부산대학교 도서관

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy highlighting the need for novel approaches. In this study we compared the pre-clinical efficacy of SAR442085, a next generation anti-CD38 mAb with enhanced affinity for activating Fc gamma receptors (FcγR), with first generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a) receptors. SAR442085 also exhibited better in vitroADCC (antibody dependent cellular cytotoxicity) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158V/F variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher NK cell activation and degranulation against primary plasma cells than pre-existing Fc wild-type anti-CD38 mAbs. Finally, using huFcgRtransgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell dependent in vivoanti-tumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.