SAR 650984, a Therapeutic Anti-CD38 Monoclonal Antibody, Blocks CD38-CD31 Interaction in Multiple Myeloma

CD38, a type II transmembrane glycoprotein with both ecto-enzyme activity and receptor function, is highly expressed at the surface of many hematological cancer cells. Recently, SAR 650984 (SAR), a novel humanized anti-CD38 monoclonal antibody in early clinical development, has shown an impressive and durable single agent activity in patients with multiple myeloma (MM). To further characterize the biological function of CD38 in MM cells, we generated RPMI8226 MM cells overexpressing CD38 (R-CD38) by lentiviral infection followed by blascitidin selection. R-CD38, maintained in 10 mg/ml of blascitidin-containing media, expresses 6-fold greater CD38 mRNA and protein levels than control RPMI8226 cells, as confirmed by RNAseq and quantitative flow cytometry. To study whether CD38 levels affect cell signaling cascade in MM cells, the phosphorylated forms of various signaling proteins were analyzed using Kinexa Antibody Microarray. At least 20 and 8 phospho-signaling molecules were significantly increased and reduced, respectively, in R-38 vs control RPMI8226 cells. Upregulated kinases include HO1, CREB1, IRAK1, and ERK1/2, whereas calreticulin and RSK1/2 are downregulated. RNAseq profiling on Illumina HiSeq was next done to identify CD38-targeted genes in MM cells. A volcano plot shows that 123 genes are induced and 32 repressed with FC>= 4 (positive or negative) and p value Disclosures Cai: Sanofi: Employment. Yang: Sanofi: Employment. Song: Sanofi: Employment. Theilhaber: Sanofi: Employment. Adrian: Sanofi: Employment. Anderson: Celgene: Consultancy; Onyx: Consultancy; Gilead Sciences: Consultancy; Sanofi-Aventis US: Consultancy; Acetylon: Scientific Founder Other; Oncoprep: Scientific Founder Other.