scholarly journals IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With Relapsed Low-Grade Non-Hodgkin's Lymphoma

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2188-2195 ◽  
Author(s):  
David G. Maloney ◽  
Antonio J. Grillo-López ◽  
Christine A. White ◽  
David Bodkin ◽  
Russell J. Schilder ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Specific Antigen ◽  
Antibody Therapy ◽  
High Serum ◽  
Low Grade ◽  
Antibody Pharmacokinetics ◽  
Anti Cd20 ◽  
Hodgkin's Lymphomas

Abstract IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell–specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

scholarly journals IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With Relapsed Low-Grade Non-Hodgkin's Lymphoma

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2188-2195 ◽  
Author(s):  
David G. Maloney ◽  
Antonio J. Grillo-López ◽  
Christine A. White ◽  
David Bodkin ◽  
Russell J. Schilder ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Specific Antigen ◽  
Antibody Therapy ◽  
High Serum ◽  
Low Grade ◽  
Antibody Pharmacokinetics ◽  
Anti Cd20 ◽  
Hodgkin's Lymphomas

IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell–specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

scholarly journals Chronic Refractory Idiopathic Thrombocytopenic Purpura (ITP) and Anti-CD20 Monoclonal Antibody: A Case Report

2006 ◽  
Vol 12 (4) ◽  
pp. 489-492 ◽  
Author(s):  
S. Z. Latifzadeh ◽  
V. Entezari
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Count ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Specific Antigen ◽  
Genetically Engineered ◽  
Low Grade ◽  
Treatment Schedule ◽  
Thrombocytopenic Purpura ◽  
Anti Cd20 ◽  
Refractory Itp

Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disorder characterized by accelerated and premature destruction of platelets by reticuloendothelial system. CD20, a trans-membrane B-cell-specific antigen, is a potential target for treatment of certain malignant and nonmalignant plasma cell disorders including refractory ITP. Rituximab is a genetically engineered human anti-CD20 monoclonal antibody, which is approved for the treatment of low-grade non-Hodgkin’s lymphoma. Recent clinical reports suggest that rituximab may be useful in treating certain patients with chronic refractory ITP. A 59-year-old woman with refractory ITP was placed on rituximab (four weekly doses of 375 mg/m2) and her condition and platelet count were observed for 18 months. There was a gradual increase in platelet count and she was symptom free in this period and no side effects of the drug were reported. Anti-CD20 antibodies are likely to be used in the treatment of refractory ITP cases, but further studies about treatment schedule and criteria for patient selection should be done.

Antibody Therapy in Aggressive Lymphomas

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 257-264 ◽  
Author(s):  
Thomas M. Habermann
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Natural History ◽  
B Cell ◽  
Antibody Therapy ◽  
Lymphoproliferative Disorders ◽  
Monoclonal Antibody Therapy ◽  
Aggressive Lymphomas ◽  
History Of ◽  
Anti Cd20

AbstractThe aggressive lymphomas are potentially curable. The natural history of certain aggressive lymphomas has been altered by monoclonal antibody therapy. Targeted monoclonal antibody therapy to the CD20 antigen has altered the outcome of patients with diffuse large B-cell lymphoma in patients of all ages. Anti-CD20–based radioimmunoconjugates are being evaluated as radioimmunotherapy approaches in patients who have relapsed and in stem cell transplant settings. Antibody-directed therapy to the B-cell–specific antigen CD22 are ongoing. New approaches include different CD20 antibodies and an antibody to the CD40 antigen, which is a member of the tumor necrosis factor (TNF) receptor family, which is expressed on B-cells. Antibody therapy has been incorporated into CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) therapy and other regimens such as EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) and HyperCVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone). Single-agent anti-CD20 therapy is active in the post-transplantation lymphoproliferative disorders. T-cell antibodies are under evaluation in a number of T-cell lymphoproliferative disorders. Targeted therapy has changed the natural history of a number of aggressive non-Hodgkin lymphomas. This review will describe the contributions of antibody therapies to the treatment of these diseases.

Development of a New Fully Human Anti-CD20 Monoclonal Antibody for the Treatment of B-Cell Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2349-2349
Author(s):  
Gadi Gazit Bornstein ◽  
Christophe Queva ◽  
Mohammad Tabrizi ◽  
Anne VanAbbema ◽  
Carlos Chavez ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Clinical Activity ◽  
Human Antibody ◽  
B Cell Malignancies ◽  
B Lymphoma ◽  
Hodgkin's Lymphomas ◽  
Anti Tumor Activity

Abstract In spite of the widespread use of Rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin’s lymphomas, there is a recognized need to develop fully human antibodies with improved efficacy. Towards this end, using XenoMouse™ technology, a fully human IgG1 monoclonal antibody specific to human CD20 was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to Rituximab, in the Ramos human lymphoma cell line. In addition, mAb 1.5.3 was active in mediating complement dependent cytotoxicity (CDC) and elicited improved antibody-dependent cellular cytotoxicity (ADCC) relative to Rituximab in Ramos, Raji, and Daudi human B-lymphoma lines. To recapitulate various aspects of acquired resistance to Rituximab, as observed in a subpopulation of patients, Rituximab-resistant clones were established from lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior cytolytic activity against engineered Rituximab-refractory lymphoma clones, as well as across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Rituximab-sensitive cell lines and -refractory engineered lymphoma clones in vivo. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to Rituximab in a primate PD model. In contrast to Rituximab, mAb 1.5.3 is a fully human antibody and is thus anticipated to exhibit a longer serum half-life with minimal immunogenicity following repeated administration. In sum, these results demonstrate the superior anti-tumor activity of mAb 1.5.3 relative to Rituximab and its potential for improved clinical activity in the treatment of B-cell malignancies.

The Anti-CD20 Monoclonal Antibody GA101 Displays More Robust Anti-Tumor Activity Versus Rituximab In Waldenstrom's Macroglobulinemia (WM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4904-4904 ◽  
Author(s):  
Guang Yang ◽  
Christina Hanzis ◽  
Sigitas Verselis ◽  
Lian Xu ◽  
Zachary Hunter ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Death ◽  
B Cell ◽  
Nk Cells ◽  
Healthy Donor ◽  
B Cell Depletion ◽  
Adcc Activity ◽  
Direct Cell ◽  
Anti Cd20

Abstract Abstract 4904 Background: Rituximab is an IgG class CD20-directed monoclonal antibody used in the treatment of B-cell malignancies, including WM. We and others have previously demonstrated dependence for IgG class therapeutic antibodies on polymorphisms at FcγRIIIA-158. Approximately half of WM patients express V/V or V/F, and the remainder half express F/F at this polymorphic locus. Patients with WM expressing FcγRIIIA-158 V/V or V/F show improved rituximab single agent activity, as well as attainment of deeper responses (VGPR or CR) with combination Rituximab therapy. GA101 is a novel humanized anti-CD20 antibody with a glyco-engineered Fc domain that exhibits increased Fcg receptor binding and ADCC activity. Methods: In this study, we examined the in vitro activity of GA101 and Rituximab against WM cells, and also examined the activity of these antibodies in context of FcγRIIIA-158 polymorphisms. ADCC activity for GA101 and Rituximab was assessed using genotyped healthy donor derived NK cells against BCWM.1 WM cells, as well autologous NK cells against the patient's own lymphoplasmacytic cells. In vitro B-cell depletion and direct cell death induction assays were also performed. Results: We observed significantly greater ADCC activity against WM cells for GA101 versus Rituximab in both healthy donor, as well as autologous NK cell assays. GA101 mediated ADCC activity was particularly more robust versus Rituximab in patients expressing FcγRIIIA-158 F/F versus V/V or V/F (Figure 1). In addition, GA101 induced significant direct cell death against WM lymphoplasmacytic cells, as well as in vitro B-cell depletion assays in comparison to Rituximab, which exhibited little direct cell death induction activity. Nuclear translocation of apoptosis inducing factor (AIF) was observed following GA101 by immunofluorescence microscopy. Conclusions: GA101 is associated with enhanced ADCC activity relative to Rituximab by NK cells, particularly for those subjects expressing FcγRIIIA-158 F/F. In addition, GA101 demonstrated direct cell death in WM lymphoplasmacytic cells through an AIF mediated caspase-independent pathway. These studies provide the framework for the investigation of GA101 in WM, and suggest particular benefit for those patients who express FcγRIIIA-158 F/F. Disclosures: No relevant conflicts of interest to declare.

Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3900-3908 ◽  
Author(s):  
Josée Golay ◽  
Luisella Zaffaroni ◽  
Thomas Vaccari ◽  
Manuela Lazzari ◽  
Gian-Maria Borleri ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Low Grade ◽  
Lymphoma Cells ◽  
B Lymphoma Cells ◽  
Biologic Response ◽  
Anti Cd20 ◽  
Hodgkin's Lymphomas

Abstract The chimeric anti-CD20 MAb rituximab has recently become a treatment of choice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a response rate of about 50%. In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (BL) cell lines, 3 fresh FL samples and normal B cells in vitro. Rituximab efficiently blocks the proliferation of normal B cells, but not that of the lymphoma lines. We did not detect significant apoptosis of the cell lines in response to rituximab alone. All cell lines were targets of antibody-dependent cellular cytotoxicity (ADCC). On the other hand, human complement-mediated lysis was highly variable between cell lines, ranging from 100% lysis to complete resistance. Investigation of the role of the complement inhibitors CD35, CD46, CD55, and CD59 showed that CD55, and to a lesser extent CD59, are important regulators of complement-mediated cytotoxicity (CDC) in FL cell lines as well as in fresh cases of FL: Blocking CD55 and/or CD59 function with specific antibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and that a heterogeneous susceptibility of different lymphoma cells to complement may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that the relative levels of CD55 and CD59 may become useful markers to predict the clinical response.

Abstract 26: Anti-TIM-1 Monoclonal Antibody Therapy Expands Atheroprotective B1a B Cells in vivo and Attenuates Development and Progression of Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Tin Kyaw ◽  
Hamid Hosseini ◽  
Peter Kanellakis ◽  
Christopher Tay ◽  
Anh Cao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Apoptotic Cell ◽  
Antibody Therapy ◽  
Atherosclerosis Progression ◽  
Atherosclerosis Development ◽  
Deficient Mice

Background: B1a B cells attenuate atherosclerosis by secreting natural IgM, but their therapeutic application is limited by lack of availability. Regulatory B cells identified by Tim-1 expression and expanded through Tim-1 ligation by anti-TIM-1 low affinity monoclonal antibody (RMT1-10 mAb) induced tolerance. Here, we examined the capacity of this mAb to expand B1a B cells to inhibit atherosclerosis development and progression of established atherosclerosis. Methods and Results: Six-week old male ApoE-deficient mice were treated with RMT1-10 mAb and fed a high-fat diet (HFD) for 8 weeks. B1a TIM-1+IgM+ B cells and B1a TIM-1+IgM+IL-10+ B cells were selectively expanded. These effects reduced lesion size, markedly increased plasma and lesion IgM and decreased lesion oxidatively modified LDL. Lesion CD4+ and CD8+ T cells, macrophages and MCP-1, VCAM-1, proinflammatory cytokine expression, apoptotic cell numbers and necrotic cores were reduced. Splenectomy indicated that these effects were B1a B cell-dependent. B1a B cell stimulation in vitro with RMT1-10 mAb promoted dose-response B1a B cell proliferation and B1a-derived IgM production. To determine whether treatment attenuated developed atherosclerosis progression, 6 week-old male ApoE-deficient mice were fed a HFD for 6 weeks, and treated with anti-TIM-1 mAb for another 6 weeks while continuing the HFD. Treatment also increased B1a TIM-1+IgM+ B cells, B1a TIM-1+IgM+IL-10+ B cells and IgM levels and greatly attenuated atherosclerosis progression. Conclusions: Anti-TIM-1 treatment attenuates atherosclerosis development and progression by selectively expanding atheroprotective B1a B cells and modulating its immunoinflammatory component. TIM-1 mAb therapy could be an attractive approach for treating atherosclerosis.

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