The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fc gamma Receptor-Mediated Cross-Linking

摘要

Emerging evidence suggests that Fc gamma R-mediated cross-linking of tumor-bound mAbs may induce signaling in tumor cells that contributes to their therapeutic activity. In this study, we show that daratumumab (DARA), a therapeutic human CD38 mAb with a broad-spectrum killing activity, is able to induce programmed cell death (PCD) of CD38(+) multiple myeloma tumor cell lines when cross-linked in vitro by secondary Abs or via an Fc gamma R. By comparing DARA efficacy in a syngeneic in vivo tumor model using FcR gamma-chain knockout or NOTAM mice carrying a signaling-inactive FcR gamma-chain, we found that the inhibitory Fc gamma RIIb as well as activating Fc gamma Rs induce DARA cross-linking-mediated PCD. In conclusion, our in vitro and in vivo data show that Fc gamma R-mediated cross-linking of DARA induces PCD of CD38-expressing multiple myeloma tumor cells, which potentially contributes to the depth of response observed in DARA-treated patients and the drug's multifaceted mechanisms of action.