Abstract 4735: SAR650984: Characterization of a potent phase I humanized anti-CD38 antibody for the treatment of multiple myeloma and other hematologic malignancies

SAR650984, a humanized antibody targeting the type II transmembrane glycoprotein CD38 is currently in phase I dose escalation in patients with selected CD38+ hematological malignancies. CD38 is an ectoenzyme which catalyzes the formation of nucleotide metabolites involved in calcium signalling. Nearly 90% of MM patients express CD38 and this expression correlates with poor disease prognosis. The robust multiple mechanisms of action of SAR650984 include antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis induction, leading to in vivo efficacy in different tumor models, as reported previously (AACR 2010 #714; AACR 2009 #859, #2048, #2797; ASH 2008 #2756). Here, we report additional studies aimed to further elucidate the mechanism of action of SAR650984. These studies include solving the crystal structure of the SAR650984/CD38 complex, measuring enzymatic inhibition, testing in vitro activity against human primary MM cells, studying the mechanism of apoptosis induction in vivo and lastly assessing in vivo activity in combination with bortezomib (Velcade®). Fab fragments derived from SAR650984 were co-crystallized with soluble human CD38 to a 1.5 Å resolution. Loop H3 of the paratope (residues Asp100, Tyr101, Tyr102, Gly103, Ser104 and Asn105) protrudes out of the SAR650984 Fab structure and is particularly critical for the complex formation. Significant conformational changes are observed in CD38 upon binding of SAR650984 while the configuration of the key residues that are involved in the ADP-ribosyl cyclase activity of CD38 is conserved as well as the access to the catalytic site. SAR650984 shows potent inhibition of the catalytic activity of CD38 (86 % at 10 nM), Taken together this would suggest that SAR650984 is not a direct orthosteric antagonist but more likely an allosteric antagonist of CD38. Consistent with the in vitro activity observed against cell lines, SAR650984 also demonstrated potent pro-apoptotic activity against a panel of CD38+ human primary MM cells. In SCID mice bearing SU-DHL-8 lymphoma, SAR650984 induced apoptosis of tumor cells, evidenced by a robust and sustained induction of cleaved caspase 7. In combination with bortezomib, a standard of care for MM treatment, SAR650984 demonstrated synergy in NCI-H929 MM xenografts in SCID mice. Together with previous reports the humanized anti-CD38 antibody, SAR650984, has demonstrated potent anti-tumor activities including ADCC, CDC and