SAR650984: A Potent Anti-CD38 Therapeutic Antibody with Three Mechanisms of Action (Apoptosis, ADCC, CDC) for Hematological Malignancies (2008)

Abstract CD38 is a promising target for antibody therapeutics for the treatment of various hematological malignancies, including multiple myeloma as well as non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia. CD38 is a type II transmembrane glycoprotein with ectozyme activity that has been implicated in Ca2+ mobilization. CD38 expression correlates with the poor disease prognosis in some hematological malignancies. It has been proposed that rituximab, a well-established anti-CD20 antibody for the treatment of non-Hodgkin’s lymphoma, works by several mechanisms, including antibodydependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. A panel of murine anti-CD38 antibodies was first screened for their ability to induce apoptosis, as measured by Annexin V staining, in various lymphoma, leukemia, and multiple myeloma cell lines. Chimeric human IgG1 versions of the selected murine antibodies with potent apopototic activity were then produced and screened for ADCC and CDC activities. Among the screened antibodies, a chimeric version of SAR650984, a humanized anti-CD38 antibody, had the best overall activities. SAR650984 induced potent apoptosis in Daudi, Raji, Ramos, and SU-DHL-8 lymphoma cells, as well as MOLP-8 multiple myeloma (MM) cells and DND-41 acute T lymphocytic leukemia (T-ALL) cells, which like most, if not, all MM and T-ALL cells, express CD38, but not CD20. SAR650984 also induced potent ADCC and CDC in these tumor cells. When the activities of SAR650984 and rituximab were directly compared in Daudi and Raji lymphoma cells that express similar levels of CD38 and CD20, SAR650984 had similar ADCC and CDC activities as rituximab, and, in addition, SAR650984 induced a greater percentage of lymphoma cells to undergo apoptosis than did rituximab. SAR650984 and rituximab showed similar efficacy in a SCID disseminated survival model with Daudi lymphoma cells. Groups of 10 mice were intravenously injected with 5 × 106 Daudi cells on day 0 and then treated with 40 mg/kg SAR650984, 40 mg/kg rituximab, or PBS control on days 7, 11, 14, 18, 21 and 25. The median survival (range) was 28 days (26–30 days) for the PBS-treated group, 47 days (40–51 days) for the SAR650984-treated group and 42.5 days (40–51 days) for the rituximab-treated group. SAR650984 also showed strong anti-tumor activity in a subcutaneous xenograft SCID model with CD38+ CD20− NCI-H929 multiple myeloma cells. Groups of 10 mice were subcutaneously injected with 106 NCI-H929 cells on day 0, and then treated with 40 mg/kg SAR650984, 40 mg/kg rituximab (non-binding IgG1 control), or PBS control twice weekly for three weeks starting on day 6 when the tumors were palpable. A mean tumor volume of 1000 mm3 was reached by PBS-treated group on day 89 and rituximab-treated group on day 84 (70–80% tumor take rate for NCI-H929). SAR650984 treatment completely prevented the tumor growth in all 10 mice (tumor free at the end of study on day 128). In summary, the humanized anti-CD38 antibody, SAR650984, has potent ADCC, CDC, and apoptotic activities in vitro and anti-tumor activity in vivo. SAR650984 is a promising therapeutic antibody candidate for various hematological malignancies, especially in diseases such as multiple myeloma, where rituximab is inactive.