Abstract 2266: SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma

CD38 is a cell surface glycoprotein highly expressed in multiple myeloma (MM) cells making it an attractive target for antibody–based therapy. Anti–CD38 treatment represents a major breakthrough in the treatment of relapsing and refractory multiple myeloma (RRMM) patients. However, a number of patients do not respond to anti–CD38 single agent therapy stressing the need for novel approaches. Here we describe SAR442085, a next generation anti–CD38 antibody, with higher affinity for the activating FcγRIIIa and FcγRIIa receptors expressed on effector cells as compared to the approved anti–CD38 antibody daratumumab, resulting in greater effector functions. SAR442085 targets CD38 with high affinity and is able to destroy CD38 expressing tumor cells in vitro through effector function mechanisms (ADCC and antibody dependent cellular phagocytosis, ADCP) as well as by direct apoptosis. SAR442085 exhibits better ADCC activity as compared to daratumumab with more than 8–fold EC50 improvement against RPMI–8226 MM cells. SAR442085 also inhibits CD38 enzymatic activity. Using primary bone marrow aspirates from MM patients, an increased ability of SAR442085 to engage CD16 was demonstrated, resulting in a higher level of NK cell activation and degranulation against primary plasma cells, as compared to daratumumab. In addition, SAR442085 demonstrated potent in vivo single–agent activity against murine tumor cells expressing human CD38, in a transgenic C57BL/6 mouse model humanized for all Fcγ receptors, with 90% mice survival at 10 and 1.25 mg/kg and up to 90 days median survival time. Overall, these data support the current evaluation of this next generation anti–CD38 antibody in phase I clinical trials in patients with relapsed/refractory MM. Citation Format: Angela Virone-Oddos, Sahar Kassem, Bere Diallo, Alexandre Tang, Alain Fournier, Nizar El-Murr, Nadege Carrie-Constantin, Celine Nicolazzi, Isabelle Arnould, Herve Avet-Loiseau, Sukhvinder S. Sidhu, Ludovic Martinet, Marielle Chiron. SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2266.