SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies
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Open Access
- 1 September 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 20 (17), 4574-4583
- https://doi.org/10.1158/1078-0432.ccr-14-0695
Abstract
Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984. Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice. Results: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells. Conclusion: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies. Clin Cancer Res; 20(17); 4574–83. ©2014 AACR.Keywords
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This publication has 47 references indexed in Scilit:
- Novel CD20 monoclonal antibodies for lymphoma therapyJournal of Hematology & Oncology, 2012
- Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicityBlood, 2010
- Conformational Closure of the Catalytic Site of Human CD38 Induced by CalciumBiochemistry, 2008
- CD38/CD19: a lipid raft–dependent signaling complex in human B cellsBlood, 2007
- Monoclonal Antibodies for B-Cell Lymphomas: Rituximab and BeyondHematology-American Society Hematology Education Program, 2007
- Structural Basis for the Mechanistic Understanding of Human CD38-controlled Multiple CatalysisJournal of Biological Chemistry, 2006
- In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemiaBlood, 2006
- Flow Cytometric Immunophenotypic Analysis of 306 Cases of Multiple MyelomaAmerican Journal of Clinical Pathology, 2004
- CD38 signaling by agonistic monoclonal antibody prevents apoptosis of human germinal center B cellsEuropean Journal of Immunology, 1994
- Discontinuous expression of a membrane antigen (HB‐7) during B lymphocyte differentiationTissue Antigens, 1984