Abstract
Abstract SAR650984 is a humanized IgG1 monoclonal antibody selectively targeting CD38 that is in clinical development for the treatment of multiple myeloma (MM). SAR650984 eliminates MM cells through different mechanisms, including antibody dependent cytotoxicity and phagocytosis (ADCC and ADCP, respectively), complement dependent cytotoxicity (CDC), and direct induction of apoptosis. The aim of this study was to assess the cell killing activity of SAR650984 following genetic and chemical manipulation of CD38 expression in MM cells. We established several MM cell lines engineered to overexpress CD38; median levels of CD38 were 537,000 receptors/cell, versus 29,000 receptors/cell in the parental cell lines. ADCC, ADCP, CDC, and apoptosis induced by SAR650984 treatment were all significantly increased in the CD38-overexpressing lines compared with the parental cell lines. Based on these data, we hypothesized that pre-treatment of MM cells with all-trans retinoic acid (ATRA) would enhance the activity of SAR650984, since ATRA can induce up-regulation of CD38 expression. Treatment of the MM cell lines JJN-3, ARH-77, U266, Karpas-620, SKMM-2, RPMI-8226, NCI-H929, KMS-12PE and MOLP-8 with ATRA resulted in a dose-dependent 1.4- to 6.7-fold up-regulation of cell surface expressed CD38. Pretreatment of MM cells with ATRA for 48 hours resulted in enhanced SAR650984-mediated ADCC and ADCP compared to non-pretreated cells. The enhancement of ADCC and ADCP activity by ATRA pretreatment was recorded in all the cell lines tested. In conclusion, these in vitro data are supportive of further evaluation of the combination of SAR650984 and ATRA for the treatment of MM. Citation Format: Lucas Bush, David Harper, Rita Greco, Zhili Song, Guang Yang, Francisco Adrian. All-trans retinoic acid enhances the effector functions of the anti-CD38 antibody SAR650984. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4282. doi:10.1158/1538-7445.AM2015-4282
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