SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies

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 þ and CD38 þ 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 þ 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.

The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor–Mediated Cross-Linking

“…However, on the Burkitt's lymphoma cell line Ramos we did show caspase-3 activation upon cross-linking of DARA with secondary Ab (8). The homotypic aggregation-related caspase-independent and -dependent PCD was also shown for SAR650984, a chimeric CD38 Ab (40,41), in the absence of secondary cross-linking. Nonetheless, we have previously shown that the direct effect of SAR650984 to induce PCD is comparable to DARA-induced PCD in the presence of a secondary Ab (8).…”

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

“…17 An ongoing phase 1-2 study of daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed myeloma or relapsed and refractory myeloma has shown high response rates and responses that improved over time. 18 SAR650984, a humanized IgG1 monoclonal antibody, also targets CD38, 19 and clinical responses have been reported in patients with relapsed myeloma or relapsed and refractory myeloma who received the drug as monotherapy 20 or in combination with lenalidomide and dexamethasone, findings that further validate this approach. 21 Elotuzumab, a humanized IgG1 monoclonal antibody that targets the signaling lymphocytic activation molecule F7 (SLAMF7), 22 was associated with stable disease as the best response when it was used as a single agent 23 but has shown clinically relevant activity in combination with lenalidomide and dexamethasone in two studies.…”

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…12 Macrophages are known to be abundantly present in the bone marrow of MM patients, 4,5 and macrophage-mediated phagocytosis has been demonstrated to be induced by several mAbs targeting MM cells. [13][14][15] The capacity of DARA to induce macrophage-mediated phagocytosis has not been studied thus far.…”