Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma

Abstract

Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma (MM) cells. Preclinical studies have shown that daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and apoptosis. Given the encouraging efficacy and acceptable safety profile of daratumumab demonstrated in clinical trials, daratumumab has emerged as a novel treatment option for myeloma and became the first monoclonal antibody approved by the FDA for the treatment of MM.

Fig. 1

Daratumumab mechanisms of action. Upper left: daratumumab binds CD38, and its Fc fragment is bound by C1q, initiating complement cascade and resulting in a MAC which leads to cell lysis and death. Upper right: daratumumab binds CD38, and its Fc fragment is then bound by an FcR-bearing effector cell, such as a natural killer cell, leading to activation of cytotoxic processes. Bottom left: daratumumab binds CD38, and its Fc fragment is then bound by an FcR-bearing macrophage, inducing phagocytosis. Bottom right: FcR-mediated crosslinking of daratumumab induces direct cellular apoptosis. MM cell multiple myeloma cell, CDC complement-dependent cytotoxicity, MAC membrane attack complex, ADCC antibody-dependent cell-mediated cytotoxicity, ADCP antibody-dependent cellular phagocytosis