantation. However, the impact of rituximab on stem cell mobilization kinetics is not well characterized. The purpose of this study was to study the effect of high-dose rituximab given with chemotherapy on stem cell mobilization in patients with intermediate-grade B-cell non-Hodgkin's lymphoma. Thirty-six patients received ifosfamide, etoposide, and rituximab followed by filgrastim for stem cell mobilization. The chemotherapy regimen was well tolerated. Thirty-four of 36 patients (94%) were able to mobilize at least 2 x 10(6) CD34+ cells/kg body weight after a median of 2 apheresis procedures. The median CD34+ cell dose collected per kilogram of recipient body weight was 6.5 x 10(6) (range, 4.65-31.15). All patients who subsequently underwent high-dose chemotherapy and stem cell transplantation experienced sustained engraftment. In conclusion, high-dose rituximab given during stem cell mobilization does not negatively affect stem cell mobilization kinetics.

  8. Cancer Imaging and Therapy with Bispecific Antibody Pretargeting

    OpenAIRE

    Goldenberg, David M.; Chatal, Jean-Francois; Barbet, Jacques; Boerman, Otto; Sharkey, Robert M.

    2007-01-01

    This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly-labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation...

  9. Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction.

    Directory of Open Access Journals (Sweden)

    Jérémie Ménager

    Full Text Available Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA. Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells. We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established.

  10. Radiolabeling of trastuzumab with {sup 177}Lu via DOTA, a new radiopharmaceutical for radioimmunotherapy of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rasaneh, Samira [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Rajabi, Hossein [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of)], E-mail: hrajabi@modares.ac.ir; Babaei, Mohammad Hossein; Daha, Fariba Johari [Department of Radioisotope, Nuclear Science and Technology Research Institute, Tehran (Iran, Islamic Republic of); Salouti, Mojtaba [Department of Biology, School of Sciences, Islamic Azad University - Zanjan Branch, Zanjan (Iran, Islamic Republic of)

    2009-05-15

    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.

  11. Rituximab for the treatment of type B insulin resistance syndrome: a case report and review of the literature.

    Science.gov (United States)

    Iseri, K; Iyoda, M; Shikida, Y; Inokuchi, T; Morikawa, T; Hara, N; Hirano, T; Shibata, T

    2017-12-01

    Type B insulin resistance syndrome is a rare disease characterized by refractory transient hyperglycaemia and severe insulin resistance associated with circulating anti-insulin receptor antibodies. A standardized treatment regimen for type B insulin resistance syndrome has yet to be established. We report the case of a 64-year-old man undergoing haemodialysis for antineutrophil cytoplasmic antibody-associated vasculitis and diabetic nephropathy, who developed rapid onset of hyperglycaemia (glycated albumin 52.1%). Type B insulin resistance syndrome was diagnosed, on the basis of positivity for anti-insulin receptor antibodies and the man's autoimmune history of antineutrophil cytoplasmic antibody-associated vasculitis and idiopathic thrombocytopenic purpura. Although severe hyperglycaemia persisted in spite of corticosteroids and high-dose insulin therapy, rituximab treatment resulted in remarkable improvement of the man's severe insulin resistance and disappearance of anti-insulin receptor antibodies without any adverse effects. According to a literature review of 11 cases in addition to the present case, rituximab appears to be a safe and effective strategy for the treatment of corticosteroid-resistant type B insulin resistance syndrome. © 2017 Diabetes UK.

  12. Degradation of radioiodinated B cell monoclonal antibodies: inhibition via a FCgamma-receptor-II-mediated mechanism and by drugs

    NARCIS (Netherlands)

    Vervoordeldonk, S. F.; Balkenende, A. Y.; van den Berg, H.; von dem Borne, A. E.; van der Schoot, C. E.; van Leeuwen, E. F.; Slaper-Cortenbach, I. C.

    1996-01-01

    Our aim is to treat patients with B cell malignancies with radioimmunotherapy using monoclonal antibodies (mAb) such as CD19, CD20 and CD22. In this study we investigated the rate of internalization and catabolism of these mAb. After 24 h at 37 degrees C, 20%-25% of initially cell-bound (125)I-CD19

  13. An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica.

    Science.gov (United States)

    Collongues, Nicolas; de Seze, Jérôme

    2016-05-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future.

  14. Alpha radioimmunotherapy of multiple myeloma: study of feasibility of ex vivo medullary purge; Radioimmunotherapie alpha du myelome multiple: etude de faisabilite de purge de moelle ex vivo

    Energy Technology Data Exchange (ETDEWEB)

    Couturier, O.; Filippovitch, I.V.; Sorokina, N.I.; Cherel, M.; Thedrez, P.; Faivre-Chauvet, A.; Chatal, J.F. [INSERM U463, Nantes (France)

    1997-12-31

    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 {mu}m). 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 / 10{sup 5} cells (0.4 {mu}Ci) to 29.6 kBq/10{sup 5} cells (0.8 {mu}Ci). The cellular mortality was total at 300 kBq/10{sup 5} cells (8 {mu}Ci). The cells in an apoptosis state were evidenced at rates up to 40% for a dose of 7.4 kBq/10{sup 5} cells (0.2 {mu} 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

  15. Progressive outer retinal necrosis after rituximab and cyclophosphamide therapy

    Directory of Open Access Journals (Sweden)

    Mohit Dogra

    2018-01-01

    Full Text Available We report a case of progressive outer retinal necrosis (PORN in a patient of microscopic polyangitis (MPA, being treated with immunosuppressive drugs such as cyclophosphamide and rituximab. Her aqueous tap was positive for Varicella Zoster virus and she was treated with oral and intravitreal antivirals, along with discontinuation of one of the immunosuppressive agents, i.e. rituximab, which might have led to reactivation of the virus causing necrotizing retinitis lesions. Rituximab and cyclophosphamide are extremely potent drugs, which are necessary to manage immunological disorders such as MPA. However, they may predispose the patient to serious complications like viral infections, including PORN.

  16. Progressive outer retinal necrosis after rituximab and cyclophosphamide therapy.

    Science.gov (United States)

    Dogra, Mohit; Bajgai, Priya; Kumar, Ashok; Sharma, Aman

    2018-04-01

    We report a case of progressive outer retinal necrosis (PORN) in a patient of microscopic polyangitis (MPA), being treated with immunosuppressive drugs such as cyclophosphamide and rituximab. Her aqueous tap was positive for Varicella Zoster virus and she was treated with oral and intravitreal antivirals, along with discontinuation of one of the immunosuppressive agents, i.e. rituximab, which might have led to reactivation of the virus causing necrotizing retinitis lesions. Rituximab and cyclophosphamide are extremely potent drugs, which are necessary to manage immunological disorders such as MPA. However, they may predispose the patient to serious complications like viral infections, including PORN.

  17. Follicular lymphoma: in vitro effects of combining lymphokine-activated killer (LAK) cell-induced cytotoxicity and rituximab- and obinutuzumab-dependent cellular cytotoxicity (ADCC) activity.

    Science.gov (United States)

    García-Muñoz, Ricardo; López-Díaz-de-Cerio, Ascensión; Feliu, Jesus; Panizo, Angel; Giraldo, Pilar; Rodríguez-Calvillo, Mercedes; Grande, Carlos; Pena, Esther; Olave, Mayte; Panizo, Carlos; Inogés, Susana

    2016-04-01

    Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity. We analyzed the LAK cell-induced cytotoxicity and rituximab (R)- and obinutuzumab (GA101)-induced ADCC activity. We show that LAK cells generated from FL patients induce cytotoxicity against tumor cell lines. R and GA101 enhance cytolysis through ADCC activity of LAK cells. Impaired LAK cell cytotoxicity and ADCC activity were detected in 50 % of patients. Percentage of NK cells in LAK infusions were correlated with the R- and GA101-induced ADCC. Our results indicate that the combination of R or GA101 and LAK cells should be an option as frontline maintenance therapy in patients with FL.

  18. Radioimmunotherapy in Non-Hodgkin Lymphoma: Opinions of Nuclear Medicine Physicians and Radiation Oncologists

    Science.gov (United States)

    Schaefer, Niklaus G.; Huang, Peng; Buchanan, Julia W.; Wahl, Richard L.

    2015-01-01

    Despite approval by the Food and Drug Administration and consistent reports of the efficacy and safety of 90Y-ibritumomab tiuxetan and 131I-tositumomab, these therapies are infrequently used. This study investigates the opinions and patterns of the use of radioimmunotherapy by nuclear physicians, affiliated researchers, nuclear medicine technologists, and radiation oncologists and aims to identify possible barriers to the use of this promising therapy. Methods An e-mail–based survey with 13 broad questions related to radioimmunotherapy was sent electronically to 13,221 Society of Nuclear Medicine members and radiation oncologists throughout the United States. Results Six hundred thirteen individuals (4.6%) responded to the electronic survey. Two hundred fifty-one responders (40.9%) had treated patients with non-Hodgkin lymphoma (NHL) with radioimmunotherapy in the last 24 mo. Of the responders, 29.5% used only 90Y-ibritumomab tiuxetan, 7.6% used only 131I-tositumomab, and 24.9% used both radiopharmaceuticals; 37.9% did not treat NHL with radioimmunotherapy. Most responders said their patients came from university hospitals (33.9%) or private offices (25.6%), and they mainly treated in a second-line (42.9%), third-line (35.6%), or consolidation (23.5%) setting. Major concerns were that referring oncologists and hematologists wanted to treat by themselves with nonradioactive compounds (mean ± SD, 3.418 ± 1.49) and that 90Y-ibritumomab tiuxetan and 131I-tositumomab were expensive (mean ± SD, 3.413 ± 1.35). Of the responders and involved physicians, 40.4% and 35.2%, respectively, did not know if their institution accepted Medicare patients for radioimmunotherapy. Almost 30% (29.6%) of the responders thought radioimmunotherapy would probably grow and 38.0% thought it would grow in importance in the future. Responders who did not administer radioimmunotherapy for NHL thought it took too much time to administer radioimmunotherapy (P < 0.01) and had concerns about

  19. Evaluating changes in stable chromosomal translocation frequency in patients receiving radioimmunotherapy

    International Nuclear Information System (INIS)

    Wong, Jeffrey Y.C.; Wang Jianyi; Liu An; Odom-Maryon, Tamara; Shively, John E.; Raubitschek, Andrew A.; Williams, Lawrence E.

    2000-01-01

    Purpose: The lack of any consistent correlation between radioimmunotherapy (RIT) dose and observed hematologic toxicity has made it difficult to validate RIT radiation dose estimates to marrow. Stable chromosomal translocations (SCT) which result after radiation exposure may be a biologic parameter that more closely correlates with RIT radiation dose. Increases in the frequency of SCT are observed after radiation exposure and are highly correlated with absorbed radiation dose. SCT are cumulative after multiple radiation doses and conserved through an extended number of cell divisions. The purpose of this study was to evaluate whether increases in SCT frequency were detectable in peripheral lymphocytes after RIT and whether the magnitude of these increases correlated with estimated radiation dose to marrow and whole body. Methods and Materials: Patients entered in a Phase I dose escalation therapy trial each received 1-3 intravenous cycles of the radiolabeled anti-carcinoembryonic antigen (CEA) monoclonal antibody, 90 Y-chimeric T84.66. Five mCi of 111 In-chimeric T84.66 was co-administered for imaging and biodistribution purposes. Blood samples were collected immediately prior to the start of therapy and 5-6 weeks after each therapy cycle. Peripheral lymphocytes were harvested after 72 hours of phytohemagglutinin stimulation and metaphase spreads prepared. Spreads were then stained by fluorescence in situ hybridization (FISH) using commercially available chromosome paint probes to chromosomes 3 and 4. Approximately 1000 spreads were evaluated for each chromosome sample. Red marrow radiation doses were estimated using the AAPM algorithm and blood clearance curves. Results: Eighteen patients were studied, each receiving at least one cycle of therapy ranging from 5-22 mCi/m 2 . Three patients received 2 cycles and two patients received 3 cycles of therapy. Cumulative estimated marrow doses ranged from 9.2 to 310 cGy. Increases in SCT frequencies were observed after

  20. Calculation of dose point kernels for five radionuclides used in radio-immunotherapy

    International Nuclear Information System (INIS)

    Okigaki, S.; Ito, A.; Uchida, I.; Tomaru, T.

    1994-01-01

    With the recent interest in radioimmunotherapy, attention has been given to calculation of dose distribution from beta rays and monoenergetic electrons in tissue. Dose distribution around a point source of a beta ray emitting radioisotope is referred to as a beta dose point kernel. Beta dose point kernels for five radionuclides such as 131 I, 186 Re, 32 P, 188 Re, and 90 Y appropriate for radioimmunotherapy are calculated by Monte Carlo method using the EGS4 code system. Present results were compared with the published data of experiments and other calculations. Accuracy and precisions of beta dose point kernels are discussed. (author)

  1. Rituximab: Apakah Efektif dalam Tata Laksana Sindrom Nefrotik?

    Directory of Open Access Journals (Sweden)

    Sudung O. Pardede

    2016-11-01

    LPB diberikan dua dosis selang waktu dua minggu. Rituximab dapat mengurangi aktivitas penyakit dan memperbaiki sensitivitas terhadap obat imunsupresan. Efek samping yang sering terjadi berupa reaksi akut seperti demam, nyeri abdomen, diare, muntah, ruam kulit, bronkospasme, takikadia, dan hipertensi. Rituximab memberikan hasil yang baik dalam tata laksana sindrom nefrotik refrakter, namun diperlukan uji klinik dengan jumlah sampel yang cukup untuk menilai efikasi dan keamanan obat

  2. 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.)

  3. Pretargeted radioimmunotherapy in rapidly progressing, metastatic, medullary thyroid cancer.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Salaun, Pierre-Yves; Oudoux, Aurore; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2010-02-15

    Medullary thyroid cancer (MTC) patients with localized residual disease and/or distant metastases may survive for several years or rapidly progress and die of their disease. Thus, highly reliable prognostic factors are needed for an early distinction between high-risk patients who need to be treated and low-risk patients who warrant a watch-and-wait approach. Calcitonin doubling time is an independent predictor of survival, with a high predictive value in a population of patients who have not normalized their calcitonin, even after repeated surgery. Several imaging methods should be proposed for patients with abnormal residual calcitonin levels persisting after complete surgery: ultrasonography and computed tomography (CT) for neck exploration, and CT for chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) appears to have an advantage over CT for the detection of liver metastases from endocrine tumors. Moreover, MRI appears to be a sensitive imaging technique for detecting the spread of MTC to bone/bone marrow. 2-Fluoro-2-deoxy-D-glucose positron emission tomography/CT could be used for staging patients with progressive MTC, with possible prognostication by standard uptake value quantification. For systemic treatment of patients with rapidly progressing metastatic MTC, chemotherapy is not considered a valid therapeutic option. It is too early to evaluate the potential effectiveness of multikinase inhibitors, although interesting results of phase 2 studies have shown a transient stabilization in 30% to 50% of patients. Pretargeted radioimmunotherapy has been the only innovative treatment modality convincingly showing some survival benefit when compared with a historical untreated control group. (c) 2010 American Cancer Society.

  4. A Prototype 212Pb Medical Dose Calibrator for Alpha Radioimmunotherapy

    International Nuclear Information System (INIS)

    Mueller, W.F.; Patil, A.; Russ, W.R.; Newman, J.; Torgue, J.

    2015-01-01

    AREVA Med, an AREVA group subsidiary, is developing innovative cancer-fighting therapies involving the use of 212 Pb for alpha radioimmunotherapy. Canberra Industries, the nuclear measurement subsidiary of AREVA, has been working with AREVA Med to develop a prototype measurement system to assay syringes containing a 212 Pb solution following production by an elution system. The relative fraction of emitted radiation from the source associated directly with the 212 Pb remains dynamic for approximately 6 hours after the parent is chemically purified. A significant challenge for this measurement application is that the short half-life of the parent nuclide requires assay prior to reaching equilibrium with progeny nuclides. A gross counting detector was developed to minimize system costs and meet the large dynamic range of source activities. Prior to equilibrium, a gross counting system must include the period since the 212 Pb was pure to calculate the count rate attributable to the parent rather than the progeny. The dynamic state is determined by solving the set of differential equations, or Bateman equations, describing the source decay behavior while also applying the component measurement efficiencies for each nuclide. The efficiencies were initially estimated using mathematical modeling (MCNP) but were then benchmarked with source measurements. The goal accuracy of the system was required to be within 5%. Independent measurements of the source using a high resolution spectroscopic detector have shown good agreement with the prototype system results. The prototype design was driven by cost, compactness and simplicity. The detector development costs were minimized by using existing electronics and firmware with a Geiger-Mueller tube derived from Canberra's EcoGamma environmental monitoring product. The acquisition electronics, communications and interface were controlled using Python with the EcoGamma software development kit on a Raspberry Pi Linux computer

  5. Subacute cutaneous lupus erythematosus in the course of rheumatoid arthritis: a relationship with TNF-α antagonists and rituximab therapy?

    Science.gov (United States)

    Lis-Święty, Anna; Brzezińska-Wcisło, Ligia; Widuchowska, Małgorzata; Kucharz, Eugeniusz

    2013-06-01

    Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) is caused by different medicines, first of all: calcium channel blockers, angiotensin converting enzyme inhibitors, thiazides, terbinafine, statins and antagonists of tumor necrosis factor-α (TNF-α). DI-SCLE does not distinguish from idiopathic form of the disease, clinically, histopathologically and immunologically. However, receding of symptoms is observed after recapture of the provoking drug. To present a patient with rheumatoid arthritis (RA), who developed SCLE after treatment with TNF-α antagonists and rituximab. In a 31-year-old woman with RA leucopenia due to treatment with etanercept and adalimumab was observed. Therefore, the treatment was changed to rituximab, but after starting the therapy, erythematous and oedematous skin lesions of an oval or annular shape appeared on the cheeks, auricles, lips and the decolette. Histopathological evaluation of the skin lesions revealed SCLE. Ro/SS-A and La/SS-B antibodies were detected in serum. Regression of skin lesions and hematologic disturbances was achieved after starting corticosteroid therapy. Co-existence of SCLE with RA should be considered in some patients. The role of TNF-α antagonists and rituximab therapy in induction of idiopathic form of SCLE requires further investigations.

  6. Successful radioimmunotherapy of established syngeneic rat colon carcinoma with 211At-mAb

    DEFF Research Database (Denmark)

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

    2013-01-01

    Most carcinomas are prone to metastasize despite successful treatment of the primary tumor. One way to address this clinical challenge may be targeted therapy with α-emitting radionuclides such as astatine-211 (211At). Radioimmunotherapy utilizing α-particle emitting radionuclides is considered...

  7. Launching biosimilar rituximab: an industry opinion on biosimilar uptake in Europe.

    Science.gov (United States)

    Trollope, Richard; Johnson, Sue; Ireland, Henry

    2017-06-01

    Richard Trollope and Sue Johnson talk with Henry Ireland, Senior Editor about the recent approval of biosimilar rituximab (Truxima ® ) & the current state of biosimilar uptake across Europe Richard Trollope, Head of Biosimilars, Mundipharma International Limited, qualified as a biochemist before joining Wyeth's commercial operations, prior to its acquisition by Pfizer. Richard later joined Yamanouchi Pharmaceuticals (now Astellas Pharma). His fascination with oncology led him to join Mundipharma in Europe and after joining the company's UK arm (Napp Pharmaceuticals Limited), Richard began his journey in biosimilars. He now heads up the biosimilar franchise at Mundipharma International as it launches biosimilar rituximab (Truxima ® ) - the first biosimilar monoclonal antibody for the treatment of cancer, which will be distributed by Napp Pharmaceuticals in the UK. Sue Johnson, PhD, Medical Insights at Mundipharma International Limited, is a scientist by background and completed her postdoc fellowship at Harvard Medical School. On returning to the UK, she began her career in the pharmaceutical industry, working in UK Medical Affairs before transitioning to a European role with Mundipharma 2 years ago, where she leads on Medical Insights for the biosimilars franchise.

  8. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Badoux, Xavier C; Keating, Michael J; Wang, Xuemei; O'Brien, Susan M; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop; Wierda, William G

    2011-08-25

    Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.

  9. Rituximab in steroid-sensitive nephrotic syndrome: lessons from clinical trials.

    Science.gov (United States)

    Iijima, Kazumoto; Sako, Mayumi; Kamei, Koichi; Nozu, Kandai

    2017-07-17

    Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. A total of 80-90% of patients with childhood idiopathic nephrotic syndrome achieve remission with steroid therapy [steroid-sensitive nephrotic syndrome (SSNS)]. However, approximately 50% of children with SSNS develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS or SDNS are usually treated with immunosuppressive agents, but 10-20% of children receiving immunosuppressive agents still show frequent relapses or steroid dependence during or after treatment, defined as complicated FRNS or SDNS. Rituximab, a chimeric anti-CD20 monoclonal antibody that was originally developed to treat patients with B-cell non-Hodgkin's lymphoma, is currently used for treating SSNS. In this review we highlight recent studies, mainly randomized controlled trials of rituximab for SSNS, including complicated and uncomplicated forms of FRNS or SDNS in children. We also discuss the effects of these studies on the management of patients suffering from these conditions.

  10. Synergy between vascular targeting agents and antibody-directed therapy

    International Nuclear Information System (INIS)

    Pedley, R. Barbara; El-Emir, Ethaar; Flynn, Aiden A.; Boxer, Geoffrey M.; Dearling, Jason; Raleigh, James A.; Hill, Sally A.; Stuart, Sam; Motha, Reeya; Begent, Richard H.J.

    2002-01-01

    Purpose: Tumor heterogeneity necessitates the use of combined therapies. We have shown that combining antibody-directed therapy with antivascular agents converts a subcurative to a curative treatment. The purpose of this study was to investigate, by radioluminographic and microscopic techniques, the regional effects of the two complementary therapies. Methods and Materials: Nude mice bearing colorectal tumors were injected with 125 I-labeled anti-carcinoembryonic antigen antibody, and images were obtained for antibody distribution and modeling studies using radioluminography. For therapy studies, the mice were given radioimmunotherapy alone ( 131 I-A5B7 anti-carcinoembryonic antigen antibody), the antivascular agent combretastatin A-4 3-0-phosphate (200 mg/kg), or both. Extra mice were used to study the regional tumor effects of these therapies over time: relevant histochemical procedures were performed on tissue sections to obtain composite digital microscopic images of apoptosis, blood vessels, perfusion, hypoxia, and morphology. Results: Antibody distribution, modeling, and immunohistochemistry showed how radioimmunotherapy (7.4 MBq/40 μg antibody) effectively treated the outer, well-oxygenated tumor region only. Combretastatin A-4 3-0-phosphate treated the more hypoxic center, and in doing so altered the relationship between tumor parameters. Conclusion: The combined complementary therapies produced cures by destroying tumor regions with different pathophysiologies. Relating these regional therapeutic effects to the relevant tumor parameters microscopically allows optimization of therapy and improved translation to clinical trials

  11. Pharmacokinetics and tumor targeting of 131I-labeled F(ab')2 fragments of the chimeric monoclonal antibody G250: preclinical and clinical pilot studies.

    NARCIS (Netherlands)

    Brouwers, A.H.; Mulders, P.F.A.; Oosterwijk, E.; Buijs, W.C.A.M.; Corstens, F.H.M.; Boerman, O.C.; Oyen, W.J.G.

    2004-01-01

    INTRODUCTION: Clinical and animal studies of chimeric monoclonal antibody G250 (moAb cG250) for the targeting of clear-cell renal cell carcinoma (RCC), to date, have been with the intact IgG form. To determine whether F(ab')2 fragments are more suited for radioimmunotherapy (RIT) than intact IgG,

  12. Quantitative 89Zr immuno-PET for in vivo scouting of 90Y-labeled monoclonal antibodies in xenograft-bearing nude mice.

    NARCIS (Netherlands)

    Verel, I.; Visser, G.W.; Boellaard, R.; Boerman, O.C.; Eerd-Vismale, J.E.M. van; Snow, G.B.; Lammertsma, A.A.; Dongen, G.A.M.S. van

    2003-01-01

    Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at the confirmation of tumor targeting and the accurate estimation of radiation dose delivery to both tumor and normal tissues. Immuno-PET with (89)Zr-labeled monoclonal antibodies (mAbs) and (90)Y-mAb RIT might form such a

  13. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    Science.gov (United States)

    2013-10-01

    antibodies to the endothelial marker, CD31 (Serotec, Raleigh, NC) followed by Cy3-conjugated secondary antibody ( Jackson Immunoresearch Laboratories...in the brain. Cancer Res 67, 4190-4198, doi:67/9/4190 [pii] 10.1158/0008-5472.CAN-06- 3316 (2007). 7 Percy , D. B. et al. In vivo characterization of

  14. A case of anti-MDA5-positive rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis ameliorated by rituximab, in addition to standard immunosuppressive treatment.

    Science.gov (United States)

    Koichi, Yamaguchi; Aya, Yamaguchi; Megumi, Uchida; Shunichi, Kono; Masafumi, Suzuki; Hiroaki, Masubuchi; Masahiko, Kanbe; Shinsuke, Kitahara; Manabu, Ueno; Kenichiro, Hara; Fumiaki, Aoki; Nozomi, Aoki; Toshitaka, Maeno; Masayoshi, Yamanaka; Chikako, Kishi; Yoshinao, Muro; Tatsuo, Suga; Masahiko, Kurabayashi

    2017-05-01

    Rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) associated with antibodies to melanoma differentiation-associated gene5 (MDA5) results in a high mortality rate. We experienced a case of anti-MDA5-positive RP-ILD of CADM which showed a response to rituximab, although there was no significant effect due to standard immunosuppressive treatment. This case suggests that rituximab has the potential to offer an effective agent for the treatment of anti-MDA5-positive RP-ILD of CADM.

  15. Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries

    Science.gov (United States)

    De Cock, Erwin; Kritikou, Persefoni; Sandoval, Mariana; Tao, Sunning; Wiesner, Christof; Carella, Angelo Michele; Ngoh, Charles; Waterboer, Tim

    2016-01-01

    Background Rituximab is a standard treatment for non-Hodgkin lymphoma. The SABRINA trial (NCT01200758) showed that a subcutaneous (SC) rituximab formulation did not compromise efficacy or safety compared with intravenous (IV) infusion. We aimed to quantify active healthcare professional (HCP) time and patient chair time for rituximab SC and IV, including potential time savings. Methods This non-interventional time and motion study was run in eight countries and 30 day oncology units. Rituximab SC data were collected alongside the MabCute trial (NCT01461928); IV data were collected per routine real-world practice. Trained observers recorded active HCP time for pre-specified tasks (stopwatch) and chair time (time of day). A random intercept model was used to analyze active HCP time (by task and for all tasks combined) in the treatment room and drug preparation area, drug administration duration, chair time and patient treatment room time by country and/or across countries. Active HCP and chair time were extrapolated to a patient’s first year of treatment (11 rituximab sessions). Results Mean active HCP time was 35.0 and 23.7 minutes for IV and SC process, respectively (-32%, p time was 27–58%. Absolute reduction in extrapolated active HCP time (first year of treatment) was 1.1–5.2 hours. Mean chair time was 262.1 minutes for IV, including 180.9 minutes infusion duration, vs. 67.3 minutes for SC, including 8.3 minutes SC injection administration (-74%, p time for the first year of treatment was 3.1–5.5 eight-hour days. Conclusions Compared with rituximab IV, rituximab SC was associated with reduced chair time and active HCP time. The latter could be invested in other activities, whereas the former may lead to more available appointments, reducing waiting lists and increasing the efficiency of day oncology units. Trial Registration ClinicalTrials.gov NCT01200758 PMID:27362533

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

    International Nuclear Information System (INIS)

    Griffiths, Gary L.; Govindan, Serengulam V.; Sharkey, Robert M.; Fisher, Darrell R.; Goldenberg, David M.

    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

  17. Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Saï-Maurel, Catherine; Campion, Loïc; Faivre-Chauvet, Alain; Mirallié, Eric; Chérel, Michel; Supiot, Stéphane; Barbet, Jacques; Chatal, Jean-François; Thédrez, Philippe

    2002-02-01

    A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P

  18. Severe Primary Raynaud's Disease Treated with Rituximab.

    Science.gov (United States)

    Shabrawishi, Mohammed; Albeity, Abdurahman; Almoallim, Hani

    2016-01-01

    Raynaud's phenomenon refers to reversible spasms of the peripheral arterioles that can be primary Raynaud's phenomenon (PRP) or secondary Raynaud's phenomenon (SRP) to underlying connective tissue disease, both of which are characterized by a triphasic color response triggered by cold exposure or stress. PRP is typically a benign disease, whereas SRP may progress into digital ulcers and/or gangrene. Here, we report a case of a 55-year-old female diagnosed with PRP 7 years ago. Treatment with first-line agents, including calcium channel blocker, aspirin, and phosphodiesterase inhibitor, did not control her symptoms, which progressed to digital ulceration and gangrene. There were no symptoms of underlying autoimmune disease or malignancy, and autoimmune, serology, and immunology test results were normal; a biopsy of her left little finger was negative for vasculitis. Development to critical digital ischemia necessitated treatment with intravenous iloprost and heparin infusion followed by angioplasty, which led to a partial improvement. Due to persistent symptoms, rituximab therapy was initiated and two cycles induced a complete resolution of symptoms.

  19. 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 the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http...

  20. Distribution and pharmacokinetics of radiolabeled monoclonal antibody OC 125 after intravenous and intraperitoneal administration in gynecologic tumors

    International Nuclear Information System (INIS)

    Haisma, H.J.; Moseley, K.R.; Battaile, A.; Griffiths, T.C.; Knapp, R.C.

    1988-01-01

    Radiolabeled monoclonal antibodies may be useful for radioimmunotherapy of gynecologic tumors. Iodine 131-labeled F(ab')2 fragments of a monoclonal antibody, OC 125, with specificity for ovarian carcinoma, were used to study the distribution and pharmacokinetics of this antibody in patients with gynecologic tumors. The radiolabeled antibody was injected intravenously or intraperitoneally into 10 patients suspected of having ovarian cancer. Blood and urine samples were used for pharmacokinetic studies, and biopsy specimens were examined for the uptake of antibody. The serum half-life of the labeled antibody was 30 hours after intravenous administration, with 20% of the injected dose per liter detected at 24 hours. After intraperitoneal injection, the appearance of antibody in serum was slow, with a maximum level of 1.4% of the injected dose per liter at 24 hours. Urinary excretion of the radiolabeled antibody was similar for intravenous and intraperitoneal administration, with approximately 50% of the injected dose excreted after 48 hours. Intraperitoneal administration of the radiolabeled antibody resulted in a higher uptake of antibody in the tumor and a lower uptake of antibody in normal tissues. On the basis of this limited study, intraperitoneal administration of radiolabeled antibody is preferred over intravenous administration for radioimmunotherapy of ovarian cancer

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

    Science.gov (United States)

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

    2015-01-01

    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 (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.

  2. Improved radioimmunotherapy of hematologic malignancies. Progress report, 1988--1991

    Energy Technology Data Exchange (ETDEWEB)

    Press, O.W.; Barofsky, D.F.

    1991-12-31

    This progress report describes accomplishments under four headings, namely: The study of the relative rates of metabolic degradation of radiolabeled monoclonal antibodies (MAb) targeting tumor associated antigens; Effects of lysosomotropic amines, carboxylic ionophores, and thioamides on the retention of radiolabeled MAbs by tumor cells; Subcellular site of radioimmunoconjugate degradation and the sizes of fragments generated by intracellular metabolism of radiolabeled antibodies; and Patterns of metabolic degradation of radioimmunoconjugates made with different techniques and with different radionuclides.

  3. Radiolabeled antibodies for cancer imaging and therapy.

    Science.gov (United States)

    Barbet, Jacques; Bardiès, Manuel; Bourgeois, Mickael; Chatal, Jean-François; Chérel, Michel; Davodeau, François; Faivre-Chauvet, Alain; Gestin, Jean-François; Kraeber-Bodéré, Françoise

    2012-01-01

    Radiolabeled antibodies were studied first for tumor detection by single-photon imaging, but FDG PET stopped these developments. In the meantime, radiolabeled antibodies were shown to be effective in the treatment of lymphoma. Radiolabeling techniques are well established and radiolabeled antibodies are a clinical and commercial reality that deserves further studies to advance their application in earlier phase of the diseases and to test combination and adjuvant therapies including radiolabeled antibodies in hematological diseases. In solid tumors, more resistant to radiations and less accessible to large molecules such as antibodies, clinical efficacy remains limited. However, radiolabeled antibodies used in minimal or small-size metastatic disease have shown promising clinical efficacy. In the adjuvant setting, ongoing clinical trials show impressive increase in survival in otherwise unmanageable tumors. New technologies are being developed over the years: recombinant antibodies and pretargeting approaches have shown potential in increasing the therapeutic index of radiolabeled antibodies. In several cases, clinical trials have confirmed preclinical studies. Finally, new radionuclides, such as lutetium-177, with better physical properties will further improve the safety of radioimmunotherapy. Alpha particle and Auger electron emitters offer the theoretical possibility to kill isolated tumor cells and microscopic clusters of tumor cells, opening the perspective of killing the last tumor cell, which is the ultimate challenge in cancer therapy. Preliminary preclinical and preliminary clinical results confirm the feasibility of this approach.

  4. Favourable response to rituximab by an ocular adnexal primary lymphoma.

    Science.gov (United States)

    Luque Valentin-Fernandez, M L; Alvarez Rodríguez, F; Rodríguez Jiménez, I

    2016-11-01

    A 70-year-old woman who presented with an extranodal marginal zone B-cell lymphoma in lacrimal gland and conjunctiva. Initial treatment with rituximab yielded an immediate good response. Five months later she showed lymphoid proliferation in her contralateral conjunctiva. Although no additional treatment was performed, the patient has been free of systemic symptoms and recurrences. Rituximab is a quite good therapeutic agent in low grade adnexal lymphomas. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Anti-N-methyl-D-aspartate receptor encephalitis with positive serum antithyroid antibodies, IgM antibodies against mycoplasma pneumoniae and human herpesvirus 7 PCR in the CSF.

    Science.gov (United States)

    Venâncio, Paulo; Brito, Maria João; Pereira, Gabriela; Vieira, José Pedro

    2014-08-01

    We report the case of a boy with an encephalopathy associated with extrapyramidal and psychiatric symptoms and anti-N-methyl-D-aspartate receptor antibodies. He had positive serum antithyroid antibodies, IgM antibodies against Mycoplasma pneumoniae and human herpesvirus 7 polymerase chain reaction in the cerebrospinal fluid. He was successfully treated with rituximab, after steroids, intravenous immunoglobulin and plasma exchange. The pathophysiology of this disorder may be post-infectious and autoimmune.

  6. Internalization of rituximab and the efficiency of B Cell depletion in rheumatoid arthritis and systemic lupus erythematosus.

    Science.gov (United States)

    Reddy, Venkat; Cambridge, Geraldine; Isenberg, David A; Glennie, Martin J; Cragg, Mark S; Leandro, Maria

    2015-05-01

    Rituximab, a type I anti-CD20 monoclonal antibody (mAb), induces incomplete B cell depletion in some patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), thus contributing to a poor clinical response. The mechanisms of this resistance remain elusive. The purpose of this study was to determine whether type II mAb are more efficient than type I mAb at depleting B cells from RA and SLE patients, whether internalization influences the efficiency of depletion, and whether Fcγ receptor type IIb (FcγRIIb) and the B cell receptor regulate this internalization process. We used an in vitro whole blood B cell-depletion assay to assess the efficiency of depletion, flow cytometry to study cell surface protein expression, and surface fluorescence-quenching assays to assess rituximab internalization, in samples from patients with RA and patients with SLE. Paired t-test or Mann-Whitney U test was used to compare groups, and Spearman's rank correlation test was used to assess correlation. We found that type II mAb internalized significantly less rituximab than type I mAb and depleted B cells from patients with RA and SLE at least 2-fold more efficiently than type I mAb. Internalization of rituximab was highly variable between patients, was regulated by FcγRIIb, and inversely correlated with cytotoxicity in whole blood B cell-depletion assays. The lowest levels of internalization were seen in IgD- B cells, including postswitched (IgD-CD27+) memory cells. Internalization of type I anti-CD20 mAb was also partially inhibited by anti-IgM stimulation. Variability in internalization of rituximab was observed and was correlated with impaired B cell depletion. Therefore, slower-internalizing type II mAb should be considered as alternative B cell-depleting agents for the treatment of RA and SLE. © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

  7. 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.

  8. The Role of Monoclonal Antibodies in the Management of Leukemia

    Directory of Open Access Journals (Sweden)

    Mohamad Cherry

    2010-10-01

    Full Text Available This article will review the monoclonal antibodies more commonly used in leukemias. In the last three decades, scientists have made considerable progress understanding the structure and the functions of various surface antigens, such as CD20, CD33. The introduction of rituximab, an anti CD20 monoclonal antibody, had a great impact in the treatment of lymphoproliferative disorders. Gemtuzumab, an anti CD 33 conjugated monoclonal antibody has activity in acute mylegenous leukemia (AML. As this field is undergoing a rapid growth, the years will see an increasing use of monoclonal antibodies in hematological malignancies.

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

    International Nuclear Information System (INIS)

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

    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 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

  10. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors.

    OpenAIRE

    Cherel Michel; Davodeau Francois; Barbet Jacques; Chatal Jean-Francois

    2009-01-01

    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 pa...

  11. 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.

  12. 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...

  13. Is rituximab effective in childhood nephrotic syndrome? Yes and no.

    Science.gov (United States)

    Kemper, Markus J; Lehnhardt, Anja; Zawischa, Anna; Oh, Jun

    2014-08-01

    The idiopathic nephrotic syndrome (i.e. MCNS and FSGS) in children has been regarded as a disorder of T-cell function. Recent studies, however, also describe abnormalities of B-cell function. This supports the use of B-cell modulating treatment for idiopathic nephrotic syndrome (INS), especially rituximab, which has been used in other glomerular disorders as well. Many studies indicate that rituximab is effective in steroid-sensitive and -dependent nephrotic syndrome, by either inducing long-term remission or reducing relapses. In most series, children with primary (and recurrent) focal segmental glomerulosclerosis (FSGS) do not respond as well. The exact mechanisms of action of rituximab (as well as those of the other treatment options) in INS are as yet unclear. In addition to hosting mechanisms a direct stabilizing effect on the podocyte may also be of relevance, especially in FSGS. Although results are encouraging especially in steroid-sensitive patients, further studies on the clinical use of rituximab and the short- and long-term immunological effects and side-effects are necessary.

  14. Microcosting Study of Rituximab Subcutaneous Injection Versus Intravenous Infusion

    NARCIS (Netherlands)

    Mihajloviç, Jovan; Bax, Pieter; van Breugel, Erwin; Blommestein, Hedwig M.; Hoogendoorn, Mels; Hospes, Wobbe; Postma, Maarten J.

    Purpose: The goal of this study is to identify and compare all direct costs of intravenous and subcutaneous rituximab given to patients with diffuse large B-cell lymphoma in the Netherlands.  Methods: Using a prospective, observational, bottom-up microcosting study, we collected primary data on the

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

    International Nuclear Information System (INIS)

    Buchmann, I.; Helisch, A.; Bartenstein, P.; Meyer, R.G.; Herr, W.

    2005-01-01

    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. Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome

    Science.gov (United States)

    2014-01-01

    Introduction Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. Methods To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Results Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. Conclusions For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an

  17. Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren's syndrome.

    Science.gov (United States)

    Hershberg, Uri; Meng, Wenzhao; Zhang, Bochao; Haff, Nancy; St Clair, E William; Cohen, Philip L; McNair, Patrice D; Li, Ling; Levesque, Marc C; Luning Prak, Eline T

    2014-02-11

    Subjects with primary Sjögren's syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means

  18. Cancer Imaging and Therapy with Bispecific Antibody Pretargeting.

    Science.gov (United States)

    Goldenberg, David M; Chatal, Jean-Francois; Barbet, Jacques; Boerman, Otto; Sharkey, Robert M

    2007-03-01

    This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly-labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or 1-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (3 Fab's) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called Dock and Lock (DNL).

  19. Recent developments in monoclonal antibody radiolabeling techniques

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, S.C.; Mease, R.C.

    1989-01-01

    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.

  20. Recent developments in monoclonal antibody radiolabeling techniques

    International Nuclear Information System (INIS)

    Srivastava, S.C.; Mease, R.C.

    1989-01-01

    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

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

    International Nuclear Information System (INIS)

    Forrer, Flavio; Mueller-Brand, Jan; Chen, Jianhua; Fani, Melpomeni; Powell, Pia; Maecke, Helmut R.; Lohri, Andreas; Moldenhauer, Gerhard

    2009-01-01

    131 I- and 90 Y-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 ( 177 Lu or 90 Y. 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 10 5 times excess of diethylenetriaminepentaacetic acid (DTPA, 37 C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m 2 body surface 177 Lu-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 177 Lu-DOTA-rituximab was tolerated well. Our results show that DOTA-rituximab (4:1) can be labelled with 177 Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177 Lu-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.)

  2. Rituximab treatment in a case of antisynthetase syndrome with severe interstitial lung disease and acute respiratory failure

    Directory of Open Access Journals (Sweden)

    Zappa Maria

    2011-08-01

    Full Text Available Abstract We present a case of severe interstitial pneumonitis, mild polyarthritis and polymyositis, and Raynaud's syndrome with the presence of anti-Jo-1 antibodies, which had been diagnosed as anti-synthetase syndrome. The presence, however, of anti-Ro/SSA antibodies led us to understand that we were dealing here with a more severe form of interstitial lung disease. The patient was treated for acute respiratory failure but he showed resistance to glucocorticoids and cyclosporine. Thus, he was treated with infusions of anti-CD20 therapy (rituximab: his clinical conditions improved very rapidly and a significant decrease in the activity of pulmonary disease was detected using high-resolution computerized tomography (HRCT of the thorax and pulmonary function tests.

  3. Intralesional Rituximab in the Treatment of Refractory Oral Pemphigus Vulgaris.

    Science.gov (United States)

    Vinay, Keshavamurthy; Kanwar, Amrinder J; Mittal, Ankit; Dogra, Sunil; Minz, Ranjana W; Hashimoto, Takashi

    2015-08-01

    Oral lesions of pemphigus vulgaris are usually recalcitrant and respond slowly to treatments. Corticosteroid injection is considered to be the most effective local treatment in oral pemphigus vulgaris. However, intralesional corticosteroids are not effective in all remnant lesions. In 3 such patients with pemphigus vulgaris, we evaluated the utility of 2 injections (on days 1 and 15) of intralesional rituximab, 5 mg/cm², in terms of accelerated healing, limitation of the use of systemic immunosuppressants, and reduction of their adverse effects. Three patients (1 man and 2 women) received 2 doses of intralesional rituximab in March and April 2013. All 3 patients responded to the treatment. In patients 1 and 2, the objective severity score was reduced to 0 at the final visit from a baseline score of 4 and 5, respectively (range, 0-11). The subject severity score in these patients was reduced to 1.0 and 0 from a baseline score of 22.0 and 22.5, respectively. After clinical remission was achieved, patient 3 developed a relapse of mucosal lesions. At the final visit, all of the patients were satisfied with the treatment, with a mean satisfaction score of 8 (maximum score, 10). We found a marked decline in the CD19 cell count from a pretreatment mean count of 287 cells/µL to 6 cells/µL on day 15 after a single intralesional rituximab injection. Adverse events were limited to local pain in 1 patient. Intralesional rituximab administration lacks the adverse effects of intravenous administration. This method reduces the amount of drug administered and therefore is less expensive. Encouraging results from our study should prompt further evaluation of this novel route of rituximab administration in patients with refractory oral pemphigus vulgaris.

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

    International Nuclear Information System (INIS)

    Roscher, Mareike

    2013-01-01

    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.

  5. 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.)

  6. 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

    Purpose: To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. Materials and methods: Testicular uptake and retention of 131I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54+/-11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy. Results: The absorbed dose to the testes showed considerable variability (range=4.4-70.2 Gy). Pretherapy 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] compared with 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. Finally, patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.

  7. Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.

    Science.gov (United States)

    Salaun, Pierre-Yves; Campion, Loïc; Bournaud, Claire; Faivre-Chauvet, Alain; Vuillez, Jean-Philippe; Taieb, David; Ansquer, Catherine; Rousseau, Caroline; Borson-Chazot, Françoise; Bardet, Stéphane; Oudoux, Aurore; Cariou, Bertrand; Mirallié, Eric; Chang, Chien-Hsing; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques; Kraeber-Bodéré, Françoise

    2012-08-01

    The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome. From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later. The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004). pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

  8. Evaluation of glycodendron and synthetically modified dextran clearing agents for multistep targeting of radioisotopes for molecular imaging and radioimmunotherapy.

    Science.gov (United States)

    Cheal, Sarah M; Yoo, Barney; Boughdad, Sarah; Punzalan, Blesida; Yang, Guangbin; Dilhas, Anna; Torchon, Geralda; Pu, Jun; Axworthy, Don B; Zanzonico, Pat; Ouerfelli, Ouathek; Larson, Steven M

    2014-02-03

    A series of N-acetylgalactosamine-dendrons (NAG-dendrons) and dextrans bearing biotin moieties were compared for their ability to complex with and sequester circulating bispecific antitumor antibody streptavidin fusion protein (scFv4-SA) in vivo, to improve tumor-to-normal tissue concentration ratios for multistep targeted (MST) radioimmunotherapy and diagnosis. Specifically, a total of five NAG-dendrons employing a common synthetic scaffold structure containing 4, 8, 16, or 32 carbohydrate residues and a single biotin moiety were prepared (NAGB), and for comparative purposes, a biotinylated-dextran with an average molecular weight of 500 kD was synthesized from amino-dextran (DEXB). One of the NAGB compounds, CA16, has been investigated in humans; our aim was to determine if other NAGB analogues (e.g., CA8 or CA4) were bioequivalent to CA16 and/or better suited as MST reagents. In vivo studies included dynamic positron-emission tomography (PET) imaging of (124)I-labeled-scFv4-SA clearance and dual-label biodistribution studies following MST directed at subcutaneous (s.c.) human colon adenocarcinoma xenografts in mice. The MST protocol consists of three injections: first, a scFv4-SA specific for an antitumor-associated glycoprotein (TAG-72); second, CA16 or other clearing agent; and third, radiolabeled biotin. We observed using PET imaging of the (124)I-labeled-scFv4-SA clearance that the spatial arrangement of ligands conjugated to NAG (i.e., biotin linked with an extended spacer, referred to herein as long-chain (LC)) can impact the binding to the antibody in circulation and subsequent liver uptake of the NAG-antibody complex. Also, NAGB CA32-LC or CA16-LC can be utilized during MST to achieve comparable tumor-to-blood ratios and absolute tumor uptake seen previously with CA16. Finally, DEXB was equally effective as NAGB CA32-LC at lowering scFv4-SA in circulation, but at the expense of reducing absolute tumor uptake of radiolabeled biotin.

  9. Kinetics of Rituximab Excretion into Urine and Peritoneal Fluid in Two Patients with Nephrotic Syndrome

    Directory of Open Access Journals (Sweden)

    Klaus Stahl

    2017-01-01

    Full Text Available Clinical observations suggest that treatment of Rituximab might be less effective in patients with nephrotic range proteinuria when compared to nonnephrotic patients. It is conceivable that the reason for this is that significant amounts of Rituximab might be lost in the urine in a nephrotic patient and that these patients require a repeated or higher dosage. However, this has not been systematically studied. In this case report we describe two different patients with nephrotic range proteinuria receiving Rituximab. The first patient received Rituximab for therapy resistant cryoglobulinemic membranoproliferative glomerulonephritis and the other for second line treatment of Felty’s syndrome. We employed flow cytometry to determine the amount of Rituximab excretion in both urine and peritoneal fluid specimens in these patients following administration of Rituximab. We found that a significant amount of Rituximab is lost from the circulation by excretion into the urine. Furthermore we saw a close correlation of the excretion of Rituximab to the excretion of IgG molecules suggesting selectivity of proteinuria as the determining factor of Rituximab excretion. Further larger scale clinical studies could have the potential to evaluate an optimal cut-off value of IgG urinary loss before a possible administration of Rituximab therefore contributing to a more individualized treatment approach in patients with nonselective and nephrotic range proteinuria.

  10. Population pharmacokinetics of Reditux™, a biosimilar Rituximab, in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Gota, Vikram; Karanam, Ashwin; Rath, Sanhita; Yadav, Akanksha; Tembhare, Prashant; Subramanian, P; Sengar, Manju; Nair, Reena; Menon, Hari

    2016-08-01

    Rituximab (MabThera™, Roche) is a chimeric IgG1 monoclonal antibody targeting the CD20 surface antigen on normal and neoplastic B cells. It revolutionized the treatment of non-Hodgkin's lymphoma with superior progression-free and overall survival. However, its prohibitively high cost makes it inaccessible to majority of patients in developing countries. Reditux™ (Dr. Reddy's Laboratories, India), a biosimilar, was introduced in India in 2007 at nearly half the price of the innovator. However, there is a dearth of data regarding the pharmacokinetics and efficacy of Reditux™. Twenty-one patients of diffuse large B-cell lymphoma on R-CHOP regimen were enrolled for the study. Reditux™ was administered as a slow intravenous infusion at a dose of 375 mg/m(2) on day 1 of a 21-day cycle. Pharmacokinetic sampling was performed at pre-dose, post-infusion, 24, 48 h, 7 and 21 days. Rituximab levels were estimated by ELISA. Population pharmacokinetics was performed using NONMEM. In addition, B-cell count was determined at baseline and days 3 and 21 of the first cycle. Survival analysis was performed using Kaplan-Meier plots. The volume of distribution of central compartment and clearance of Reditux™ were estimated at 0.95 L and 5.98 mL/h, respectively. No covariate effects were seen. B-cell count was completely depleted by day 3 and remained so on day 21. Overall survival was 84.6 % at a median follow-up of 36 months. The pharmacokinetic profile and B-cell response to Reditux™ are comparable with those reported for MabThera™. Thus, MabThera™ can be substituted with Reditux™ for the treatment of B-cell lymphomas.

  11. 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...

  12. 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

    NARCIS (Netherlands)

    Salles, Gilles; Seymour, John Francis; Offner, Fritz; López-Guillermo, Armando; Belada, David; Xerri, Luc; Feugier, Pierre; Bouabdallah, Réda; Catalano, John Vincent; Brice, Pauline; Caballero, Dolores; Haioun, Corinne; Pedersen, Lars Moller; Delmer, Alain; Simpson, David; Leppa, Sirpa; Soubeyran, Pierre; Hagenbeek, Anton; Casasnovas, Olivier; Intragumtornchai, Tanin; Fermé, Christophe; da Silva, Maria Gomes; Sebban, Catherine; Lister, Andrew; Estell, Jane A.; Milone, Gustavo; Sonet, Anne; Mendila, Myriam; Coiffier, Bertrand; Tilly, Hervé

    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 plus

  13. Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

    Science.gov (United States)

    2014-10-01

    cells of brain metastases. • PS-targeting antibody, PGN635F(ab’)2 has been successfully conjugated with radioisotope , enabling in vivo PET imaging ...A. Brekken CONTRACTING ORGANIZATION: U Southwestern Center REPORT DATE: October 2014 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical ...NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University of Texas Southwestern Medical Center Dallas, TX 75390-9058 9

  14. 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.

  15. Eficiency of different doses of rituximab in rheumatoid arthritis.

    Science.gov (United States)

    Mena-Vázquez, Natalia; Manrique-Arija, Sara; Ureña-Garnica, Inmaculada; Romero-Barco, Carmen M; Jiménez-Núñez, Francisco G; Coret, Virginia; Irigoyen-Oyarzábal, María Victoria; Fernández-Nebro, Antonio

    2016-01-01

    Evaluate the effectiveness, cost and safety of rituximab in patients with rheumatoid arthritis (RA) depending on the dose used. Retrospective observational study conducted on 52 patients with RA treated with at least one dose of rituximab for 135.3 patient-years were included. Three treatment groups were obtained: (G1) First course and following two 1g infusions separated by 15 days; (G2) First course 2 infusions of 1g followed by 2 infusions of 500mg; (G3) First course and followed by 2 infusions of 500mg separated by 15 days. Re-treatments were administered on-demand according to the clinical activity. The retention time (Log-Rank), retreats and adverse events rates (incidence rate ratio) and treatment costs per patient-month of rituximab were analysed by groups. Group 2 showed a better cost-effectiveness ratio than group 1, as it was associated with a longer retention of rituximab (mean [95% CI] 65.7 [60.8 to 70.7] months vs 33.5 [22.7 to 44.3]; P<.001) and a lower rate of severe adverse events with only a slight increase in the rate of retreatment (courses/patient-year [95% CI] 1.66 [1.39 to 1.93] vs. 1.01 [0.69 to 1.34]; P=.005), and in the costs (median/patient-month, €484.89 vs. €473.45). Although group 3 was €41.20/patient-month cheaper than group 2, it was associated with a higher rate of re-treatments and shorter retention of rituximab (P<.001). The use of full-dose rituximab at onset, followed by reduced doses in successive courses administered on-demand retreatment may be the most cost-effective option. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  16. Rituximab as a monotherapy or in combination therapy for the treatment of non-paraneoplastic autoimmune retinopathy

    Directory of Open Access Journals (Sweden)

    Maleki A

    2017-02-01

    Full Text Available Arash Maleki,1,2 Neerav Lamba,1,2 Lina Ma,1,2 Stacey Lee,1,2 Alexander Schmidt,1,2 C Stephen Foster1–3 1Massachusetts Eye Research and Surgery Institution, 2Ocular Immunology and Uveitis Foundation, Waltham, 3Harvard Medical School, Boston, MA, USA Purpose: To examine the efficacy of rituximab as a monotherapy or in combination therapy for the treatment of patients with non-paraneoplastic autoimmune retinopathy. Methods: Twelve eyes of six patients with non-paraneoplastic autoimmune retinopathy who were treated with rituximab and had at least 6 months of follow-up were included. Demographic data, clinical data, visual field parameters, electroretinography parameters, and anti-retinal and anti-optic nerve autoantibody bands were collected from the Massachusetts Eye Research and Surgery Institution database between September 2010 and January 2015. Changes in visual acuity, visual field parameters, electroretinography parameters, and anti-retinal and anti-optic nerve autoantibody bands from the initial visit to the most recent visit were examined. Results: From the initial visit to the last visit, visual acuity was stable in eight (66.7% eyes. Visual field was stable in six (50% eyes and improved in two (16.7% eyes. Electroretinography was stable or improved in eight (66.7% eyes. The average number of anti-retinal and anti-optic nerve antibody bands was reduced. Conclusion: Stabilization and/or improvement of visual acuity, visual field parameters, and electroretinography parameters were observed in a high number of patients (75% on rituximab, as a monotherapy (one patient or in combination therapy. Keywords: birdshot retinochoroidopathy, bortezomib, CD20, cyclophosphamide, HLA-A29, HLA-B27, immunomodulatory therapy, systemic lupus erythematosus

  17. 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.

  18. Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis.

    Science.gov (United States)

    Costa, Rubens; Fazal, Salman; Kaplan, Robert B; Spero, Joel; Costa, Ricardo

    2013-03-01

    Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disorder characterized by venous and/or arterial thrombosis or recurrent fetal loss associated with the presence of antiphospholipid antibodies and/or a lupus anticoagulant. The skin appears to be an important target organ and many cases of APS may present with skin manifestations. These lesions may be manifold and may take the form of livedo reticularis, livedo racemosa, ulcerations, digital gangrene, subungeal splinter hemorrhages, superficial venous thrombosis, thrombocytopenic purpura, pseudovasculitic manifestations, extensive cutaneous necrosis, or primary anetoderma. We report a case of fulminant APS-related cutaneous necrosis. A 38-year-old Caucasian male with a past history of APS, multiple deep vein thrombi/pulmonary emboli, presented with necrotic lesions on his right upper and right lower extremities. Initially, baseline anticoagulation was increased without improvement. Subsequently, plasma exchange was initiated on a daily schedule. Furthermore, rituximab 1,000 mg IV was administered on days 1 and 15. After six consecutive daily sessions of plasma exchange, there was significant regression of the necrotic lesions. After a 22-day hospital stay, the patient was discharged to home on fondaparinux. The patient presented approximately 2 months later after missing follow-up appointments. At the time, his initial lesions looked remarkably improved.

  19. Low dose of mycophenolate mofetil is enough in desensitized kidney transplantation using rituximab

    OpenAIRE

    Baek, Chung Hee; Kim, Hyosang; Yu, Hoon; Shin, Eunhye; Cho, Hyungjin; Yang, Won Seok; Han, Duck Jong; Park, Su-Kil

    2015-01-01

    Background Rituximab is widely used in kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressant in rituximab-treated kidney transplantation (KT) are appropriate. In our previous study, decreasing mycophenolate mofetil (MMF) dose due to infection did not increase the incidence of rejection or graft failure. Based on these experiences, we developed a new protocol with a lower dose of MMF and studied its clinical outcomes in rituximab-treat...

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

    International Nuclear Information System (INIS)

    Perera Pintado, Alejandro; Peña Quián, Yamilé; Batista Cuéllar, Juan F.; Prats Capote, Anaís; Torres Aroche, Leonel A.; Casacó Santana, Caridad; Sánchez Mendosa, Elvia L.; Sánchez González, Yolaine; Romero Collado, Susana; Quesada Pozo, Rodobaldo; Valladares Oviedo, Lourdes; Masquida García, Elsa M.; Leyva Montaña, René; Casacó, Angel; Ramos Suzarte, Mayra; Crombet, Tania

    2016-01-01

    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 188 Re 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)

  1. Intralesional rituximab in primary conjunctival follicular lymphoma relapsed.

    Science.gov (United States)

    Rodríguez Villa, S; Ruiz Rodríguez, M J; Vargas Pabón, M

    2017-07-01

    A 49-year-old woman experienced a local relapse of a primary follicular lymphoma (FL) of the conjunctiva. She received 4 weekly intra-lesional injections followed by 6 monthly injections of rituximab (6mg/ml). A clinical response was achieved after first injection. No adverse ocular event or signs of lymphoma relapse were seen after 10 months of follow-up. Intralesional administration of rituximab for treating primary FL of the conjunctiva was an effective and safe therapeutic option; therefore it could be an alternative to other conventional treatments, such as radiotherapy or chemotherapy. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. 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 CT-scan before treatment (3 had bilateral and 7 unilateral orbital involvement). Orbital symptoms at study baseline included pain, pressure sensation behind the eyes, epiphora, diplopia, and affection of the visual acuity. Nine out of ten patients experienced subjective improvement. Four patients...

  3. Successful Treatment of Type B Insulin Resistance With Rituximab

    OpenAIRE

    Manikas, Emmanouil-Dimitrios; Isaac, Iona; Semple, Robert K.; Malek, Rana; F?hrer, 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...

  4. Successful treatment of type B insulin resistance with rituximab.

    Science.gov (United States)

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

    2015-05-01

    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. A 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose levels > 500 mg/dL, which could not be controlled with up to 600 IU/d of insulin. Because of the severity of the insulin resistance combined with features of insulin deficiency, type B insulin resistance was suspected. Detection of high levels of insulin receptor autoantibodies confirmed the diagnosis. Neither immunosuppressive therapy with Ig iv nor plasmapheresis had an effect on glucose levels or insulin dose. Because the patient's condition was deteriorating, we started rituximab (750 mg/m(2) in two doses 2 wk apart) together with cyclophosphamide (100 mg/d orally) and dexamethasone 40 mg/d for 4 days. Two months after initiation of rituximab therapy, fasting glucose levels ranged from 80 to 110 mg/dL and could be controlled with very low insulin doses. Glycated hemoglobin decreased from 11.8 to 6.5%. Two months later, insulin therapy was stopped, and the patient showed normal blood glucose readings. In this patient with type B insulin resistance, Ig treatment and plasmapheresis failed to improve the condition. Finally, treatment with rituximab, cyclophosphamide, and steroids was successful in inducing a complete remission.

  5. Rituximab: a novel treatment for refractory Riedel’s thyroiditis

    Directory of Open Access Journals (Sweden)

    Leanne Hunt

    2018-02-01

    Full Text Available This case report reviews the rare condition of Riedel’s thyroiditis via a patient case. The report highlights the difficulties that one may encounter when managing such a case in regards to patient symptoms, side effects of medications and the relapsing nature of the condition. The case report also highlights novel treatment in the treatment of Riedel’s thyroiditis, rituximab, how this works and the resolution of symptoms that we have achieved with our patient on this treatment.

  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. Is rituximab effective for induction of remission in lupus nephritis?

    Directory of Open Access Journals (Sweden)

    Macarena Mac-Namara

    2014-08-01

    Full Text Available La combinación de ciclofosfamida y corticoides constituye el tratamiento estándar en pacientes con nefritis lúpica con indicación de terapia inmunosupresora mayor. Sin embargo, se asocia a importantes efectos adversos, por lo que existe interés en otros inmunosupresores como rituximab. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 19 bases de datos, identificamos 5 revisiones sistemáticas que en conjunto incluyen 24 estudios. Realizamos una síntesis mediante tablas de resumen de los resultados utilizando el método GRADE y concluimos que existe incertidumbre sobre la eficacia de rituximab en nefritis lúpica porque la certeza de la evidencia es muy baja, se asocia a efectos adversos importantes, y tiene alto costo. Rituximab no debiera utilizarse fuera de un estudio clínico, o sólo en casos en que otras alternativas han fracasado si es que no existen limitaciones de recursos.

  8. Rituximab effectively reverses Tyrosine kinase inhibitors (TKIs) resistance through inhibiting the accumulation of rictor on mitochondria-associated ER-membrane (MAM).

    Science.gov (United States)

    Xu, Zhi-Hong; Liu, Cai-Hong; Hang, Jun-Biao; Gao, Bei-Li; Hu, Jia-An

    2017-12-06

    Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anti lung cancer drugs, have recently been found to resistant to some NSCLC cells which have the T790M EGFR mutation. However, recent investigations on the therapies of resistance to EGFR-TKIs are very limited. Therefore, it is important to develop more effective therapies to reverse EGFR-TKIs resistance. In our present study, erlotinib was used as the TKIs drug and the effects of the erlotinib on cell growth were evaluated. Cell viability and concentration dependent studies were performed using HCI-H1975 and HCI-H1299 cells alone with erlotinib, respectively. Further combined with rituximab, the results showed that erlotinib and rituximab were significantly inhibited the cell growth. Furthermore, the combination of erlotinib and rituximab greatly decreased the expression of p-mTOR and p-EGFR. Additional results from western blotting and immunofluorescence assays demonstrated that the accumulation of rictor was also decreased on MAM. Thus, all these results suggested that EGFR-TKIs combined with CD20 mono-antibody significantly decrease the cell growth of H1975 cells and H1299, with T790M EGFR mutation, and inhibit the localization of the key mTOR pathway proteins to MAM. So, it may be a promising strategy for overcoming EGFR TKI resistance in NSCLC patients.

  9. Human herpes virus-6 encephalitis causing severe anterograde amnesia associated with rituximab, azathioprine and prednisolone combination therapy for dermatomyositis.

    Science.gov (United States)

    Baumer, Thomas; Fry, Charlie; Luppe, Sebastian; Gunawardena, Harsha; Sieradzan, Kasia

    2017-06-01

    Human herpes virus-6 (HHV-6) reactivation is a well-recognised complication following haematological stem cell transplantation, but it is novel in the context of combination immunomodulatory therapy for autoimmune disease. We report a case of severe anterograde amnesia caused by HHV-6 encephalitis in a young female patient on rituximab, azathioprine and prednisolone for dermatomyositis (DM). The use of targeted biologic treatments for systemic autoimmune connective tissue diseases (CTDs) is increasing, particularly when refractory to conventional management. The anti-CD20 B cell depleting monoclonal antibody, rituximab is now increasingly used, often in combination with conventional immunomodulatory treatments, in certain autoimmune neurological conditions and systemic CTDs including DM. Physicians should be aware of the possibility of HHV-6 in those who develop encephalitis while CD20 B cell deplete, especially in the presence of additional immunomodulatory therapies. Prompt diagnosis and treatment of HHV-6 encephalitis with evidence-based anti-viral therapy may help reduce the extent of irreversible morbidity such as amnesia.

  10. Application and evolution of several therapy nuclides labelled antibody in tumour therapy

    International Nuclear Information System (INIS)

    He Jiaheng; Luo Shunzhong; Wang Guanquan

    2004-12-01

    Radiolabeled Monoclonal antibody had a lot of merits, such as decreasing the lesion because of the external exposure to normal tissue and the whole body, destroying cancer cells which McAb could not reach, and little ornamentation effect by Antigen. Therefor, it gradually became a kind of guiding therapy method which endowed with practical value. Up to now, the radionuclides which be used for tumour radioimmunotherapy included mostly 131 I, 90 Y, 188 Re, 186 Re, 153 Sm, 211 At, et al. The application and evolution of several therapy nuclides labelled antibody in tumour therapy are in troduced. (authors)

  11. 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.

    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

  12. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors.

    Science.gov (United States)

    Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel; Barbet, Jacques

    2009-09-01

    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.

  13. Evaluation of effects on the peritoneum after intraperitoneal α-radioimmunotherapy with (211)At

    DEFF Research Database (Denmark)

    Cederkrantz, Elin; Angenete, Eva; Bäck, Tom

    2012-01-01

    The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70 μm) and the short half-life (7.21 h) of the nuclide yield a dose distribution in which the peritoneum......-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical...

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

    Energy Technology Data Exchange (ETDEWEB)

    Forrer, Flavio; Mueller-Brand, Jan [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Chen, Jianhua; Fani, Melpomeni; Powell, Pia; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Lohri, Andreas [Basel University Medical Clinic, Liestal (Switzerland); Moldenhauer, Gerhard [German Cancer Research Center, Division of Molecular Immunology, Heidelberg (Germany)

    2009-09-15

    {sup 131}I- and {sup 90}Y-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 (<20 min) with either {sup 177}Lu or {sup 90}Y. 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 10{sup 5} times excess of diethylenetriaminepentaacetic acid (DTPA, 37 C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m{sup 2} body surface {sup 177}Lu-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 {sup 177}Lu-DOTA-rituximab was tolerated well. Our results show that DOTA-rituximab (4:1) can be labelled with {sup 177}Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. {sup 177}Lu-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. Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

    Science.gov (United States)

    Rousset-Rouvière, Caroline; Cailliez, Mathilde; Garaix, Florentine; Bruno, Daniele; Laurent, Daniel; Tsimaratos, Michel

    2014-06-01

    Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab. We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab. Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway

  16. 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...... 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.......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...

  17. 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...

  18. The efficacy and safety of rituximab in treating childhood refractory nephrotic syndrome: a meta-analysis.

    Science.gov (United States)

    Zhao, Zhihong; Liao, Guixiang; Li, Yongqiang; Zhou, Shulu; Zou, Hequn

    2015-02-03

    Rituximab is considered to be a promising drug for treating childhood refractory nephrotic syndrome. However, the efficacy and safety of rituximab in treating childhood refractory nephrotic syndrome remain inconclusive. This meta-analysis aimed to investigate the efficacy and safety of rituximab treatment compared with other immunosuppressive agents in children with refractory nephrotic syndrome. Three randomized controlled trials and two comparative control studies were included in our analysis. The included studies were of moderately high quality. Compared with other immunotherapies, rituximab therapy significantly improved relapse-free survival (hazard ratio = 0.49, 95% confidence interval [CI], 0.26-0.92, P = 0.03). Rituximab also achieved a higher rate of complete remission (risk ratio,1.62; 95% CI, 0.92 to 2.84, P = 0.09) and reduced the occurrence of proteinuria (mean difference = -0.25, 95% CI = -0.29 to -0.21, P childhood refractory nephrotic syndrome; however, the long-term effects and cost-effectiveness of rituximab treatment were not fully assessed, and there were limited studies that evaluated the clinical benefits of a concurrent infusion of rituximab plus a steroid compared with an infusion of rituximab only. Additional studies are required to address these issues.

  19. 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...

  20. Rituximab para la oftalmopatía asociada a la tiroides

    Directory of Open Access Journals (Sweden)

    Neda Minakaran

    2013-09-01

    Conclusiones de los autores: Actualmente no hay pruebas suficientes para apoyar la administración de rituximab en los pacientes con OAT. Se necesitan ECA grandes que investiguen rituximab versus placebo o corticosteroides en pacientes con OAT activo para hacer valoraciones adecuadas sobre la eficacia y la seguridad de este tratamiento nuevo para esta enfermedad.

  1. Micro-costing study of rituximab subcutaneous injection versus intravenous infusion in dutch setting

    NARCIS (Netherlands)

    Mihajlović, J.; Bax, P.; Van Breugel, E.; Blommestein, H.M.; Hoogendoorn, M.; Hospes, W.; Postma, M.J.

    2015-01-01

    Background: Rituximab for subcutaneous (SC) administration has recently been approved for use in common forms of diffuse large B-cell lymphoma (DLBCL). This form of rituximab is supplied in ready-to-use vials that do not require individual dose adjustment. It is expected that SC-injection will

  2. High rates of durable responses with anti-CD22 fractionated radioimmunotherapy: results of a multicenter, phase I/II study in non-Hodgkin's lymphoma.

    Science.gov (United States)

    Morschhauser, Franck; Kraeber-Bodéré, Françoise; Wegener, William A; Harousseau, Jean-Luc; Petillon, Marie-Odile; Huglo, Damien; Trümper, Lorenz H; Meller, Johannes; Pfreundschuh, Michael; Kirsch, Carl-Martin; Naumann, Ralph; Kropp, Joachim; Horne, Heather; Teoh, Nick; Le Gouill, Steven; Bodet-Milin, Caroline; Chatal, Jean-Francois; Goldenberg, David M

    2010-08-10

    Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkin's lymphoma (NHL). A multicenter trial evaluated two or three weekly infusions of yttrium-90 ((90)Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined. At the maximum total (90)Y dose of 45 mCi/m(2) (1,665 MBq/m(2)), grade 3 to 4 hematologic toxicities were reversible to grade 1 in patients with less than 25% bone marrow involvement. The overall OR rate and median PFS for all 61 evaluable patients was 62% (CR/CRu, 48%) and 9.5 months, respectively. Patients without prior ASCT obtained high OR rates of 71% (CR/CRu, 55%) across all NHL subtypes and (90)Y doses, even in poor-risk categories (refractory to last anti-CD20-containing regimen, 73% [CR/CRu, 60%]; bulky disease: 71% [CR/CRu, 43%]). Patients with prior ASCT received lower doses, but achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total (90)Y-dose, reaching 100% (CR/CRu, 92%) and 24.6 months, respectively, at the highest dose levels (> 30 mCi/m(2) total (90)Y-dose [1,110 MBq/m(2)]). Further, patients with FL refractory to prior anti-CD20-containing regimens achieved 90% (nine of 10 patients) OR and CR/CRu rates and a median PFS of 21.5 months. Fractionated anti-CD22 radioimmunotherapy provides high total doses of (90)Y, yielding high rates of durable CR/CRus in relapsed/refractory NHL, resulting in 20 mCi/m(2) x 2 weeks as the recommended dose for future studies.

  3. The feasibility of 225Ac as a source of α-particles in radioimmunotherapy

    International Nuclear Information System (INIS)

    Geerlings, M.W.; Hout, R. van der; Kaspersen, F.M.; Apostolides, C.

    1993-01-01

    This paper proposes the utilization of 225 Ac for the α-radioimmunotherapy of cancer. The isotope decays with a radioactive half-life of 10 days into a cascade of short-lived α-and β-emitting isotopes. In addition, when indicated by the pharmacokinetic requirements of particular clinical applications, 213 Bi, with a radioactive half-life of 47 min, can be chosen as an alternative source of α-particles in radioimmunotherapy. This isotope is the last α emitter in the 225 Ac decay-cascade and can be extracted from a 225 Ac source at the bedside of the patient. 225 Ac can quasi ad infinitum be obtained from one of its precursors, 229 Th, which can be made available by various means. The indications for the use of α-particles as an alternative to more traditional classes of radiation are derived from the particle-kinetic characteristics and the radioactive half-life of their source isotope, as well as from the properties of the target-selective carrier moiety for the source isotope. It may be expected that useful applications, complementary to and/or in conjunction with other means of therapy will be identified. (author)

  4. Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies.

    Science.gov (United States)

    Tipton, Thomas R W; Roghanian, Ali; Oldham, Robert J; Carter, Matthew J; Cox, Kerry L; Mockridge, C Ian; French, Ruth R; Dahal, Lekh N; Duriez, Patrick J; Hargreaves, Philip G; Cragg, Mark S; Beers, Stephen A

    2015-03-19

    Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo. © 2015 by The American Society of Hematology.

  5. Central Diabetes Insipidus in Refractory Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

    Science.gov (United States)

    Ohashi, Keiji; Morishita, Michiko; Watanabe, Haruki; Sada, Ken-Ei; Katsuyama, Takayuki; Miyawaki, Yoshia; Katsuyama, Eri; Narazaki, Mariko; Tatebe, Noriko; Watanabe, Katsue; Kawabata, Tomoko; Wada, Jun

    2017-11-01

    We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.

  6. 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.

  7. 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

    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......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...... that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime....

  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

    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......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...... that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime....

  9. Controversies on Rituximab Therapy in Sjögren Syndrome-Associated Lymphoproliferation

    Directory of Open Access Journals (Sweden)

    Luca Quartuccio

    2009-01-01

    Full Text Available Sjögren's syndrome (SS is a systemic autoimmune disease characterized by chronic inflammation of salivary and lachrymal glands, and frequently accompanied by systemic symptoms. A subgroup of SS patients develops malignant B cell non-Hodgkin's lymphoma (NHL, usually of the mucosa-associated lymphoid tissue (MALT type and very often located in the major salivary glands. Currently, there is a lack of evidence-based intervention therapy which may influence SS-related chronic inflammation and lymphoproliferation. B cells are involved in the pathogenesis of SS, and B cell downregulation may lead to a decrease of disease activity. Rituximab (RTX, a chimeric monoclonal antibody targeting the CD20 antigen on the B cell surface, has been successfully investigated in other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, ANCA-associated vasculitis, and mixed cryoglobulinemic syndrome. Preliminary experiences of RTX therapy in SS patients with or without a lymphoproliferative disorder suggest that SS patients with more residual exocrine gland function might better benefit from RTX. Efficacy of RTX in SS-associated B-cell lymphoma, mainly in low-grade salivary gland lymphomas, remains an open issue.

  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. Hyperthermia and fibrinolytic therapy do not improve the beneficial effect of radioimmunotherapy following cytoreductive surgery in rats with peritoneal carcinomatosis of colorectal origin.

    NARCIS (Netherlands)

    Aarts, F.; Hendriks, T.; Boerman, O.C.; Oyen, W.J.G.; Bleichrodt, R.P.

    2008-01-01

    BACKGROUND AND OBJECTIVE: Cytoreductive surgery (CS) and heated intraperitoneal chemotherapy (HIPEC) are standard treatment for peritoneal carcinomatosis (PC) of colorectal cancer. Previously, we demonstrated that preclinical radioimmunotherapy (RIT) adjuvant to surgery in PC is a good alternative

  12. Is rituximab effective for induction of remission in lupus nephritis?

    OpenAIRE

    Macarena Mac-Namara; Gabriel Rada

    2014-01-01

    La combinación de ciclofosfamida y corticoides constituye el tratamiento estándar en pacientes con nefritis lúpica con indicación de terapia inmunosupresora mayor. Sin embargo, se asocia a importantes efectos adversos, por lo que existe interés en otros inmunosupresores como rituximab. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 19 bases de datos, identificamos 5 revisiones sistemáticas que en conjunto incluyen 24 estudios. Realizamos una síntesis med...

  13. 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

  14. Development of 177Lu-DOTA-anti-CD20 for radioimmunotherapy

    International Nuclear Information System (INIS)

    Hassan Yousefnia; Amir Reza Jalilian; Ali Bahrami-Samani; Simindokht Shirvani-Arani; Mohammad Ghannadi-Maragheh; Azim Arbabi; Edalat Radfar

    2011-01-01

    Rituximab was successively labeled with 177 Lu-lutetium chloride. 177 Lu chloride was obtained by thermal neutron flux (4 x 1013 n cm -2 s -1 ) of natural Lu 2 O 3 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 CH 2 Cl 2 . 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 177 Lu-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)

  15. Radioimmunoimaging of human breast carcinoma xenografts in nude mouse model with 111In-labeled new monoclonal antibody EBA-1 and F(ab')2 fragments

    International Nuclear Information System (INIS)

    Yemul, Shrishailam; Leon, J.A.; Pozniakoff, Ted; Esser, P.D.; Estabrook, Alison; Met-Path Inc., Teterboro, NJ

    1993-01-01

    Radioimmunoimaging characteristics of a new monoclonal antibody EBA-1 and its F(ab') 2 fragments utilizing nu/nu mice bearing human breast carcinoma xenografts are described. 111 In-DPTA conjugates of EBA-1 localized with tumor/blood ratios of 0.99 ± 0.10 (P 2 radioconjugates at 48 h. These results suggest that EBA-1 and its F(ab') 2 might be useful reagents in radioimmunoimaging and radioimmunotherapy. (author)

  16. Bendamustine mitoxantrone and rituximab (BMR): a new effective regimen for refractory or relapsed indolent lymphomas.

    Science.gov (United States)

    Weide, Rudolf; Heymanns, Jochen; Gores, Annette; Köppler, Hubert

    2002-02-01

    Bendamustine (B) and mitoxantrone (M) have been shown to be potent cytotoxic drugs for the treatment of relapsed or refractory indolent lymphomas. The anti-CD20 monoclonal antibody rituximab (R) has produced an overall response rate (ORR) of 50% as a single agent in relapsed or refractory indolent lymphomas. We posed the question whether a combination of the above agents (BMR) could improve these results. This study was an open label, single center pilot study for patients with relapsed or refractory, CD20-positive (indolent) lymphoma or chronic lymphocytic leukaemia. The therapy consisted of bendamustine (80 mg/m2, day 1-3), mitoxantrone (10 mg/m2, day 1), rituximab (375 mg/m2, week 2-5). BM was repeated on day 36 or when the haematological parameters had recovered. The maximum therapy consisted of one BMR-cycle, followed by five BM courses. Treatment was stopped when the disease responded with PR/CR. During March 1999 and December 2000, 20 patients received the BMR-regimen (four secondary high grade lymphoma, 12 indolent lymphoma, four B-CLL). The median age of the patients was 67 years (range 36-82) and their performance status ranged from 0 to 3. Median number of previous treatment regimens was two (1-6). Of the lymphoma patients, 14 had stage IV disease, 1 stage III and 1 stage II. B-CLL patients were all Rai stage IV (Binet C). Overall response rate was 95% (19/20) with seven patients achieving a CR (35%) and 12 patients achieving a PR (60%). Median time to progression is 7 months (1-21) with a median observation time of 7 months (1-21). Response is still durable in 15/20 patients (75%) (1+ to 21+ months after therapy). Symptomatic, reversible grade three or four haematotoxicity occurred in 4/20 patients (20%). Non-symptomatic grade three or four haematotoxicity was seen in 9/20 patients (45%). No major non-haematological toxicity was observed. In conclusion, BMR is a well tolerated, very effective outpatient regimen of treatment for relapsed and refractory

  17. In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis.

    Science.gov (United States)

    Salinas-Jazmín, Nohemi; González-González, Edith; Vásquez-Bochm, Luz X; Pérez-Tapia, Sonia M; Velasco-Velázquez, Marco A

    2017-05-04

    Therapeutic monoclonal antibodies (mAbs) are relevant to the treatment of different pathologies, including cancers. The development of biosimilar mAbs by pharmaceutical companies is a market opportunity, but it is also a strategy to increase drug accessibility and reduce therapy-associated costs. The protocols detailed here describe the evaluation of target binding and CDC induction by rituximab in Daudi cells. These two functions require different structural regions of the antibody and are relevant to the clinical effect induced by rituximab. The protocols allow the side-to-side comparison of a reference rituximab and a marketed rituximab biosimilar. The evaluated products showed differences both in target binding and CDC induction, suggesting that there are underlying physicochemical differences and highlighting the need to analyze the impact of those differences in the clinical setting. The methods reported here constitute simple and inexpensive in vitro models for the evaluation of the activity of rituximab biosimilars. Thus, they can be useful during biosimilar development, as well as for quality control in biosimilar production. Furthermore, the presented methods can be extrapolated to other therapeutic mAbs.

  18. 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.

  19. Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome.

    Science.gov (United States)

    Webb, Hazel; Jaureguiberry, Graciana; Dufek, Stephanie; Tullus, Kjell; Bockenhauer, Detlef

    2016-04-01

    Steroid-sensitive nephrotic syndrome is the most common form of nephrotic syndrome in childhood, defined by the response to treatment with glucocorticoids with consequent remission. While most children eventually experience spontaneous resolution of the disease, some have a difficult course with frequent relapses or steroid dependence nephrotic syndrome (FRSDNS). The consequent steroid toxicity often prompts administration of other immunosuppressive drugs, traditionally cyclophosphamide. Recently, rituximab has been reported as effective in this disorder, but long-term experience is lacking. Retrospective note review of all children with FRSDNS treated with a first course of cyclophosphamide and/or rituximab in our center between December 2006 and April 2015. We reviewed time to first relapse after treatment, co-medications, and side effects. A total of 102 children were treated with cyclophosphamide (79) and/or rituximab (42). Of these, 34 received cyclophosphamide prior to rituximab. Median time to first relapse was 7 months after cyclophosphamide and 14 months after rituximab. Documented side effects of cyclophosphamide included neutropenia, hair loss, and hemorrhagic cystitis (1). Rituximab was associated with an allergic reaction at infusion in two patients. Rituximab was used in children with the most difficult to treat FRSDNS, yet was associated with longer remission time and less side effects than cyclophosphamide. A randomized controlled trial is needed to directly compare these drugs.

  20. Dosimetric aspects of radiolabeled antibodies for tumor therapy

    International Nuclear Information System (INIS)

    Humm, J.L.

    1986-01-01

    Radioimmunotherapy (RIT) is rapidly attracting interest as a potential new weapon in the arsenal for cancer therapy. This article concentrates on some of the dosimetric aspects affecting the potential success of RIT, and examines factors which influence the choice of a radiolabel for RIT. No radionuclide is likely to give an optimum tumor/nontumor insult for all tumor types; therefore, the concept of matching the source to tumor morphology is introduced. Lists of candidate radionuclides are given, classified according to the type of decay, range, and energy of the emission. The article examines how the choice of radionuclide for radiolabeling the antibody affects the local energy deposition in the tumor. Both the effect of tumor size on the energy absorbed fraction and the problem of antibody binding heterogeneity are discussed. The approach to RIT is to relate the choice of radionuclide to the physical properties of the tumor. 26 references

  1. Effectiveness of disease-modifying antirheumatic drug co-therapy with methotrexate and leflunomide in rituximab-treated rheumatoid arthritis patients: results of a 1-year follow-up study from the CERERRA collaboration

    DEFF Research Database (Denmark)

    Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny

    2012-01-01

    were treated with rituximab plus methotrexate, 177 with rituximab plus leflunomide and 505 with rituximab alone. Significantly more patients achieved a European League Against Rheumatism good response at 6 months when treated with rituximab plus leflunomide (29.1%) compared with rituximab plus...

  2. 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.

  3. EXPERIENCE OF TREATMENT WITH RITUXIMAB IN PATIENT WITH SYSTEMIC TYPE OF JUVENILE RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    K.B. Isaeva

    2009-01-01

    Full Text Available The article gives a case report on patient with severe systemic type of juvenile arthritis, refractory to treatment with classical immuno suppressants and blocker of tumor necrotizing factor Successive application of biological agent — rituximab was described. In 9 weeks, extra articular symptoms of disease and acute inflammatory lesions in joints were stopped, and functional activity of child increased. Presented case report demonstrates high effectiveness of rituximab: patient with severe systemic type of juvenile arthritis has clinical and laboratory remission of disease during 12 months.Key words: children, juvenile rheumatoid arthritis, rituximab.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2009;8(3:132-138

  4. 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.

  5. Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells

    International Nuclear Information System (INIS)

    Friesen, Claudia; Lubatschofski, Annelie; Debatin, Klaus-Michael; Kotzerke, Joerg; Buchmann, Inga; Reske, Sven N.

    2003-01-01

    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-x L , 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.)

  6. Evaluation of glycodendron and synthetically-modified dextran clearing agents for multi-step targeting of radioisotopes for molecular imaging and radioimmunotherapy

    Science.gov (United States)

    Cheal, Sarah M.; Yoo, Barney; Boughdad, Sarah; Punzalan, Blesida; Yang, Guangbin; Dilhas, Anna; Torchon, Geralda; Pu, Jun; Axworthy, Don B.; Zanzonico, Pat; Ouerfelli, Ouathek; Larson, Steven M.

    2014-01-01

    A series of N-acetylgalactosamine-dendrons (NAG-dendrons) and dextrans bearing biotin moieties were compared for their ability to complex with and sequester circulating bispecific anti-tumor antibody (scFv4) streptavidin (SA) fusion protein (scFv4-SA) in vivo, to improve tumor to normal tissue concentration ratios for targeted radioimmunotherapy and diagnosis. Specifically, a total of five NAG-dendrons employing a common synthetic scaffold structure containing 4, 8, 16, or 32 carbohydrate residues and a single biotin moiety were prepared (NAGB), and for comparative purposes, a biotinylated-dextran with average molecular weight (MW) of 500 kD was synthesized from amino-dextran (DEXB). One of the NAGB compounds, CA16, has been investigated in humans; our aim was to determine if other NAGB analogs (e.g. CA8 or CA4) were bioequivalent to CA16 and/or better suited as MST reagents. In vivo studies included dynamic positron-emission tomography (PET) imaging of 124I-labelled-scFv4-SA clearance and dual-label biodistribution studies following multi-step targeting (MST) directed at subcutaneous (s.c.) human colon adenocarcinoma xenografts in mice. The MST protocol consists of three injections: first, a bispecific antibody specific for an anti-tumor associated glycoprotein (TAG-72) single chain genetically-fused with SA (scFv4-SA); second, CA16 or other clearing agent; and third, radiolabeled biotin. We observed using PET imaging of 124I-labelled-scFv4-SA clearance that the spatial arrangement of ligands conjugated to NAG (i.e. biotin) can impact the binding to antibody in circulation and subsequent liver uptake of the NAG-antibody complex. Also, NAGB CA32-LC or CA16-LC can be utilized during MST to achieve comparable tumor- to-blood ratios and absolute tumor uptake seen previously with CA16. Finally, DEXB was equally effective as NAGB CA32-LC at lowering scFv4-SA in circulation, but at the expense of reducing absolute tumor uptake of radiolabeled biotin. PMID:24219178

  7. 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)

    Gruenberg, Juergen; Lindenblatt, Dennis; Cohrs, Susan; Fischer, Eliane; Dorrer, Holger; Zhernosekov, Konstantin; Koester, Ulli; Tuerler, Andreas; Schibli, Roger

    2014-01-01

    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 67 Cu- and 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 177 Lu and the potential alternative 161 Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched 160 Gd targets. 161 Tb and 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 177 Lu- and 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. 177 Lu- and 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. 161 Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the 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 161 Tb-DOTA-chCE7 than the 177 Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM 161 Tb RIT is more effective compared to 177 Lu RIT in ovarian cancer xenografts. These results suggest that 161 Tb is a promising candidate for future clinical

  8. 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.

  9. 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

    2016-01-01

    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...... further at weeks 24 and 52. Conclusions. This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients...

  10. A series of patients with minimal change nephropathy treated with rituximab during adolescence and adulthood

    NARCIS (Netherlands)

    M.J. Dekkers (Marinus J.); J. Groothoff (Jaap); R. Zietse (Bob); M.G.H. Betjes (Michiel)

    2015-01-01

    markdownabstract__Background:__ The treatment of immune suppression dependent minimal change nephropathy (MCN) can be challenging and frequently leads to serious complications. In paediatric patients, successful treatment with rituximab is described in steroid-dependent MCN. There is limited

  11. 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.

  12. Four cases of recalcitrant pemphigus vulgaris salvaged with rituximab

    Directory of Open Access Journals (Sweden)

    Samyak Ganjre

    2017-01-01

    Full Text Available Although the long-term use of immunosuppressives – supplemented with more aggressive treatments such as immunoadsorption, intravenous immunoglobulins, or plasmapheresis in recalcitrant cases has dramatically improved the prognosis of pemphigus vulgaris, opportunistic infections secondary to immunosuppression continue to cause significant mortality. We report four cases– three old ones, who had accumulated significant morbidities over their disease duration ranging from 5 to 10 years, and the fourth, a teenage female intolerant to corticosteroids and idiosyncratic to methotrexate– who achieved complete remission on administration of rituximab by the lymphoma protocol. One of the old cases who had recalcitrant mucositis experienced its complete subsidence without any adjuvant whatsoever. All continue to remain asymptomatic for 11–20 months. None had infusion reactions or any delayed side effects.

  13. Rituximab in the treatment of refractory pemphigus vulgaris

    OpenAIRE

    Fernandes, I.; Sanches, M.; Velho, G.; Selores, M.

    2012-01-01

    O pênfigo vulgar é uma doença bolhosa auto-imune rara, que atinge a pele e as mucosas. Geralmente tem um curso clínico severo, sendo necessário o recurso a terapêutica prolongada com corticóides sistémicos e outros fármacos imunossupressores, que podem conduzir a efeitos adversos graves. O rituximab é um anticorpo monoclo- nal quimérico dirigido ao antigénio CD20, expresso pelos linfócitos B. Recentemente, têm surgido alguns estudos que documentam o seu sucesso terapêutico no tratamento de pê...

  14. Rituximab in the treatment of shrinking lung syndrome in systemic lupus erythematosus.

    Science.gov (United States)

    Peñacoba Toribio, Patricia; Córica Albani, María Emilia; Mayos Pérez, Mercedes; Rodríguez de la Serna, Arturo

    2014-01-01

    Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus. We report the case of a patient with non-responding SLS (neither to glucocorticoids nor immunosupresors), who showed remarkable improvement after the onset of treatment with rituximab. Although there is a little evidence, treatment with rituximab could be proposed in SLS when classical treatment fails. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  15. 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.

  16. A Case of Rituximab-Induced Necrotizing Fasciitis and a Review of the Literature

    OpenAIRE

    Abdulkareem, Abdullateef; D’Souza, Ryan S.; Shogbesan, Oluwaseun; Donato, Anthony

    2017-01-01

    Necrotizing fasciitis is a fulminant soft tissue infection characterized by rapid progression and high mortality. Rituximab is a generally well-tolerated immunosuppresive medication used for B-cell malignancies and some rheumatological disorders. We report a case of a 69-year-old male with chronic lymphocytic leukemia who suffered necrotizing fasciitis of his left lower extremity secondary to Clostridium septicum 7 weeks after treatment with rituximab. Despite immediate intravenous antimicrob...

  17. Cutaneous improvement in refractory adult and juvenile dermatomyositis after treatment with rituximab.

    Science.gov (United States)

    Aggarwal, Rohit; Loganathan, Priyadarshini; Koontz, Diane; Qi, Zengbiao; Reed, Ann M; Oddis, Chester V

    2017-02-01

    The aim was to assess the efficacy of rituximab for the cutaneous manifestations of adult DM and JDM. Patients with refractory adult DM (n = 72) and JDM (n = 48) were treated with rituximab in a randomized placebo-phase-controlled trial [either rituximab early drug (week 0/1) or rituximab late arms (week 8/9), such that all subjects received study drug]. Stable concomitant therapy was allowed. Cutaneous disease activity was assessed using the Myositis Disease Activity Assessment Tool, which grades cutaneous disease activity on a visual analog scale. A myositis damage assessment tool, termed the Myositis Damage Index, was used to assess cutaneous damage. Improvement post-rituximab was evaluated in individual rashes as well as in cutaneous disease activity and damage scores. The χ 2 test, Student's paired t-test and Wilcoxon test were used for analysis. There were significant improvements in cutaneous disease activity from baseline to the end of the trial after rituximab administration in both adult DM and JDM subsets. The cutaneous visual analog scale activity improved in adult DM (3.22-1.72, P = 0.0002) and JDM (3.26-1.56, P <0.0001), with erythroderma, erythematous rashes without secondary changes of ulceration or necrosis, heliotrope, Gottron sign and papules improving most significantly. Adult DM subjects receiving rituximab earlier in the trial demonstrated a trend for faster cutaneous response (20% relative improvement from baseline) compared with those receiving B cell depletion later (P = 0.052). Refractory skin rashes in adult DM and JDM showed improvement after the addition of rituximab to the standard therapy in a clinical trial. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab.

    Science.gov (United States)

    Mahévas, Matthieu; Michel, Marc; Vingert, Benoit; Moroch, Julien; Boutboul, David; Audia, Sylvain; Cagnard, Nicolas; Ripa, Julie; Menard, Cédric; Tarte, Karin; Mégret, Jérôme; Le Gallou, Simon; Patin, Pauline; Thai, Lan; Galicier, Lionel; Bonnotte, Bernard; Godeau, Bertrand; Noizat-Pirenne, France; Weill, Jean-Claude; Reynaud, Claude-Agnès

    2015-08-01

    Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. [Radiolabeled antibodies for cancer treatment].

    Science.gov (United States)

    Barbet, Jacques; Chatal, Jean-François; Kraeber-Bodéré, Françoise

    2009-12-01

    The first treatment ever by radio-immunotherapy (RIT) was performed by William H. Beierwaltes in 1951 and was a success. Fifty years later, the main question is to find ways of extending the success of radiolabelled anti-CD20 antibodies in indolent non-Hodgkin's lymphoma to other forms of cancer. Solid tumours are much more radioresistant than lymphomas, but they respond to RIT if the lesions are small. Clinical situations of residual or minimal disease are thus the most likely to benefit from RIT in the adjuvant or consolidation settings. For disseminated disease, like leukemias or myelomas, the problem is different: beta- particles emitted by the radioactive atoms classically used for cancer treatment (iodine-131 or yttrium-90) disperse their energy in large volumes (ranges 1 mm to 1 cm) and are not very effective against isolated cells. Advances in RIT progress in two directions. One is the development of pretargeting strategies in which the antibody is not labelled but used to provide binding sites to small molecular weight radioactivity vectors (biotin, haptens). These techniques have been shown to increase tumour to non-target uptake ratios and anti-tumour efficacy has been demonstrated in the clinic. The other approach is the use of radionuclides adapted to the various clinical situations. Lutetium-177 or copper-67, because of the lower energy of their emission, their relatively long half-life and good gamma emission, may significantly improve RIT efficacy and acceptability. Beyond that, radionuclides emitting particles such as alpha particles or Auger electrons, much more efficient to kill isolated tumour cells, are being tested for RIT in the clinic. Finally, RIT should be integrated with other cancer treatment approaches in multimodality protocols. Thus RIT, now a mature technology, should enter a phase of well designed and focused clinical developments that may be expected to afford significant therapeutic advances.

  20. Evaluation of a glycoengineered monoclonal antibody via LC-MS analysis in combination with multiple enzymatic digestion

    Science.gov (United States)

    Liu, Renpeng; Giddens, John; McClung, Colleen M.; Magnelli, Paula E.; Wang, Lai-Xi; Guthrie, Ellen P.

    2016-01-01

    ABSTRACT Glycosylation affects the efficacy, safety and pharmacokinetics/pharmacodynamics properties of therapeutic monoclonal antibodies (mAbs), and glycoengineering is now being used to produce mAbs with improved efficacy. In this work, a glycoengineered version of rituximab was produced by chemoenzymatic modification to generate human-like N-glycosylation with α 2,6 linked sialic acid. This modified rituximab was comprehensively characterized by liquid chromatography-mass spectrometry and compared to commercially available rituximab. As anticipated, the majority of N-glycans were converted to α 2,6 linked sialic acid, in contrast to CHO-produced rituximab, which only contains α 2,3 linked sialic acid. Typical posttranslational modifications, such as pyro-glutamic acid formation at the N-terminus, oxidation at methionine, deamidation at asparagine, and disulfide linkages were also characterized in both the commercial and glycoengineered mAbs using multiple enzymatic digestion and mass spectrometric analysis. The comparative study reveals that the glycoengineering approach does not cause any additional posttranslational modifications in the antibody except the specific transformation of the glycoforms, demonstrating the mildness and efficiency of the chemoenzymatic approach for glycoengineering of therapeutic antibodies. PMID:26514686

  1. Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model

    Science.gov (United States)

    Kenoyer, Aimee L.; Bäck, Tom; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Park, Steven I.; Frayo, Shani; Axtman, Amanda; Orgun, Nural; Orozco, Johnnie; Shenoi, Jaideep; Lin, Yukang; Gopal, Ajay K.; Green, Damian J.; Appelbaum, Frederick R.; Press, Oliver W.

    2011-01-01

    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. 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 more than 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 acute myeloid leukemia. PMID:21613259

  2. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

    Directory of Open Access Journals (Sweden)

    Kwon Joong Yong

    2016-05-01

    Full Text Available 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.

  3. 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.

  4. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group.

    Science.gov (United States)

    Chatal, Jean-François; Campion, Loïc; Kraeber-Bodéré, Françoise; Bardet, Stephane; Vuillez, Jean-Philippe; Charbonnel, Bernard; Rohmer, Vincent; Chang, Chien-Hsing; Sharkey, Robert M; Goldenberg, David M; Barbet, Jacques

    2006-04-10

    No effective therapy is currently available for the management of patients with metastatic medullary thyroid carcinoma (MTC). The efficacy of pretargeted radioimmunotherapy (pRAIT) with bispecific monoclonal antibody (BsMAb) and a iodine-131 (131I) -labeled bivalent hapten is evaluated. Twenty-nine patients with advanced, progressive MTC, as documented by short serum calcitonin doubling times (Ct DTs), received an anti-carcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) -indium BsMAb, followed 4 days later by a 131I-labeled bivalent hapten. Overall survival (OS) was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators. OS was significantly longer in high-risk, treated patients (Ct DT < 2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; P < .030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in CtDT, experienced significantly longer survival than nonresponders (median OS, 159 v 109 months; P < .035) and untreated patients (median OS, 159 v 61 months; P < .010). Treated patients with bone/bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% v 14%; P < .023). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread. pRAIT against CEA induced long-term disease stabilization and a significantly longer survival in high-risk patients with Ct DTs less than 2 years, compared with similarly high-risk, untreated patients. Ct DT and bone-marrow involvement appear to be prognostic indicators in MTC patients who undergo pRAIT.

  5. 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.

  6. Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment.

    Science.gov (United States)

    Stasi, Cristina; Triboli, Elisa; Arena, Umberto; Urraro, Teresa; Petrarca, Antonio; Gragnani, Laura; Laffi, Giacomo; Zignego, Anna Linda

    2014-01-24

    Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion.

  7. 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

    , 25 patients had been treated with high-dose IgG, and in 16 patients a splenectomy had been performed. Sixteen patients had been treated with azathioprine. Other treatments included, e.g., cyclosporine, danazol, cyclophosphamide, vincristine, interferon, and dexamethasone. The patients were treated...

  8. Risk of hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients with undetectable serum HBV DNA after treatment with rituximab for lymphoma: a meta-analysis.

    Science.gov (United States)

    Tang, Zilin; Li, Xiaodong; Wu, Shunquan; Liu, Yan; Qiao, Yan; Xu, Dongping; Li, Jin

    2017-09-01

    Hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (HBcAb)-positive patients with undetectable serum hepatitis B virus (HBV) DNA have experienced and resolved hepatitis B virus (HBV) infection. Lymphoma patients with resolved HBV infection have high risk of HBV reactivation when treated with robust immunosuppressive agents, but the reported rate varies extensively between different studies. This study aims to estimate the risk of HBV reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab-containing chemotherapy for lymphoma. Databases were searched for papers published in English until 8 August 2016. The pooled risk of HBV reactivation was estimated using a random-effects model. Data from 15 studies were retrieved, including a total of 1312 HBsAg-negative/HBcAb-positive lymphoma patients treated with rituximab-containing chemotherapy. The results revealed HBV reactivation rate of 9.0 % [95 % confidence interval (CI) 0.05-0.15]. In subgroup analysis, the reactivation rates for prospective and retrospective studies were 17 % (I 2  = 87.3 %; 95 % 0.08-0.39, p HBcAb-positive patients with rituximab treatment for lymphoma. Prophylactic use of anti-HBV agents should be seriously considered for such patients.

  9. 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. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Autoimmune polyendocrine syndrome type 1: Utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab.

    Science.gov (United States)

    Popler, Jonathan; Alimohammadi, Mohammad; Kämpe, Olle; Dalin, Frida; Dishop, Megan K; Barker, Jennifer M; Moriarty-Kelsey, Margaret; Soep, Jennifer B; Deterding, Robin R

    2012-01-01

    Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECD) is a disorder caused by mutations in the autoimmune regulator (AIRE) gene. In some APS-1 patients, significant pulmonary disease is observed. Autoantibodies directed against the potassium channel regulatory protein (KCNRG), found in epithelial cells of terminal bronchioles, have been suggested as a marker for pulmonary disease in APS-1 patients. We report two patients with APS-1; one with and one without lung disease. Patient 1 had multiple admissions for pneumonia and respiratory insufficiency, required non-invasive ventilation, and had findings of bronchiectasis on thoracic imaging and significant lymphocytic infiltrates of the airways on lung biopsy. To verify the autoimmune cause of pulmonary symptoms APS-1 patients, both were tested in a blinded manner for the presence of autoantibodies to KCNRG in serum. We found that only Patient 1 had autoantibodies present. Additionally, Patient 1 had progressive disease despite treatment with several immunomodulating agents, including corticosteroids, azathioprine, and mycophenolate. Patient 1 had a lung biopsy performed which was consistent with B cell lymphocytic aggregates. Rituximab treatment was initiated with apparent good response. This report illustrates the practical use of KCNRG autoantibodies to identify APS-1 patients with pulmonary risk and the successful use of the monoclonal antibody, Rituximab, to treat pulmonary disease in APS-1 patients. Copyright © 2011 Wiley Periodicals, Inc.

  11. Cold Autoimmune Hemolytic Anemia due to High-grade non Hodgkin's B cell Lymphoma with Weak Response to Rituximab and Chemotherapy Regimens.

    Science.gov (United States)

    Nazel Khosroshahi, Behzad; Jafari, Mohammad; Vazini, Hossein; Ahmadi, Alireza; Shams, Keivan; Kholoujini, Mahdi

    2015-07-01

    Autoimmune hemolytic anemia (AIHA) is characterized by shortening of red blood cell (RBC) survival and the presence of autoantibodies directed against autologous RBCs. Approximately 20% of autoimmune hemolytic anemia cases are associated with cold-reactive antibody. About half of patients with AIHA have no underlying associated disease; these cases are termed primary or idiopathic. Secondary cases are associated with underlying diseases or with certain drugs. We report herein a rare case of cold autoimmiune hemolytic anemia due to high-grade non-Hodgkin's lymphoma of B-cell type with weak response to rituximab and chemotherapy regimens. For treatment B cell lymphoma, Due to lack of treatment response, we used chemotherapy regimens including R- CHOP for the first time, and then Hyper CVAD, R- ICE and ESHAP were administered, respectively. For treatment of autoimmune hemolytic anemia, we have used the corticosteroid, rituximab, plasmapheresis and blood transfusion and splenectomy. In spite of all attempts, the patient died of anemia and aggressive lymphoma nine months after diagnosis. To our knowledge, this is a rare report from cold autoimmune hemolytic anemia in combination with high-grade non-Hodgkin's lymphoma of B-cell type that is refractory to conventional therapies.

  12. Radioimmunotherapy with Y-90-epratuzumab in patients with previously treated B-cell lymphoma. A fractionated dose-escalation study

    International Nuclear Information System (INIS)

    Linden, O.; Cavallin-Stahl, E.; Tennvall, J.; Hindorf, C.; Olsson, T.; Strand, S.E.; Stenberg, L.; Wingardh, K.

    2002-01-01

    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 90 Y-labelled epratuzumab possible. Materials and Methods: Patients with previously treated B-cell lymphoma received increasing number (2-4) of weekly infusions of 90 Y-epratuzumab. Patients received either 185 MBq/m 2 per infusion (group A), or, if they had a history of high-dose chemotherapy with stem-cell rescue, 92.5 MBq/m 2 per infusion (group B). The first infusion included 150 MBq of 111 Indium 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/m 2 . 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

  13. Preparation and biological evaluation of radiolabelled antibodies with selected carbohydrate modifications

    International Nuclear Information System (INIS)

    Qi, P.; Koganty, R.R.; Selvaraj, S.

    1993-01-01

    Two carbohydrates, N-acetylgalactosamine (GalNAc) and galactose-β-1,3-GalNAc have been attached to human IgG (hIgG) by a novel linking reagent, hexafluoroglutaric acid dimethyl ester. Fluorine-19 NMR signals were used for the determination of the conjugation ratio. A third carbohydrate, sialic acid, was conjugated via reductive amination and the conjugation ratio determined by a resorcinol assay. The biological behaviour of these radiodinated antibodies with carbohydrate modification in normal mice indicates an enhanced liver uptake at 15 min post-injection with an associated change in circulating blood levels occurs for the galactose-based hIgG preparations. However, no significant differences in the biodistribution were observed for the sialic acid conjugate. These studies confirm the potential of carbohydrate-antibody conjugation for modifying the behaviour of antibodies in immunoscintigraphy and radioimmunotherapy. (author)

  14. A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab.

    Science.gov (United States)

    Ahmed, A Razzaque; Shetty, Shawn

    2015-04-01

    Approximately 500 treatment recalcitrant pemphigus vulgaris patients have been treated with rituximab. They were treated according to the lymphoma protocol (N=224) or rheumatoid arthritis protocol (RAP) (N=209) patients. Others were treated with modifications or combinations of the two. The mean duration of follow-up with the lymphoma protocol was 28.9months and 21.9 in the rheumatoid arthritis protocol. The majority of the patients received corticosteroids and immunosuppressive therapy before, during, and after rituximab therapy. A clinical remission on therapy was observed in 90%-95% of patients within less than six weeks. A complete resolution occurred within three to four months. A small percentage of patients were able to stay in clinical remission without the need for additional systemic therapy. The incidence of relapse was at least 50%. The number of patients who required additional rituximab was 60% to 90%. A majority of patients in clinical remission post-rituximab therapy, were still on CS and ISA, albeit at lower doses. Serious adverse events were reported in a mean of five patients (range 2-9), the most important was infection and frequently resulting in septicemia. The mortality rate related to rituximab was a mean of 2 patients (range 1-3). Hence, the preliminary conclusions that can be drawn are that rituximab is an excellent agent to induce early remission. The protocols that were used were not ideal for producing a prolonged and sustained remission without additional therapy. The advantages and specificity of targeting B-cells demonstrate that rituximab is one of the best biological agents, currently available for treating recalcitrant pemphigus. Its further use is encouraged. Future research needs to focus on modifying, improving and possibly adding additional agents, so that prolonged and sustained remissions can be obtained by its use. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Rituximab in the treatment of follicular lymphoma: the future of biosimilars in the evolving therapeutic landscape

    Directory of Open Access Journals (Sweden)

    Subramanian J

    2017-04-01

    Full Text Available Janakiraman Subramanian,1 Jamie Cavenagh,2 Bhardwaj Desai,3 Ira Jacobs4 1Division of Medical Oncology, Saint Luke’s Cancer Institute, Kansas City, MO, USA; 2Department of Haematology, St. Bartholomew’s Hospital, London, UK; 3Prospect Heights, IL, 4Global Established Pharma, Pfizer Inc., New York, NY, USA Abstract: Follicular lymphoma (FL is the second most common type of non-Hodgkin’s lymphoma. FL is an incurable disease with treatment options ranging from a “watch-and-wait” approach to localized therapy with radiation or systemic therapy with rituximab in combination with chemotherapy regimens. This review summarizes the role of rituximab across the spectrum of FL treatment and the evolving therapeutic landscape with the emergence of novel agents currently in clinical development. Despite the prospect of new agents on the horizon, it is widely accepted that rituximab will remain as the cornerstone of therapy because of its established long-term efficacy. Many biologics, including rituximab, have lost exclusivity of composition-of-matter patent or will do so in the next few years, which is a concern for patients and physicians alike. Moreover, access to rituximab is challenging, particularly in countries with restricted resources. Together, these concerns have fueled the development of safe and effective biosimilars. The term “biosimilar” refers to a biologic product that is highly similar to an approved reference (or originator product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences in purity, potency, or safety. Biosimilars are developed to treat the same condition(s using the same treatment regimens as an approved reference biologic, and have the potential to increase access to more affordable treatment of FL. Herein, we also discuss the potential benefits of eagerly awaited rituximab biosimilars, which may mitigate the impact of the lack of

  16. Anti CD20 (Rituximab therapy in refractory pediatric rheumatic diseases

    Directory of Open Access Journals (Sweden)

    Joel Reis

    2016-01-01

    Full Text Available Objectives: We aim to report the efficacy and safety of rituximab (RTX in patients diagnosed with juvenile systemic lupus erythematosus (JSLE or juvenile idiopathic arthritis (JIA refractory to conventional treatment. Methods: A retrospective review was made of all medical records of patients with JSLE or JIA treated with RTX between January 2009 and January 2015 in the Pediatric Rheumatology Unit of a central hospital. Results: Five patients, 4 with JSLE and 1 with extended oligoarticular JIA, received 10 cycles of RTX (23 infusions. The scheme of RTX frequently used was 750 mg/m2 two weeks apart. The median follow-up time after receiving the first cycle of RTX was 24 months (12 – 70. The four patients with JSLE were female (three caucasian and one black. The patient with JIA was a caucasian male. The median age at diagnosis was 10 years (16 months – 17years. The median evolution time until receiving RTX was 6 years (5 months – 15 years. Refractory class IV lupus nephritis was the most common indication for receiving RTX. Previous treatment to RTX included nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, immunosuppressive drugs and corticosteroids in all patients and anti-TNFα (etanercept in the patient with JIA. It was possible to reduce the mean oral corticosteroid dose after RTX, ranging from 23 mg/day (20-25mg/day before RTX to 11 mg/day (0–20 mg/day at the last evaluation. Disease activity before RTX and at last evaluation also improved. The SLEDAI score, for JSLE, decreased from a median of 15, 5 (11 – 18 to 3 (0 – 6, and the JADAS-27 score, for JIA, also diminished from 40.4 to 3.5. Adverse events occurred in 2 patients, including delayed second dose after the diagnosis of cryptococcosis and respiratory tract infection with concomitant hypogammaglobulinemia needing of immunoglobulin replacement and antibiotic therapy. Conclusions: Rituximab might have a role in the treatment of JSLE and JIA

  17. Absolute lymphocyte count predicts response to rituximab-containing salvage treatment for relapsed/refractory B-cell non-Hodgkin's lymphoma with prior rituximab exposure

    Directory of Open Access Journals (Sweden)

    Man-Hsin Hung

    2013-04-01

    Conclusion: Our study results show that for patients with relapsed/refractory B-cell NHL, rituximab-containing salvage treatment is feasible and generally tolerable. A high ALC-R value was significantly associated with a better response to this treatment.

  18. Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL.

    Science.gov (United States)

    Murawski, N; Pfreundschuh, M; Zeynalova, S; Poeschel, V; Hänel, M; Held, G; Schmitz, N; Viardot, A; Schmidt, C; Hallek, M; Witzens-Harig, M; Trümper, L; Rixecker, T; Zwick, C

    2014-09-01

    To improve outcome of elderly patients with diffuse large B-cell lymphoma, dose-dense rituximab was evaluated in the prospective DENSE-R-CHOP-14 trial. Rituximab (375 mg/m(2)) was given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99 together with six CHOP-14 cycles. Results were to be compared with patients who had received the same chemotherapy in combination with eight 2-week applications of rituximab in RICOVER-60. One hundred twenty-four patients are assessable. Dose-dense rituximab resulted in considerably higher serum levels during the first 50 days of treatment, but rituximab exposure time was not prolonged. Grade 3 and 4 infections were exceptionally high in the first 20 patients without anti-infective prophylaxis, but decreased after introduction of prophylaxis with aciclovir and cotrimoxazole in the remaining 104 patients (from 13% to 6% per cycle and from 35% to 18% per patient; P = 0.007 and P = 0.125, respectively). Patients with international prognostic index = 3-5 had higher complete response/complete response unconfirmed rates (82% versus 68%; P = 0.033) than in the respective RICOVER-60 population, but this did not translate into better long-term outcome, even though male hazard was decreased (event-free survival: from 1.5 to 1.1; progression-free survival: from 1.7 to 1.1; overall survival: from 1.4 to 1.0). Dose-dense rituximab achieved higher rituximab serum levels, but was not more effective than eight 2-week applications in the historical control population, even though minor improvements in poor-prognosis and male patients cannot be excluded. The increased, though manageable toxicity, precludes its use in routine practice. Our results strongly support anti-infective prophylaxis with aciclovir and cotrimoxazole for all patients receiving R-CHOP. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial.

    Science.gov (United States)

    Davies, Andrew; Merli, Francesco; Mihaljević, Biljana; Mercadal, Santiago; Siritanaratkul, Noppadol; Solal-Céligny, Philippe; Boehnke, Axel; Berge, Claude; Genevray, Magali; Zharkov, Artem; Dixon, Mark; Brewster, Michael; Barrett, Martin; MacDonald, David

    2017-06-01

    Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data. SABRINA is a two-stage, randomised, open-label phase 3 study at 113 centres in 30 countries. Eligible patients were aged 18 years or older and had histologically confirmed, previously untreated, CD20-positive grade 1, 2, or 3a follicular lymphoma; Eastern Co-operative Oncology Group performance statuses of 0-2; bidimensionally measurable disease (by CT or MRI); life expectancy of 6 months or more; adequate haematological function for 28 days or more; and one or more symptoms requiring treatment according to the Groupe d'Etudes des Lymphomes Folliculaires criteria. Patients were randomly assigned (1:1) by investigators or members of the research team via a dynamic randomisation algorithm to 375 mg/m 2 intravenous rituximab or 1400 mg subcutaneous rituximab, plus chemotherapy (six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or eight cycles of cyclophosphamide, vincristine, and prednisone [CVP]), every 3 weeks during induction, then rituximab maintenance every 8 weeks. Randomisation was stratified by selected chemotherapy, Follicular Lymphoma International Prognostic Index, and region. The primary endpoint for stage 2 was overall response (ie, confirmed complete response, unconfirmed complete response, and partial response) at the end of induction. Efficacy analyses were done in the intention-to-treat population. Pooled data from stages 1 and 2 are reported on the basis of the clinical cutoff date of the last patient completing the maintenance phase of the study. This trial is registered with ClinicalTrials.gov, number NCT01200758; new

  20. 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.

  1. A Case of Subacute Cutaneous Lupus Erythematosus in a Patient with Mixed Connective Tissue Disease: Successful Treatment with Plasmapheresis and Rituximab

    Directory of Open Access Journals (Sweden)

    M. Fantò

    2013-01-01

    Full Text Available A 30-year-old woman affected by Mixed Connective Tissue Disease with scleroderma spectrum developed a facial eruption, a clinical and histological characteristic of subacute cutaneous lupus erythematosus (SCLE. Speckled anti-nuclear antibodies, high-titer anti-ribonucleoprotein1, anti-Sm, anti-Cardiolipin (aCL IgG/IgM, and anti-Ro/SSA antibodies were positive. SCLE was resistant to Azathioprine, Hydroxychloroquine, and Methotrexate while Mycophenolate Mofetil was suspended due to side effects. Subsequently, the patient was treated with three cycles of therapeutic plasma exchange (TPE followed, one month after the last TPE, by the anti-CD20 antibody Rituximab (RTX (375 mg/m2 weekly for 4 weeks. Eight and 16 months later the patient received other two TPE and RTX cycles, respectively. This therapeutic approach has allowed to obtain a complete skin healing persistent even after 8-month follow-up. Moreover, mitigation of Raynaud's phenomenon, resolution of alopecia, and a decline of aCL IgG/IgM and anti-Ro/SSA antibodies were observed.

  2. Remission Achieved in Refractory Advanced Takayasu Arteritis Using Rituximab

    Directory of Open Access Journals (Sweden)

    D. Ernst

    2012-01-01

    Full Text Available A 25-year-old patient was referred due to subclavian stenosis, identified on echocardiography. She presented with exertional dizziness and dyspnoea. Questioning revealed bilateral arm claudication. Examination demonstrated an absent right ulnar pulse and asymmetrical brachial blood pressure. Bruits were evident over both common carotid arteries. Doppler ultrasound and MRI angiograms revealed occlusion or stenosis in multiple large arteries. Takayasu arteritis (TA was diagnosed and induction therapy commenced: 1 mg/kg oral prednisolone and 500 mg/m2 intravenous cyclophosphamide (CYC. Attempts to reduce prednisolone below 15 mg/d proved impossible due to recurring disease activity. Adjuvant azathioprine 100 mg/d was subsequently added. Several weeks later, the patient was admitted with a left homonymous hemianopia. The culprit lesion in the right carotid artery was surgically managed and the patient discharged on azathioprine 150 mg/d and prednisolone 30 mg/d. Despite this, deteriorating exertional dyspnoea and angina pectoris were reported. Reimaging confirmed new stenosis in the right pulmonary artery. Surgical treatment proved infeasible. Given evidence of refractory disease activity on maximal standard therapy, we initiated rituximab, based on recently reported B-cell activity in TA.

  3. Rituximab treatment for relapsed opsoclonus-myoclonus syndrome.

    Science.gov (United States)

    Toyoshima, Daisaku; Morisada, Naoya; Takami, Yuichi; Kidokoro, Hiroyuki; Nishiyama, Masahiro; Nakagawa, Taku; Ninchoji, Takeshi; Nozu, Kandai; Takeshima, Yasuhiro; Takada, Satoshi; Nishio, Hisahide; Iijima, Kazumoto

    2016-03-01

    Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder that is associated with paraneoplastic diseases. Because OMS can frequently relapse, patients may be inflicted with neurological problems for a long time. Recently, rituximab (RTX) was introduced as a drug to treat OMS. To assess RTX treatment, we studied a patient who experienced recurrence of OMS. A 2-year-old Japanese boy, who had left adrenal neuroblastoma, suddenly showed OMS symptoms, including ataxia and opsoclonus. Surgical resection of the tumor and subsequent steroid therapy ameliorated his symptoms. When OMS relapsed during the time when prednisolone was reduced, he was treated with full-dose RTX therapy (375 mg/m2/week) for 4 consecutive weeks. However, 1year later, he presented again with OMS symptoms. This time, we only administered an additional single dose of RTX treatment (375 mg/m2), allowing remission of OMS symptoms. During 2 years after the additional RTX treatment, OMS symptoms did not appear, even when prednisolone was reduced. He had no adverse events associated with RTX during the whole treatment period. An additional single-dose RTX therapy might be effective for relapsed OMS patients who were previously treated with full-dose RTX therapy. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  4. 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.

  5. Risks and Benefits of Rituximab in the Treatment of Hashimoto Encephalopathy in Children: Two Case Reports and a Mini Review.

    Science.gov (United States)

    Maas, Annemieke; Braun, Kees P J; Geleijns, Karin; Jansen, Floor E; van Royen-Kerkhof, Annet

    2017-01-01

    Hashimoto encephalopathy is a rare condition, characterized by the association of encephalopathy with a variety of neurological symptoms and autoantibodies to the thyroid gland. Its etiology is unknown, and symptoms are usually treated with immune suppressive therapy, e.g., high doses of corticosteroids. Here, we report the long-term outcome in two steroid-refractory adolescents with Hashimoto encephalopathy who were treated with rituximab, a monoclonal antibody directed against CD20. In addition, we reviewed the literature regarding treatment strategies in Hashimoto encephalopathy. Anti-B-cell therapy can be of value in the treatment of Hashimoto encephalopathy, especially in steroid refractory cases, but side effects due to low levels of immunoglobulins warrant careful monitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Activities of AREVA Med. Extraction and purification of the 212Pb isotope from Thorium for radio-immunotherapy

    International Nuclear Information System (INIS)

    Miquel, Pierre

    2012-01-01

    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

  7. Rituximab as maintenance therapy for ANCA associated vasculitis: how, when and why?

    Science.gov (United States)

    Alba, Marco A; Flores-Suárez, Luis Felipe

    2016-01-01

    ANCA-associated vasculitides (AAV) are chronic autoimmune diseases characterized by inflammation and destruction of small vessels. Rituximab is now licensed for use as a remission-induction agent in the treatment of these disorders. During recent years, several non-controlled studies have suggested that rituximab may be of value in maintaining disease remission in AAV. In these series, 3 techniques have been tried: "watch-and-wait", repeated cycles in fixed intervals, or administration based on proposed biomarkers. More importantly, the results of the MAINRITSAN trial showed that this anti-CD20 agent is superior to azathioprine for preventing major relapses in AAV. This review summarizes current information regarding the effectiveness, timing, dosing, duration and safety of rituximab as a valid option for remission maintenance. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  8. A Case of Rituximab-Induced Necrotizing Fasciitis and a Review of the Literature.

    Science.gov (United States)

    Abdulkareem, Abdullateef; D'Souza, Ryan S; Shogbesan, Oluwaseun; Donato, Anthony

    2017-01-01

    Necrotizing fasciitis is a fulminant soft tissue infection characterized by rapid progression and high mortality. Rituximab is a generally well-tolerated immunosuppresive medication used for B-cell malignancies and some rheumatological disorders. We report a case of a 69-year-old male with chronic lymphocytic leukemia who suffered necrotizing fasciitis of his left lower extremity secondary to Clostridium septicum 7 weeks after treatment with rituximab. Despite immediate intravenous antimicrobial therapy and emergent fasciotomy with extensive debridement, his hospital course was complicated by septic shock and he required an above-the-knee amputation. Physicians need to be aware of the possibility of necrotizing fasciitis in patients presenting with skin infections after rituximab therapy.

  9. The Efficacy and Safety of Rituximab in a Patient with Rheumatoid Spondylitis

    Directory of Open Access Journals (Sweden)

    Şenol Kobak

    2013-01-01

    Full Text Available Rheumatoid arthritis (RA is considered as a connective tissue disease while ankylosing spondylitis (AS is a prototype of spondyloarthritis. These diseases are seen concomitantly only very rarely. Also, rituximab has proven efficacy in the treatment of RA while its role in the treatment of AS is unclear. In this presentation, the concomitant presence of RA and AS in a 43-year-old male patient as well as the efficacy and safety of rituximab is discussed. Rituximab was given due to lack of response to treatment with anti-TNF-alpha. Evaluations made at the 6th and 12th months of treatment showed complete response for RA and partial response for AS.

  10. A Case of Rituximab-Induced Necrotizing Fasciitis and a Review of the Literature

    Directory of Open Access Journals (Sweden)

    Abdullateef Abdulkareem

    2017-01-01

    Full Text Available Necrotizing fasciitis is a fulminant soft tissue infection characterized by rapid progression and high mortality. Rituximab is a generally well-tolerated immunosuppresive medication used for B-cell malignancies and some rheumatological disorders. We report a case of a 69-year-old male with chronic lymphocytic leukemia who suffered necrotizing fasciitis of his left lower extremity secondary to Clostridium septicum 7 weeks after treatment with rituximab. Despite immediate intravenous antimicrobial therapy and emergent fasciotomy with extensive debridement, his hospital course was complicated by septic shock and he required an above-the-knee amputation. Physicians need to be aware of the possibility of necrotizing fasciitis in patients presenting with skin infections after rituximab therapy.

  11. The efficacy and safety of rituximab in treating childhood nephrotic syndrome: an Italian perspective.

    Science.gov (United States)

    Maratea, Dario; Bettio, Monica; Corti, Maria Grazia; Montini, Giovanni; Venturini, Francesca

    2016-07-12

    Nephrotic syndrome is a disorder characterized by proteinuria, hypoalbuminemia and dyslipidemia. Low-dose alternate-day steroid regimen is the standard of care. In case of relapse or significant adverse events, steroid-sparing agents may be used. This analysis was aimed at assessing the efficacy and safety of rituximab for the treatment of children with nephrotic syndrome. Four studies were included in the final meta-analysis. The end-point of our analysis was the percentage of patients in remission at 6 months. Pooled data from the four studies favours the use of rituximab (RR 5.25, 95 % CI: 3.05-9.06; p nephrotic syndrome: 1. favourable clinical efficacy and safety data; 2. no available alternatives; 3. outcome data collecting by AIFA through prescribers. In conclusion, our results report a significant incremental benefit of adding rituximab to corticosteroid and/or calcineurin inhibitors for the treatment of nephrotic syndrome.

  12. Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus.

    Science.gov (United States)

    Tse, J R; Schwab, K E; McMahon, M; Simon, W

    2015-06-01

    Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment typically consists of aggressive immunosuppression with pulse-dose steroids, cyclophosphamide, and plasma exchange therapy. Mortality rates remain high despite use of multiple medical therapies. We present a case of recurrent DAH in a 52-year-old female with SLE after a deceased donor renal transplant who was successfully treated with rituximab. Our report highlights the pathophysiologic importance of B-cell-mediated immunosuppression in SLE-associated DAH and suggests that rituximab may represent a viable alternative to cyclophosphamide in the treatment of this disease. We also review eight other reported cases of rituximab use in SLE-associated DAH. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  13. Experiencia con rituximab en miopatía inflamatoria idiopática refractaria

    Directory of Open Access Journals (Sweden)

    Elmer R. García-Salazar

    2013-10-01

    Full Text Available Se describe las características clínicas y de laboratorio de dos pacientes que recibieron rituximab por miopatía inflamatoria idiopática (MII. Ellas eran refractarias a tratamiento convencional con DARMES, por lo que recibieron rituximab 1 gramo cada 14 días, en dos infusiones en ciclo semestral. En las historias clínicas se obtuvo los datos clínicos de fuerza muscular proximal, lesiones cutáneas patognomónicas, elevación de CPK, TGO, DHL y VSG, resultados de electromiografía, biopsia muscular y de piel. Ninguno de los dos casos presentó reacción medicamentosa ni infecciones durante y posterior a las infusiones. Rituximab mostró efectividad en la respuesta clínica y enzimática en estas pacientes con dermatomiositis refractarias a corticoides y DARMES tradicionales.

  14. Remission Time after Rituximab Treatment for Autoimmune Bullous Disease: A Proposed Update Definition.

    Science.gov (United States)

    Iranzo, Pilar; Pigem, Ramon; Giavedoni, Priscila; Alsina-Gibert, Mercè

    2015-01-01

    A therapeutic endpoint is a very important tool to evaluate response in clinical trials. In 2005, a consensus statement identified two late endpoints of disease activity in pemphigus: complete remission off therapy and complete remission on therapy, both definitions applying to patients without lesions for at least 2 months. The same period of time was considered for partial remission off/on therapy. These definitions were later applied to bullous pemphigoid and are considered in most studies on autoimmune bullous disease. These endpoints were established for different adjuvant agents, but at that moment, rituximab was not considered. Rituximab is known for the long duration of its effect, and in most studies relapses have been reported later than 6 months after treatment. In our opinion, time to remission after rituximab treatment should be redefined. © 2015 S. Karger AG, Basel.

  15. 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.

  16. 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.

  17. Rituximab administration within 6 months of T cell-depleted allogeneic SCT is associated with prolonged life-threatening cytopenias.

    Science.gov (United States)

    McIver, Zachariah; Stephens, Nicole; Grim, Andrew; Barrett, A John

    2010-11-01

    The monoclonal anti-CD20 antibody Rituximab (RTX) is increasingly used in allogeneic stem cell transplantation (SCT) to treat lymphoproliferative disorders and chronic graft-versus-host disease (GVHD). RTX administration can be complicated by delayed and prolonged neutropenia, but the mechanism is unclear. We report the occurrence of profound cytopenias following RTX given in the conditioning regimen or early after T cell-deplete SCT to treat B cell lymphoproliferative disorders or chronic GVHD (cGVHD). Between 2006 and 2009, 102 patients (median age: 43 years, range: 13-68 years), received a myeloablative matched-sibling T cell-deplete SCT for lymphoid or myeloid hematologic disorders. Neutropenia occurring within 4 weeks of treatment developed in 16 of 17 patients given RTX within the first 190 days after SCT. Fourteen patients developed severe neutropenia (count SCT compared to patients with cGVHD not treated with early RTX (P SCT experienced only moderate neutropenia 3 to 5 months after treatment lasting 10 to 20 days while maintaining absolute neutrophil count (ANC) >1.0 × 10⁹/L. Although RTX rapidly controlled cGVHD, we conclude that its administration early after T cell-deplete SCT is associated with prolonged profound and life-threatening cytopenias, and should be avoided. Published by Elsevier Inc.

  18. B cell-depleting therapy with rituximab or ofatumumab in immunoglobulin A nephropathy or vasculitis with nephritis

    Science.gov (United States)

    Westergren, Emelie; Smolander, Jessica; Bruchfeld, Annette

    2017-01-01

    Background Approximately 30% of adult patients with immunoglobulin A (IgA) nephropathy (IgAN) or IgA vasculitis with nephritis (IgAVN) develop end-stage renal disease during long-term follow-up. In particular, patients with nephritic–nephrotic syndrome have an increased risk of rapid progression. Conventional immunosuppressive therapy with corticosteroids (CSs) may be insufficient for disease control and is associated with a number of side effects. Rituximab (RTX) has been shown to be well tolerated and effective in a range of glomerular diseases, but there is little information on its therapeutic potential in IgAN. The humanized anti-CD20 monoclonal antibody ofatumumab (OFAB) may be an alternative drug for patients intolerant or unresponsive to RTX, but so far there is no report on its use in IgAVN or IgAN. Methods We describe clinical outcomes after 17–22 months in four adult patients with biopsy-confirmed IgAVN or IgAN treated with RTX or OFAB as well as CS soon after diagnosis. All presented with nephritic–nephrotic syndrome and one had crescentic IgAN. Rebiopsy was performed in two cases. Results RTX and OFAB were well tolerated. Albuminuria was nephritic–nephrotic syndrome. A possible CS-sparing effect should be further evaluated in randomized controlled clinical trials. PMID:28638602

  19. Ocaratuzumab, an Fc-engineered antibody demonstrates enhanced antibody-dependent cell-mediated cytotoxicity in chronic lymphocytic leukemia.

    Science.gov (United States)

    Cheney, Carolyn M; Stephens, Deborah M; Mo, Xiaokui; Rafiq, Sarwish; Butchar, Jonathan; Flynn, Joseph M; Jones, Jeffrey A; Maddocks, Kami; O'Reilly, Adrienne; Ramachandran, Abhijit; Tridandapani, Susheela; Muthusamy, Natarajan; Byrd, John C

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is common in both developed and developing nations where the need for inexpensive and convenient administration of therapy is apparent. Ocaratuzumab is a novel Fc-engineered humanized IgG1 anti-CD20 monoclonal antibody (mAb) designed for effective antibody-dependent cell-mediated cytotoxicity (ADCC) at very low concentrations that may facilitate sub-cutaneous (vs. intravenous) dosing. Here, we report ocaratuzumab's potency against CLL cells. In vitro assessment of ocaratuzumab's direct cytotoxicity (DC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and ADCC was performed on CLL cells. Ocaratuzumab induced DC, CDC, and ADCP similarly to rituximab or ofatumumab (anti-CD20 mAbs). However, ocaratuzumab showed an advantage in NK cell-mediated ADCC over these antibodies. In allogeneic ADCC, [E:T (effector:target) ratios = 25:1, 12:1, 6:1], ocaratuzumab (10 µg/mL) improved ADCC by ~3-fold compared with rituximab or ofatumumab (P<0.001 all tested E:T ratios). Notably, the superiority of ocaratuzumab-induced ADCC was observed at low concentrations (0.1-10 ug/ml; P<0.03; allogeneic assays). In extended allogeneic ADCC E:T titration, ocaratuzumab (0.1 µg/mL) demonstrated 19.4% more cytotoxicity than rituximab (E:T = 0.38:1; P = 0.0066) and 21.5% more cytotoxicity than ofatumumab (E:T = 1.5:1; P = 0.0015). In autologous ADCC, ocaratuzumab (10 µg/mL) demonstrated ~1.5-fold increase in cytotoxicity compared with rituximab or ofatumumab at all E:T ratios tested (E:Ts = 25:1,12:1,6:1; all P<0.001). Obinutuzumab, a glyco-engineered anti-CD20 mAb, showed no improvement in ADCC activity compared with ocaratuzumab. The enhanced ADCC of ocaratuzumab suggests that it may be effective at low concentrations. If supported by clinical investigation, this feature could potentially allow for subcutaneous dosing at low doses that could expand the potential of administering chemoimmunotherapy in developing

  20. Experiencia con rituximab en miopatía inflamatoria idiopática refractaria

    OpenAIRE

    Elmer R. García-Salazar; Felipe Becerra; José Chávez

    2013-01-01

    Se describe las características clínicas y de laboratorio de dos pacientes que recibieron rituximab por miopatía inflamatoria idiopática (MII). Ellas eran refractarias a tratamiento convencional con DARMES, por lo que recibieron rituximab 1 gramo cada 14 días, en dos infusiones en ciclo semestral. En las historias clínicas se obtuvo los datos clínicos de fuerza muscular proximal, lesiones cutáneas patognomónicas, elevación de CPK, TGO, DHL y VSG, resultados de electromiografía, biopsia muscul...

  1. Experiencia con rituximab en miopatía inflamatoria idiopática refractaria

    OpenAIRE

    García-Salazar, Elmer R.; Becerra, Felipe; Chávez, José

    2014-01-01

    Se describe las características clínicas y de laboratorio de dos pacientes que recibieron rituximab por miopatía inflamatoria idiopática(MII). Ellas eran refractarias a tratamiento convencional con DARMES, por lo que recibieron rituximab 1 gramo cada 14 días, en dosinfusiones en ciclo semestral. En las historias clínicas se obtuvo los datos clínicos de fuerza muscular proximal, lesiones cutáneaspatognomónicas, elevación de CPK, TGO, DHL y VSG, resultados de electromiografía, biopsia muscular ...

  2. Comparability study of Rituximab originator and follow-on biopharmaceutical.

    Science.gov (United States)

    Montacir, Othman; Montacir, Houda; Eravci, Murat; Springer, Andreas; Hinderlich, Stephan; Saadati, Amirhossein; Parr, Maria Kristina

    2017-06-05

    Immunglobolin G (IgG)-based biopharmaceuticals are emerging on the pharmaceuticals market due to their high target selectivity in different diseases. In parallel, a growing interest by other companies to produce similar or highly similar follow-on biologics exits, once the patent of blockbuster biotherapeutics is about to expire. In correlation to their complex structure, an analytical challenge is facing the approval of these biosimilars. Health authorities (e.g. FDA and EMA) have issued several guidelines to define critical quality attributes during manufacturing process changes. In the current study, physicochemical characterization using state-of-the-art analytics was applied to analyse intact mass, post-translational modifications (PTMs) and higher order structure of Rituximab and one of its biosimilars. Intact mass analysis, middle-up approach as well as subunit analysis revealed similar glycoforms but additional lysine variants in the biosimilar. The N-glycosylation site was confirmed for both, the originator and the biosimilar. PTMs and higher order structure were confirmed to be similar. A special focus was given to N-glycosylation due to its potential to monitor the batch-to-batch consistency and alteration during the production bioprocess. Comparison of the N-glycosylation profiles obtained from three batches of the biosimilar and the reference product showed quantitative variations, although the N-glycans were qualitatively similar. Furthermore, a head-to-head comparability of functional properties was performed to investigate the impact of glycosylation alteration and PTMs on potency within the biosimilar batches and between originator and follow-on biodrug. The data affirm that the difference is still in the acceptable range for biosimilarity. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Antiprothrombin Antibodies

    Directory of Open Access Journals (Sweden)

    Polona Žigon

    2015-05-01

    Full Text Available In patients with the antiphospholipid syndrome (APS, the presence of a group of pathogenic autoantibodies called antiphospholipid antibodies causes thrombosis and pregnancy complications. The most frequent antigenic target of antiphospholipid antibodies are phospholipid bound β2-glycoprotein 1 (β2GPI and prothrombin. The international classification criteria for APS connect the occurrence of thrombosis and/or obstetric complications together with the persistence of lupus anticoagulant, anti-cardiolipin antibodies (aCL and antibodies against β2GPI (anti-β2GPI into APS. Current trends for the diagnostic evaluation of APS patients propose determination of multiple antiphospholipid antibodies, among them also anti-prothrombin antibodies, to gain a common score which estimates the risk for thrombosis in APS patients. Antiprothrombin antibodies are common in APS patients and are sometimes the only antiphospholipid antibodies being elevated. Methods for their determination differ and have not yet been standardized. Many novel studies confirmed method using phosphatidylserine/prothrombin (aPS/PT ELISA as an antigen on solid phase encompass higher diagnostic accuracy compared to method using prothrombin alone (aPT ELISA. Our research group developed an in-house aPS/PT ELISA with increased analytical sensitivity which enables the determination of all clinically relevant antiprothrombin antibodies. aPS/PT exhibited the highest percentage of lupus anticoagulant activity compared to aCL and anti-β2GPI. aPS/PT antibodies measured with the in-house method associated with venous thrombosis and presented the strongest independent risk factor for the presence of obstetric complications among all tested antiphospholipid antibodies

  4. 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.

  5. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words

    International Nuclear Information System (INIS)

    Mirick, G. R.; Bradt, B. M.; Denardo, S. J.; Denardo, G. L.

    2004-01-01

    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 ( 9 0yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ( 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

  6. 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.

  7. Dosimetric model for intraperitoneal targeted liposomal radioimmunotherapy of ovarian cancer micrometastases

    International Nuclear Information System (INIS)

    Syme, A M; McQuarrie, S A; Middleton, J W; Fallone, B G

    2003-01-01

    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

  8. A Prototype {sup 212}Pb Medical Dose Calibrator for Alpha Radioimmunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, W.F.; Patil, A.; Russ, W.R.; Newman, J. [CANBERRA Industries, Inc. (United States); Torgue, J. [AREVA Med (United States)

    2015-07-01

    AREVA Med, an AREVA group subsidiary, is developing innovative cancer-fighting therapies involving the use of {sup 212}Pb for alpha radioimmunotherapy. Canberra Industries, the nuclear measurement subsidiary of AREVA, has been working with AREVA Med to develop a prototype measurement system to assay syringes containing a {sup 212}Pb solution following production by an elution system. The relative fraction of emitted radiation from the source associated directly with the {sup 212}Pb remains dynamic for approximately 6 hours after the parent is chemically purified. A significant challenge for this measurement application is that the short half-life of the parent nuclide requires assay prior to reaching equilibrium with progeny nuclides. A gross counting detector was developed to minimize system costs and meet the large dynamic range of source activities. Prior to equilibrium, a gross counting system must include the period since the {sup 212}Pb was pure to calculate the count rate attributable to the parent rather than the progeny. The dynamic state is determined by solving the set of differential equations, or Bateman equations, describing the source decay behavior while also applying the component measurement efficiencies for each nuclide. The efficiencies were initially estimated using mathematical modeling (MCNP) but were then benchmarked with source measurements. The goal accuracy of the system was required to be within 5%. Independent measurements of the source using a high resolution spectroscopic detector have shown good agreement with the prototype system results. The prototype design was driven by cost, compactness and simplicity. The detector development costs were minimized by using existing electronics and firmware with a Geiger-Mueller tube derived from Canberra's EcoGamma environmental monitoring product. The acquisition electronics, communications and interface were controlled using Python with the EcoGamma software development kit on a Raspberry

  9. Microthrombotic renal involvement in an SLE patient with concomitant catastrophic antiphospholipid syndrome: the beneficial effect of rituximab treatment.

    Science.gov (United States)

    Diószegi, Á; Tarr, T; Nagy-Vincze, M; Nánásy-Vass, M; Veisz, R; Bidiga, L; Dezső, B; Balla, J; Szodoray, P; Szekanecz, Z; Soltész, P

    2018-01-01

    Antiphospholipid syndrome is characterized by multiple arterial and/or venous thrombotic events, recurrent fetal losses in the presence of antiphospholipid antibodies (aPL). Catastrophic antiphospholipid syndrome is a life-threatening, rare subset of antiphospholipid syndrome when the thrombotic events affect at least three organs, and clinical manifestations develop simultaneously or within a week. Diagnostically, small vessel occlusions can be detected by histopathology in the presence of aPL. Our case report describes an 18-year-old man who has been treated for antiphospholipid syndrome associated with systemic lupus erythematosus (SLE) since 2011. The clinical findings were dominated by recurrent deep vein thrombosis, and severe proteinuria caused by lupus nephritis, accompanied by mild serological and laboratory findings. The patient was hospitalized in March 2014 because of severe thrombocytopenia and infective diarrhoea. At this time the renal functions deteriorated rapidly. Simultaneously, left upper extremity paresis was observed; computed tomography showed ischaemic lesions in the territory of the middle cerebral artery. Abdominal discomfort and pain occurred. On computed tomography scan ischaemic lesions were seen in the spleen, the right kidney and the coeliac trunk. Laboratory and serological findings verified the presence of aPL and anti-DNA antibodies, anaemia and thrombocytopenia. Based on the above-mentioned clinical and laboratory findings, the diagnosis of catastrophic antiphospholipid syndrome was established. Anticoagulation, corticosteroids and plasma exchange treatment, as well as haemodiafiltration were initiated. Although the thrombotic cascade decelerated following these interventions, we could not see an improvement in the renal function. Rituximab treatment was started, leading to a significant improvement in renal function. After 5 weeks of treatment the patient was discharged from hospital.

  10. Improvements in hepatitis B virus screening before rituximab therapy: A community-based, safety-net hospital experience.

    Science.gov (United States)

    Junus, Kevin; Aguilar, Maria; Patel, Priya; Irwin, David; Yee, Stephen; Liu, Benny; Bhuket, Taft; Wong, Robert J

    2017-02-15

    Individuals with chronic hepatitis B virus infection (HBV) or previously resolved HBV are at increased risk of HBV exacerbation or reactivation when they receive treatment with anti-CD20 monoclonal antibodies (against B-lymphocyte antigen cluster of differentiation 20 [CD20], an activated-glycosylated phosphoprotein) like rituximab (RTX). The objective of the current study was to evaluate the rates of appropriate HBV screening before patients started receiving RTX, at the initiation of HBV treatment, and during HBV flares among an underserved safety-net population. In total, 244 consecutive adults who received treatment with RTX from 2006 to 2015 at an urban safety-net hospital were evaluated to determine appropriate HBV screening (HBV surface antigen [HBsAg] and HBV total core antibody [HBcAb]) before starting RTX. The initiation of prophylactic antiviral therapy and the development of HBV flares after starting RTX were evaluated. Predictors of appropriate HBV screening were evaluated using multivariate logistic regression models. Most patients were women (52.7%; n = 128) and of Hispanic ethnicity (30.7%; n = 74). Before starting RTX, 60.5% (n = 147) of patients received appropriate HBV screening. The HBV screening rates before RTX improved from 14.7% (2006-2009) to 74.7% (2010-2012), and to 87.1% (2013-2015; P HBcAb-positive/HBsAg-negative patients who did not receive antiviral therapy experienced HBV reactivation. No patient-specific or disease-specific predictors of receiving HBV screening before RTX therapy were identified. Among adults receiving RTX therapy in a single community-based hospital system, HBV screening rates were suboptimal, and 28.6% of HBsAg-positive patients and 7.4% of HBsAg-negative/HBcAb-positive patients who did not receive antiviral treatment experienced HBV reactivation or flare. Cancer 2017;123:650-656. © 2016 American Cancer Society. © 2016 American Cancer Society.

  11. Hematological toxicity in radioimmunotherapy is predicted both by the computed absorbed whole body dose (cGy) and by the administered dose (mCi)

    International Nuclear Information System (INIS)

    Marquez, Sheri D.; Knox, Susan J.; Trisler, Kirk D.; Goris, Michael L.

    1997-01-01

    Purpose/Objective: Radioimmunotherapy (RIT) has yielded encouraging response rates in patients with recurrent non-Hodgkin's lymphoma, but myelotoxicity remains the dose limiting factor. Dose optimization is theoretically possible, since a pretreatment biodistribution study with tracer doses allows for a fairly accurate estimate of the whole body (and by implication the bone marrow) dose in patients. It has been shown that the radiation dose as a function of the administered dose varies widely from patient to patient. The pretreatment study could therefore be used to determine the maximum tolerable dose for each individual patient. The purpose of this study was to examine whether the administered dose or the estimated whole body absorbed radiation dose were indeed predictors of bone marrow toxicity. Materials and Methods: We studied two cohorts of patients to determine if the computed integral whole body or marrow dose is predictive of myelotoxicity. The first cohort consisted of 13 patients treated with Yttrium-90 labeled anti-CD20 (2B8) monoclonal antibody. Those patients were treated in a dose escalation protocol, based on the administered dose, without correction for weight or body surface. The computed whole body dose varied from 41 to 129 cGy. The second cohort (6 patients) were treated with Iodine-131 labeled anti-CD20 (B1) antibody. In this group the administered dose was tailored to deliver an estimated 75 cGy whole body dose. The administered dose varied from 54 to 84 mCi of Iodine-131. For each patient, white blood cell count with differential, hemoglobin, hematocrit, and platelet levels were measured before and at regular intervals after RIT was administered. Using linear regression analysis, a relationship between administered dose, absorbed dose and myelotoxicity was determined for each patient cohort. Results: Marrow toxicity was measured by the absolute decrease in white blood cell (DWBC), platelet (DPLAT), and neutrophil (DN) values. In the Yttrium

  12. Pre-therapy {sup 18}F-FDG PET quantitative parameters help in predicting the response to radioimmunotherapy in non-Hodgkin lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Cazaentre, Thomas [CHU Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Lille (France); Hopital Saint Jean, Perpignan (France); Morschhauser, Franck [CHU Lille, Service des Maladies du Sang, Lille (France); Vermandel, Maximilien [CHU Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Lille (France); Univ Lille Nord de France, Lille (France); INSERM U703, Lille (France); Betrouni, Nacim [INSERM U703, Lille (France); Prangere, Thierry [CHU Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Lille (France); Steinling, Marc [CHU Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Lille (France); Univ Lille Nord de France, Lille (France); Huglo, Damien [CHU Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Lille (France); Univ Lille Nord de France, Lille (France); INSERM U703, Lille (France); Hopital Huriez, CHU de Lille, Service de Medecine Nucleaire et Imagerie Fonctionnelle, Lille cedex (France)

    2010-03-15

    Radioimmunotherapy (RIT) is a new treatment option for patients with non-Hodgkin lymphoma (NHL). Response to RIT currently remains difficult to predict using conventional prognostic factors and could be refined using functional imaging. The goal of this work is to evaluate the value of {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting response to Yttrium 90-labeled monoclonal antibodies for patients with NHL. Thirty-five patients with NHL who had undergone {sup 18}F-FDG PET prior to RIT with either {sup 90}Y-ibritumomab tiuxetan (group A; n=17) or {sup 90}Y-epratuzumab tetraxetan (group B; n=18) were included in this retrospective study. Four functional criteria were determined for each tumour lesion in a given patient: maximum and mean standard uptake values (SUVmax and SUVmean), functional lesion volume (LVol) and total lesion glycolysis (TLG, product of the volume and the SUVmean). For each patient, we determined highest SUVmax and SUVmean, cumulative TLG (TLGcum) and sum of all LVol (TVol) and compared their predictive value on response (complete or partial response according to IWC) to RIT with those of conventional prognostic factors in group A and B. A total of 154 lesions were analysed. Nineteen patients (54%) responded to RIT according to IWC. In group A, response rate was 54, 75 and 75% in patients with a SUV max <20 g/ml, a TVol <100 ml and a TLGcum <1060 g, respectively while no patient above these thresholds responded (p < 0.005). In group B, the response rate was 93% for with SUVmax <15 g/ml while no patient above this threshold responded. With TLGcum below 1,360 g, 100% of the patient responded, compared with 37% of patients whose TLGcum was above this threshold (p < 0.05). By contrast, conventional prognostic factors failed to predict response. Our preliminary results indicate that pre-therapy {sup 18}F-FDG PET functional parameters such as SUVmax and TLG may help predicting more accurately response to single agent

  13. 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.

  14. Use of rituximab as a treatment for systemic lupus erythematosus: retrospective review.

    Science.gov (United States)

    Machado, Roberta Ismael Lacerda; Scheinberg, Morton Aaron; Queiroz, Maria Yvone Carlos Formiga de; Brito, Danielle Christinne Soares Egypto de; Guimarães, Maria Fernanda Brandao de Resende; Giovelli, Raquel Altoé; Freire, Eutilia Andrade Medeiros

    2014-01-01

    To report the experience in three Brazilian institutions with the use of rituximab in patients with different clinical forms of lupus erythematosus systemic in activity. The study consisted of a sample of 17 patients with LES, who were already being treated, but that at some stage of the disease showed refractory symptoms. The patients were subdivided into groups according to the clinical manifestation, and the responses for the use of rituximab were rated as complete, partial or no response. Data were collected through a spreadsheet, and used specific parameters for each group. The treatment was carried on by using therapeutic dose of 1g, and repeating the infusion within an interval of 15 days. The clinical responses to rituximab of the group only hematological and of the group only osteoarticular were complete in all cases. In the renal group there was a clinical complete response, two partial and one absent. In the renal and hematological group complete response, there was one death and a missing response. The pulmonary group presented a complete response and two partial. The present study demonstrated that rituximab can bring benefits to patients with lupus erythematosus systemic, with good tolerability and mild side effects; it presented, however, variable response according to the system affected.

  15. Correction to: Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event.

    Science.gov (United States)

    Berger, Joseph R; Malik, Vineeta; Lacey, Stuart; Brunetta, Paul; Lehane, Patricia B

    2018-04-10

    The article "Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event," written by Joseph R. Berger, Vineeta Malik, Stuart Lacey, Paul Brunetta, and Patricia B. Lehane 3 , was originally published electronically on the publisher's internet portal (currently SpringerLink).

  16. 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...

  17. Rituximab Retreatment in Rheumatoid Arthritis in a Real-life Cohort

    DEFF Research Database (Denmark)

    Chatzidionysiou, Katerina; Lie, Elisabeth; Lukina, Galina

    2017-01-01

    OBJECTIVE: Several aspects of rituximab (RTX) retreatment in rheumatoid arthritis (RA) need to be further elucidated. The aim of this study was to describe the effect of repeated courses of RTX on disease activity and to compare 2 retreatment strategies, fixed-interval versus on-flare retreatment...

  18. Rituximab Leads to Long Remissions in Patients with Chronic Immune Thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Khalid Al-Habsi

    2015-03-01

    Full Text Available Objectives: To assess the response rate and duration of response in patients with chronic immune thrombocytopenia (ITP receiving rituximab. Methods: We retrospectively analyzed 32 consecutive patients with chronic ITP who were treated in two tertiary centers in Oman. Response assessment was based on the American Society of Hematology criteria. Results: Nineteen patients (59% had an initial response. However, six of the 19 patients lost their response leaving 13 patients with long-lasting remissions. The median age at diagnosis was 25 years (range 14–58. The median time from diagnosis to rituximab therapy was 21 months. The median follow-up after starting rituximab was 26 months. The overall cumulative response rate was 59% (complete response 44%, partial response 15% and the median time to respond was 30 days with a response rate of 44% at four weeks. In all responders, the cumulative rate of loss of response was 32% with a median time to lose response of 54 months. Conclusions: The use of rituximab in ITP achieves high response rate and long remission duration. Our study was limited by the small sample size and further larger prospective studies are recommended.

  19. Systemic adverse events following rituximab therapy in patients with Graves' disease

    DEFF Research Database (Denmark)

    El Fassi, D; Nielsen, Claus Henrik; Junker, Michael Peter

    2011-01-01

    Background and aim: Rituximab (RTX) therapy has shown promising results in Graves´ disease (GD), with or without ophthalmopathy. We examined the occurrence of adverse events in GD patients treated with RTX. Subjects and methods: Ten patients received RTX and methimazole, while ten patients receiv...

  20. Probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies.

    Science.gov (United States)

    Niikura, Takahito; Yamamoto, Izumi; Nakada, Yasuyuki; Kamejima, Sahoko; Katsumata, Haruki; Yamakawa, Takafumi; Furuya, Maiko; Mafune, Aki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    We report a case of probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies. A 44 year-old male was admitted to our hospital for a kidney transplant. The donor, his wife, was an ABO minor mismatch (blood type O to A) and had Gitelman syndrome. Graft function was delayed; his serum creatinine level was 10.1 mg/dL at 3 days after transplantation. Open biopsy was performed immediately; no venous thrombosis was observed during surgery. Histology revealed moderate peritubular capillaritis and mild glomerulitis without C4d immunoreactivity. Flow cytometric crossmatching was positive, but no panel-reactive antibodies against HLA or donor-specific antibodies (DSAbs) to major histocompatibility complex class I-related chain A (MICA) were detected. Taken together, we diagnosed him with probable C4d-negative accelerated antibody-mediated rejection due to non-HLA, non-MICA antibodies, the patient was treated with steroid pulse therapy (methylprednisolone 500 mg/day for 3 days), plasma exchange, intravenous immunoglobulin (40 g/body), and rituximab (200 mg/body) were performed. Biopsy at 58 days after transplantation, at which time S-Cr levels were 1.56 mg/dL, found no evidence of rejection. This case, presented with a review of relevant literature, demonstrates that probable C4d-negative accelerated acute AMR can result from non-HLA antibodies. © 2015 Asian Pacific Society of Nephrology.

  1. Enzymatic Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody Efficacy.

    Science.gov (United States)

    Järnum, Sofia; Runström, Anna; Bockermann, Robert; Winstedt, Lena; Crispin, Max; Kjellman, Christian

    2017-09-01

    Endogenous plasma IgG sets an immunologic threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here, we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fcγ-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab), and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor-seeking immune cells. Mol Cancer Ther; 16(9); 1887-97. ©2017 AACR . ©2017 American Association for Cancer Research.

  2. Rituximab Effectiveness and Safety for Treating Primary Sjögren’s Syndrome (pSS): Systematic Review and Meta-Analysis

    Science.gov (United States)

    Souza, Francine Bertolais do Valle; Porfírio, Gustavo José Martiniano; Andriolo, Brenda Nazaré Gomes; de Albuquerque, Julia Vajda; Trevisani, Virginia Fernandes Moça

    2016-01-01

    Background Primary Sjögren’s Syndrome (pSS) is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration. Therapeutic options include mainly symptomatic and supportive measures, and traditional immunosuppressant drugs have shown no effectiveness in randomized trials. Rituximab (RTX) is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS. The objective of this systematic review was to evaluate Rituximab effectiveness and safety for treating pSS. Methods and Findings We conducted a systematic review of RCTs published until December 2015, with no language restriction. We registered a protocol on Plataforma Brasil (40654814.6.0000.5505) and developed search strategies for the following scientific databases: MEDLINE, EMBASE, CENTRAL and LILACS. We included adults with established pSS diagnosis and considered the use of Rituximab as intervention and the use of other drugs or placebo as control. Four studies met our eligibility criteria: three with low risk of bias and one with uncertain risk of bias. The total number of participants was 276 (145 RTX, 131 placebo). We assessed the risk of bias of each included study and evaluated the following as primary outcomes: lacrimal gland function, salivary gland function, fatigue improvement and adverse events. We found no significant differences between the groups in the Schirmer test at week 24 meta-analysis (MD 3.59, 95% CI -2.89 to 10.07). Only one study evaluated the lissamine green test and reported a statistically significant difference between the groups at week 24 (MD -2.00, 95% CI -3.52 to -0.48). There was a significant difference between the groups regarding salivary flow rate (MD 0.09, 95% CI 0.02 to 0.16) and improvement in fatigue VAS at weeks 6 (RR 3.98, 95% CI 1.61 to 9.82) and week 16

  3. Rituximab Effectiveness and Safety for Treating Primary Sjögren's Syndrome (pSS): Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Souza, Francine Bertolais do Valle; Porfírio, Gustavo José Martiniano; Andriolo, Brenda Nazaré Gomes; Albuquerque, Julia Vajda de; Trevisani, Virginia Fernandes Moça

    2016-01-01

    Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration. Therapeutic options include mainly symptomatic and supportive measures, and traditional immunosuppressant drugs have shown no effectiveness in randomized trials. Rituximab (RTX) is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS. The objective of this systematic review was to evaluate Rituximab effectiveness and safety for treating pSS. We conducted a systematic review of RCTs published until December 2015, with no language restriction. We registered a protocol on Plataforma Brasil (40654814.6.0000.5505) and developed search strategies for the following scientific databases: MEDLINE, EMBASE, CENTRAL and LILACS. We included adults with established pSS diagnosis and considered the use of Rituximab as intervention and the use of other drugs or placebo as control. Four studies met our eligibility criteria: three with low risk of bias and one with uncertain risk of bias. The total number of participants was 276 (145 RTX, 131 placebo). We assessed the risk of bias of each included study and evaluated the following as primary outcomes: lacrimal gland function, salivary gland function, fatigue improvement and adverse events. We found no significant differences between the groups in the Schirmer test at week 24 meta-analysis (MD 3.59, 95% CI -2.89 to 10.07). Only one study evaluated the lissamine green test and reported a statistically significant difference between the groups at week 24 (MD -2.00, 95% CI -3.52 to -0.48). There was a significant difference between the groups regarding salivary flow rate (MD 0.09, 95% CI 0.02 to 0.16) and improvement in fatigue VAS at weeks 6 (RR 3.98, 95% CI 1.61 to 9.82) and week 16 (RR 3.08, 95% CI 1.21 to 7

  4. Rituximab Effectiveness and Safety for Treating Primary Sjögren's Syndrome (pSS: Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Francine Bertolais do Valle Souza

    Full Text Available Primary Sjögren's Syndrome (pSS is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration. Therapeutic options include mainly symptomatic and supportive measures, and traditional immunosuppressant drugs have shown no effectiveness in randomized trials. Rituximab (RTX is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS. The objective of this systematic review was to evaluate Rituximab effectiveness and safety for treating pSS.We conducted a systematic review of RCTs published until December 2015, with no language restriction. We registered a protocol on Plataforma Brasil (40654814.6.0000.5505 and developed search strategies for the following scientific databases: MEDLINE, EMBASE, CENTRAL and LILACS. We included adults with established pSS diagnosis and considered the use of Rituximab as intervention and the use of other drugs or placebo as control. Four studies met our eligibility criteria: three with low risk of bias and one with uncertain risk of bias. The total number of participants was 276 (145 RTX, 131 placebo. We assessed the risk of bias of each included study and evaluated the following as primary outcomes: lacrimal gland function, salivary gland function, fatigue improvement and adverse events. We found no significant differences between the groups in the Schirmer test at week 24 meta-analysis (MD 3.59, 95% CI -2.89 to 10.07. Only one study evaluated the lissamine green test and reported a statistically significant difference between the groups at week 24 (MD -2.00, 95% CI -3.52 to -0.48. There was a significant difference between the groups regarding salivary flow rate (MD 0.09, 95% CI 0.02 to 0.16 and improvement in fatigue VAS at weeks 6 (RR 3.98, 95% CI 1.61 to 9.82 and week 16 (RR 3.08, 95% CI 1.21 to

  5. 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.

  6. Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab.

    Science.gov (United States)

    Kamei, Koichi; Ishikura, Kenji; Sako, Mayumi; Aya, Kunihiko; Tanaka, Ryojiro; Nozu, Kandai; Kaito, Hiroshi; Nakanishi, Koichi; Ohtomo, Yoshiyuki; Miura, Kenichiro; Takahashi, Shori; Morimoto, Tetsuji; Kubota, Wataru; Ito, Shuichi; Nakamura, Hidefumi; Iijima, Kazumoto

    2017-11-01

    Although rituximab effectively prevents relapses of complicated frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS), data of long-term outcomes and safety are limited. Fifty-one patients (age, 3-38 years) with childhood-onset complicated FRNS or SDNS, who received rituximab in investigator-initiated multicenter prospective trials were enrolled. Rituximab was administered at 375 mg/m 2 once weekly for 4 weeks, and immunosuppressive agents were discontinued according to the study protocol. We investigated relapses, re-administration of immunosuppressive agents, additional rituximab treatment, body height, renal function, and late adverse events during the observation period. Forty-eight patients (94%) developed relapses during the observation period (median, 59 months) and the 50% relapse-free survival was 261 days. Thirty patients (59%) developed SDNS, 44 (86%) required re-administration of immunosuppressive agents, and 22 (43%) received additional rituximab treatment. All patients who were receiving immunosuppressive agents at rituximab treatment required either immunosuppressive agents or additional rituximab treatment. On the contrary, 5 of the 13 patients without immunosuppressive agents at rituximab treatment required neither immunosuppressive agents nor additional rituximab treatment and 3 of them did not develop relapse during observation period. Growth failure due to steroid toxicity did not progress and none of the patients developed chronic renal insufficiency. None of the patients suffered from rituximab-related late adverse events. As most patients suffer from relapses after B-cell recovery, long-term immunosuppressive agents or additional rituximab treatment is necessary. However, some patients who can discontinue immunosuppressive agents before rituximab treatment may achieve long-term remission after rituximab treatment without immunosuppressive agents.

  7. 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.

  8. Synthesis of Lutetium Phosphate/Apoferritin Core-Shell Nanoparticles for Potential Applications in Radioimmunoimaging and Radioimmunotherapy of Cancers

    International Nuclear Information System (INIS)

    Wu, Hong; Engelhard, Mark H.; Wang, Jun; Fisher, Darrell R.; Lin, Yuehe

    2008-01-01

    We report a novel approach for synthesizing LuPO4/apoferritin core-shell nanoparticles based on an apoferritin template, conjugated to the protein biotin. To prepare the nanoparticle conjugates, we used non-radioactive lutetium as a model target or surrogate for radiolutetium (177Lu). The central cavity, multi-channel structure, and chemical properties of apoferritin are well-suited for sequentially diffusing lutetium and phosphate ions into the cavity--resulting in a stable core-shell composite. We characterized the synthesized LuPO4/apoferritin nanoparticle using transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS). We tested the pre-targeting capability of biotin-modified lutetium/apoferritin nanoparticle using streptavidin-modified magnetic beads and streptavidin-modified fluorescein isothiocyanate (FITC) tracer. This paper presents a simple, fast, and efficient method for synthesizing LuPO4/apoferritin nanoparticle conjugates with biotin for potential applications in radioimmunotherapy and radioimmunoimaging of cancer

  9. A simplified suite of methods to evaluate chelator conjugation of antibodies: effects on hydrodynamic radius and biodistribution

    International Nuclear Information System (INIS)

    Al-Ejeh, Fares; Darby, Jocelyn M.; Thierry, Benjamin; Brown, Michael P.

    2009-01-01

    Introduction: Antibodies covalently conjugated with chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) are required for radioimmunoscintigraphy and radioimmunotherapy, which are of growing importance in cancer medicine. Method: Here, we report a suite of simple methods that provide a preclinical assessment package for evaluating the effects of DOTA conjugation on the in vitro and in vivo performance of monoclonal antibodies. We exemplify the use of these methods by investigating the effects of DOTA conjugation on the biochemical properties of the DAB4 clone of the La/SSB-specific murine monoclonal autoantibody, APOMAB (registered) , which is a novel malignant cell death ligand. Results: We have developed a 96-well microtiter-plate assay to measure directly the concentration of DOTA and other chelators in antibody-chelator conjugate solutions. Coupled with a commercial assay for measuring protein concentration, the dual microtiter-plate method can rapidly determine chelator/antibody ratios in the same plate. The biochemical properties of DAB4 immunoconjugates were altered as the DOTA/Ab ratio increased so that: (i) mass/charge ratio decreased; (ii) hydrodynamic radius increased; (iii) antibody immunoactivity decreased; (iv) rate of chelation of metal ions and specific radioactivity both increased and in vivo, (v) tumor uptake decreased as nonspecific uptake by liver and spleen increased. Conclusion: This simplified suite of methods readily identifies biochemical characteristics of the DOTA-immunoconjugates such as hydrodynamic diameter and decreased mass/charge ratio associated with compromised immunotargeting efficiency and, thus, may prove useful for optimizing conjugation procedures in order to maximize immunoconjugate-mediated radioimmunoscintigraphy and radioimmunotherapy.

  10. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids.

    Science.gov (United States)

    Ingen-Housz-Oro, Saskia; Valeyrie-Allanore, Laurence; Cosnes, Anne; Ortonne, Nicolas; Hüe, Sophie; Paul, Muriel; Wolkenstein, Pierre; Chosidow, Olivier

    2015-02-01

    The main component of the first-line treatment of pemphigus vulgaris is high doses of systemic corticosteroids, but adverse effects of these drugs are frequent and sometimes severe. Rituximab has shown effectiveness as a corticosteroid-sparing agent or in case of relapse. To our knowledge, the effectiveness of rituximab as a first-line treatment without systemic corticosteroids has not been evaluated. Five women in their 50s, 60s, or 70s with pemphigus vulgaris (Pemphigus Disease Area Index score, 15-84 at diagnosis) and contraindications to systemic corticosteroid treatment received rituximab with high-potency topical corticosteroids as first-line treatment. All patients experienced a favorable response, with a mean time to healing of skin and mucosal lesions of 15 weeks. Two patients, with 42- and 48-month follow-up evaluations, did not experience relapse. Three patients developed 2 to 4 relapses, with effective retreatment achieved using rituximab and topical corticosteroids. No severe adverse effects were observed. Considering the high rate of severe adverse effects induced by prolonged administration of high doses of systemic corticosteroids, new therapeutic options are warranted in the treatment of pemphigus vulgaris. The combination of rituximab and topical corticosteroids could be considered in mild to severe cutaneous disease. Larger long-term studies are needed to evaluate the optimal treatment strategies according to the severity of the disease and the benefit-risk ratio of rituximab.

  11. Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls.

    Directory of Open Access Journals (Sweden)

    Pierre de Flon

    Full Text Available To investigate changes in the cerebrospinal fluid (CSF immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS, and to compare the profile in MS patients with healthy controls (HC.Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10, IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8 decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

  12. Internalisation of uncross-linked rituximab is not essential for the induction of caspase-independent killing in Burkitt lymphoma cell lines.

    Science.gov (United States)

    Turzanski, Julie; Daniels, Ian; Haynes, Andrew P

    2008-08-01

    Characterising the mechanisms underpinning caspase-independent programmed cell death (CI-PCD) induction by uncross-linked rituximab in B-cells may positively impact upon the treatment of disease states in which the classical apoptotic pathway is disabled. The necessity of rituximab internalisation for CI-PCD induction was investigated by flow cytometry and confocal microscopy in human BL cell lines with (e.g. Mutu I) and without (Mutu III) susceptibility to rituximab-induced killing. Flow cytometry demonstrated small, significant and similar amounts of rituximab internalisation by Mutu I cells after 1, 2, 4 and 24 h (p internalisation (p = 0.02, n = 5 and p = 0.0002, n = 6, respectively) in Mutu I cells, but confocal microscopy showed no correlation between internalised rituximab and phosphatidylserine exposure. We conclude that rituximab internalisation is not essential for CI-PCD induction in BL cell lines.

  13. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10)

    DEFF Research Database (Denmark)

    Eichhorst, Barbara; Fink, Anna-Maria; Bahlo, Jasmin

    2016-01-01

    BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less....... The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS: 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included...... AG, Mundipharma, German Federal Ministry of Education and Research....

  14. Antibody biotechnology

    African Journals Online (AJOL)

    STORAGESEVER

    2009-07-06

    Jul 6, 2009 ... and automated, the hybrid cells can be stored for many years in liquid nitrogen and antibodies production is homogeneous. The hybridoma method .... they may be modified to vehicle active molecules such as radio-isotopes, toxins, cytokines, enzyme etc. In these cases, the therapeutic effect is due to ...

  15. Catalytic Antibodies

    Indian Academy of Sciences (India)

    The ability of the highly evolved machinery of immune system to produce structurally and functionally complex ... to Pauling, if the structure of the antigen binding site of antibodies were to be produced in a random ..... where the immune system of the body is destructive, as in autoimmune disorders or after organ transplant.

  16. Catalytic Antibodies

    Indian Academy of Sciences (India)

    While chemistry provides the framework for understanding the structure and function of biomolecules, the immune sys- tem provides a highly evolved natural process to generate one class of complex biomolecules – the antibodies. A combination of the two could be exploited to generate new classes of molecules with novel ...

  17. Rituximabe para o tratamento da artrite reumatoide: revisão sistemática

    Directory of Open Access Journals (Sweden)

    Lívia Lovato Pires de Lemos

    2014-06-01

    Full Text Available Introdução: A artrite reumatoide (AR é uma doença autoimune crônica caracterizada por inflamação articular sistêmica que, com frequência, leva a significativa incapacitação. Vários agentes anti-TNF têm sido usados efetivamente, mas alguns pacientes demonstraram resposta inadequada. Rituximabe é um anticorpo monoclonal terapêutico indicado em tais casos. Métodos: Realizou-se uma revisão sistemática para avaliar a eficácia e a segurança de rituximabe em pacientes com AR ativa previamente tratados ou não com agentes anti-TNF e para relacionar o desfecho com a sorologia para FR e anti-CCP. Pesquisaram-se importantes bancos de dados eletrônicos e a literatura não convencional, além de se fazer uma busca manual de referências. Para a meta-análise, utilizou-se o programa Review Manager® 5.1. Resultados: Consideramos seis ERCs comparando rituximabe 1000 mg com placebo. Em ambos os grupos usou-se Metotrexato. O tratamento com rituximabe foi mais efetivo em pacientes jamais tratados e nos que não obtiveram sucesso com a terapia anti-TNF - critérios ACR 20/50/70 e EULAR. No grupo de rituximabe, observaram-se mudanças menos expressivas nos escores de Sharp/Genant, de erosão e de estreitamento do espaço articular; nesse grupo, os escores SF-36, FACIT-T e HAQ-DI também foram melhores. Não foram notadas diferenças entre grupos com relação aos desfechos de segurança, com exceção das reações agudas à infusão, que foram mais comuns no grupo de rituximabe. Ainda no grupo de rituximabe, um número maior de pacientes soropositivos para FR/anti-CCP alcançou ACR20, em comparação com pacientes negativos para RF/anti-CCP. Conclusão: Os dados disponíveis falam em favor do uso de rituximabe para o tratamento da AR, como opção efetiva e segura para pacientes jamais tratados ou que não obtiveram sucesso com o tratamento anti-TNF. FR e anti-CCP parecem influenciar os resultados do tratamento, mas essa inferência ainda est

  18. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON)

    DEFF Research Database (Denmark)

    Jerkeman, Mats; Eskelund, Christian Winther; Hutchings, Martin

    2018-01-01

    on either regimen alone. METHODS: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group......BACKGROUND: Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data....... The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276. FINDINGS: Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark...

  19. 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.

  20. Rituximab and cyclosporine therapy for accelerated phase Chediak-Higashi syndrome.

    Science.gov (United States)

    Ogimi, Chikara; Tanaka, Risa; Arai, Takashi; Kikuchi, Akira; Hanada, Ryoji; Oh-Ishi, Tsutomu

    2011-10-01

    A 19-month-old male with Chediak-Higashi syndrome developed Epstein-Barr virus (EBV)-associated accelerated phase. Real-time polymerase chain reaction showed high EBV-DNA levels in plasma and peripheral blood mononuclear cells. His condition was refractory to conventional treatments for hemophagocytic lymphohistiocytosis, including corticosteroids, cyclosporine, and etoposide. In situ hybridization revealed higher proportion of EBER-1-positive cells in CD19+ cell fraction than in CD8+ cell fraction. Complete remission was achieved by combination therapy with rituximab and cyclosporine; subsequent bone marrow transplantation was successful. Combination therapy with rituximab and cyclosporine could be effective in patients with EBV-infected T and B cells. Copyright © 2011 Wiley-Liss, Inc.

  1. Posterior reversible encephalopathy syndrome masquerading as progressive multifocal leukoencephalopathy in rituximab treated neuromyelitis optica.

    Science.gov (United States)

    Berger, Joseph R; Neltner, Janna; Smith, Charles; Cambi, Franca

    2014-11-01

    Both progressive multifocal leukoencephalopathy (PML) and posterior reversible encephalopathy syndrome (PRES) have been reported as complications of rituximab therapy. These disorders may appear indistinguishable on magnetic resonance imaging (MRI). We report on a 42 year old woman with neuromyelitis optica (NMO) of 10 years duration who developed extensive white matter disease affecting chiefly both parietal lobes 6 months after her first and only dose of rituximab. The MRI findings suggested the diagnosis of PML, but her history was more consistent with PRES. Ultimately, a brain biopsy was performed which was consistent with the diagnosis of PRES. PRES and PML may have overlapping symptomatology and be indistinguishable on MRI. An approach to distinguishing between these two disorders is addressed. Copyright © 2014. Published by Elsevier B.V.

  2. Fatal Stevens-Johnson syndrome/toxic epidermal necrolysis induced by allopurinol-rituximab-bendamustine therapy.

    Science.gov (United States)

    Fallon, Michael J; Heck, Jessica N

    2015-10-01

    Stevens-Johnson syndrome/toxic epidermal necrolysis overlap is an acute hypersensitivity reaction that compromises the integrity of mucous membranes and cutaneous tissue. While the pathophysiology of this syndrome has not been fully elucidated, it is commonly associated with the medication use and carries a significant mortality risk of approximately 30%. No commonalities among causative medications have been identified, and determining the offending agent can be challenging. This case report describes fatal Stevens-Johnson syndrome/toxic epidermal necrolysis overlap in a patient after receiving his first cycle of allopurinol, rituximab, and bendamustine treatment for non-Hodgkin's B-cell lymphoma. An analysis of FDA Medwatch adverse reaction case reports involving allopurinol, rituximab, and bendamustine is also presented. © The Author(s) 2014.

  3. Follicular B Cell Lymphoma with Accompanying Ischemic Gastritis Completely Resolved by Rituximab

    OpenAIRE

    Tariq, Anam; Mehta, Neal; Peroutka, Kathryn

    2017-01-01

    Patient: Female, 89 Final Diagnosis: Follicular B-cell lymphoma with accompanying ischemic gastritis completely resolved by rituximab Symptoms: Nausea ? vomiting Medication: ? Clinical Procedure: ? Specialty: Oncology Objective: Rare disease Background: Follicular B cell lymphomas account for a significant portion of all newly diagnosed non-Hodgkin?s lymphomas. While involvement can be varied, the most common extranodal presentation is within the gastrointestinal tract beyond the stomach. In ...

  4. Late response to rituximab in a dialysis patient with severe lupus nephritis

    Directory of Open Access Journals (Sweden)

    Magdi M Hussein

    2013-01-01

    Full Text Available Although recently completed controlled trials failed to demonstrate a significant effect of rituximab on the clinical outcome in non-renal and renal lupus, there is growing evidence from case reports and open-label trials that the use of this medication is successful in certain subgroups of patients including refractory cases and helps in reducing the dose of steroids. We present a 26-year-old female who failed to respond to a long-course treatment with prednisolone, cyclophosphamide, mycophenolate mofetil and azathioprine and who went on to develop end-stage renal disease requiring commencement of regular maintenance hemodialysis. Ten days before starting dialysis, she was given rituximab, and a second dose was given 17 days after starting dialysis. After 7 months on dialysis, the patient began to regain kidney function and is now off dialysis for 11 months. To the best of our knowledge, this is the first case report of a lupus patient on dialysis treated with rituximab in whom dialysis could be stopped and who remained off this therapy up till now, after an observation period of 1 year.

  5. Dapsone salvage therapy for adult patients with immune thrombocytopenia relapsed or refractory to steroid and rituximab.

    Science.gov (United States)

    Zaja, Francesco; Marin, Luciana; Chiozzotto, Marianna; Puglisi, Simona; Volpetti, Stefano; Fanin, Renato

    2012-03-01

    Dapsone is an antibacterial sulfonamide with anti-inflammatory property, which showed therapeutic activity in patients with immune thrombocytopenia (ITP); the activity in patients who showed refractoriness to rituximab is unknown. We evaluated the effect of dapsone in 20 consecutive adult patients, median age 51 years, with primary ITP previously treated at least with steroids and rituximab. Median baseline platelet count was 19 × 10⁹/L, and the median interval between diagnosis of ITP and dapsone therapy was 46 months. Response (platelet count ≥ 30 × 10⁹/L) and complete response (CR; platelet count ≥ 100 × 10⁹/L) were 55 and 20%, respectively; median time to response (TTR) was 1 month. All responders were able to interrupt any other specific anti-ITP treatment. The median duration of dapsone therapy in responders and the median response duration were 31 and 42 months, respectively. None of responders lost response during treatment. One patient in CR interrupted dapsone after 9 months and still maintained the response after 48 months. None of the patients interrupted the treatment for toxicity. All the patients were screened for normal glucose-6-phosphate-dehydrogenase (G6PD); two patients showed mild increase of methemoglobin (MHb). These results highlight the therapeutic activity and good safety profile of dapsone in patients with ITP who previously failed rituximab treatment.

  6. Follicular B Cell Lymphoma with Accompanying Ischemic Gastritis Completely Resolved by Rituximab.

    Science.gov (United States)

    Tariq, Anam; Mehta, Neal; Peroutka, Kathryn

    2017-06-02

    BACKGROUND Follicular B cell lymphomas account for a significant portion of all newly diagnosed non-Hodgkin's lymphomas. While involvement can be varied, the most common extranodal presentation is within the gastrointestinal tract beyond the stomach. In addition, the stomach has a diffuse multivessel vascular supply, which decreases the likelihood of developing ischemic gastritis. CASE REPORT An 89-year-old woman with history of diabetes, deep venous thromboembolism, and hypertension was referred due to a newly diagnosed retroperitoneal mass. Biopsy of a left para-aortic node was consistent with low-grade follicular B cell lymphoma. Following mainstream treatment guidelines, rituximab was administered. Approximately 12 hours later, the patient presented to the Emergency Department with intractable vomiting and nausea. After admission, an esophagogastroduodenoscopy (EGD) revealed extensive ischemic gastritis. Due to recurrent ascites requiring frequent paracenteses, and the clinical aggressiveness of the patient's underlying lymphoma, a second dose of rituximab was administered with concurrent initiation of total parenteral nutrition. Approximately 1 week later, the patient underwent a repeat EGD for quality of life planning while in hospice. The repeat EGD revealed resolved ischemic gastritis. Her diet was advanced and she was subsequently discharged home. CONCLUSIONS Rituximab alone shows promise in treating extensive follicular B cell lymphoma complicated by ischemic gastritis, which has not been previously reported in the literature.

  7. Rituximab Therapy for Severe Cutaneous Leukocytoclastic Angiitis Refractory to Corticosteroids, Cellcept and Cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Kamel El-Reshaid

    2013-04-01

    Full Text Available We report our clinical experience with rituximab in the treatment of 2 patients with idiopathic cutaneous angiitis who relapsed after treatment with high-dose corticosteroids and cyclophosphamide. A 39-year-old woman and a 51-year-old man presented with ulcerating maculopapular rash in both lower limbs which relapsed 6 months after treatment with a combination of high-dose corticosteroids and cyclophosphamide. After treatment with 2 g of rituximab, the first patient has still been in clinical remission for 32 months while the second has finished 28 months. Interestingly, CD19 which had dropped to 0.5% 8 months later in both patients. Despite that, our patients are still in clinical remission. No significant side effects were noted during infusions and up to the period of follow-up. In conclusion, rituximab is a useful and safe agent in the treatment of idiopathic cutaneous angiitis refractory to conventional therapy. Clinical remission persists years after improvement of B-cell suppression.

  8. Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration.

    Science.gov (United States)

    Fathallah, Anas M; Turner, Michael R; Mager, Donald E; Balu-Iyer, Sathy V

    2015-03-01

    The subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after s.c. administration remains a major challenge. In this work we investigated the effects of excipient dependent hyperosmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as the animal model, we compared the effects of NaCl, mannitol and O-phospho-L-serine (OPLS) on the plasma concentration of rituximab over 5 days after s.c. administration. An increase was observed in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, compared with isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to the improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph nodes in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatics, as estimated by the model, increased from 0.05% in isotonic buffer to 13% in hypertonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. The data suggest that hypertonic solutions may be a viable option for improving s.c. bioavailability. Copyright © 2014 John Wiley & Sons, Ltd.

  9. Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

    International Nuclear Information System (INIS)

    England, Christopher G.; Rui, Lixin; Cai, Weibo

    2017-01-01

    Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

  10. Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

    Energy Technology Data Exchange (ETDEWEB)

    England, Christopher G. [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); Rui, Lixin [University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); Cai, Weibo [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

    2017-03-15

    Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (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. 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.

  13. THE EFFICACY AND SAFETY OF RITUXIMAB BIOSIMILAR (ACELLBIA® IN RHEUMATOID ARTHRITIS AS THE FIRST BIOLOGICAL AGENT: RESULTS OF PHASE III (ALTERRA CLINICAL TRIAL

    Directory of Open Access Journals (Sweden)

    E. L. Nasonov

    2017-01-01

    Full Text Available The Russian biotechnological company «BIOCAD» has designed a chimeric monoclonal antibody against CD20 (BCD-020, Acellbia® that is a biosimilar of rituximab (RTM; MabThera®, F. Hoffmann-La Roche Ltd., Switzerland. In recent years, there has been evidence that RTM can be used at lower doses than those given in the standard recommendations and instructions for the use of this drug. This serves as the basis for the BCD-020-4/ALTERRA (ALTErnative Rituximab regimen in Rheumatoid Arthritis trial, the objective of which was to investigate the efficiency and safety of using Acellbia® (at a dose of 600 mg twice at a 2-week interval as the first biological agent (BA for methotrexate (MTX-resistant active rheumatoid arthritis (RA. The investigation enrolled 159 patients aged 18 to 80 years with active RA. After 24 weeks 65.7 and 29.4% of patients achieved 20% improvement by the American College of Rheumatology (ACR criteria in the Acellbia® + MTX and placebo (PL + MTX groups, respectively (p<0.0001. The differences in the ACR20 response rate in the two groups were 36.3% (95% CI, 19.27–53.28%. There were significant differences between the groups in the ACR50 response rates: 28.4% and 5.9% (p=0.001 and in the ACR70 ones: 12.8% and only 2.0%, respectively (p=0.036. Analysis of all recorded adverse events (AE frequency showed no significant differences between the patients in the study and control groups and demonstrates its equivalence with that of RTM (MabThera®; all the AE were expectable. It is noted that antibodies to RTM with binding and neutralizing activities had no impact on the efficiency and safety of therapy.

  14. 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.

  15. Disease Activity-Guided Rituximab Therapy in Rheumatoid Arthritis The Effects of Re-Treatment in Initial Nonresponders Versus Initial Responders

    NARCIS (Netherlands)

    Thurlings, Rogier M.; Vos, Koen; Gerlag, Daniëlle M.; Tak, Paul P.

    2008-01-01

    Objective. To explore the efficacy of re-treatment with rituximab in patients with rheumatoid arthritis (RA) who were initial nonresponders to treatment, and to evaluate the effects of rituximab in RA when re-treatment is given in a standardized way based on the Disease Activity Score in 28 joints

  16. Improved pretargeted delivery of radiolabelled hapten to human tumour xenograft in mice by avidin chase of circulating bispecific antibody

    Energy Technology Data Exchange (ETDEWEB)

    Mirallie, Eric; Sai-Maurel, Catherine; Faivre-Chauvet, Alain; Chatal, Jean-Francois; Barbet, Jacques; Thedrez, Philippe [Universite de Nantes, Cancer Research Department, Nantes (France); Regenet, Nicolas [Service de Chirurgie, CHU Nantes, Nantes (France); Chang, Chien-Hsing; Goldenberg, David M. [IBC Pharmaceuticals Inc., Morris Plains, NJ (United States)

    2005-08-01

    Pretargeted therapy with radiolabelled bivalent haptens and bispecific antibodies has shown promising results, but blood clearance of the activity-carr