Mechanism of action of CD38 antibodies. (A) CD38-targeting antibodies have pleiotropic mechanisms of action, which can be subdivided into (i) Fc-dependent immune-effector mechanisms; (ii) direct effects; and (iii) immunomodulatory effects. The Fc-dependent immune-effector mechanisms include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). The process of ADCC is achieved through the activation of FcRs on NK cells and myeloid cells by tumor-cell attached CD38 antibodies. Subsequent release of perforin and granzymes from effector cells as well as interactions with death ligands FasL and tumor necrosis factor–related apoptosis-inducing ligand lead to MM cell death. In ADCP phagocytosis is mediated by monocytes, macrophages, neutrophils, and dendritic cells following interaction of the Fc tail of the therapeutic antibody with FcRs on these effector cells. CDC is initiated following the interaction of the antibody Fc domains with the classic complement-activating protein C1q, which leads to activation of downstream complement proteins, resulting in assembly of the membrane attack complex (MAC), which punches holes in MM tumor cells. The chemotactic complement molecules, C3a and C5a, are also produced during this process. These molecules can recruit and activate immune-effector cells. Direct effects include induction of apoptosis, as well as inhibition of CD38 ectoenzyme function, which may lead to reduced adenosine levels in the BM myeloma niche. Adenosine is an immunosuppressor that helps the tumor to evade the host immune response by promoting regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and depressing NK- and T-cell effectors. CD38 antibodies have immunomodulatory effects via the eradication of CD38⁺ Tregs, regulatory B cells (Bregs), and MDSCs, which result in CD4⁺ and CD8⁺ T-cell expansion, and potentially a better host-antitumor immune response. Adapted from van de Donk et al⁷⁸  with permission. (B) The relative contribution of these different mechanisms of action to MM cell killing differs among daratumumab, isatuximab, and MOR202. The efficacy of these 3 CD38 antibodies was directly compared in preclinical studies in terms of direct induction of programmed cell death (PCD), induction of PCD after crosslinking, inhibition of CD38 ectoenzyme activity, and the induction of ADCC, ADCP, and CDC. The immunomodulatory effects of the CD38 antibodies were not compared in a head-to-head analysis, and therefore were not included in panel B. MoA, mechanism of action; nd, not determined.