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

Abstract

Emerging evidence suggests that FcγR-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 FcγR. By comparing DARA efficacy in a syngeneic in vivo tumor model using FcRγ-chain knockout or NOTAM mice carrying a signaling-inactive FcRγ-chain, we found that the inhibitory FcγRIIb as well as activating FcγRs induce DARA cross-linking–mediated PCD. In conclusion, our in vitro and in vivo data show that FcγR-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.

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

“…To assess rare populations and their CD38 + subsets, WB samples from the SIRIUS trial were manually gated and analyzed. Beyond confirmation of the previously reported daratumumab‐mediated depletion of immune‐suppressive populations, like CD38 + T regs (CD4 + CD25 + CD127 − ) (Fig. A), our high‐dimensional cytometry analysis enabled the first evaluation of basophils (CD45 − CD123 + HLA‐DR − ) under daratumumab treatment.…”

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

“…Other effector cells, such as granulocytes, which are not depleted by daratumumab, are also capable of mediating ADCC and may contribute to the efficacy of daratumumab. Moreover, in addition to ADCC, daratumumab has several known mechanisms of action that may also contribute to its efficacy, including CDC, 8 antibody-dependent cellular phagocytosis, 9 apoptosis, 13 and modulation of CD38 enzymatic activity.…”

The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia–Microenvironment Interactions in Chronic Lymphocytic Leukemia

“…DARA induces killing of tumor cells, mainly via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) (20) and antibody-dependent cellular phagocytosis (ADCP) by macrophages (mϕ) (21) in MM and Burkitt lymphoma (BL) cell lines. In addition, DARA induces apoptosis upon secondary cross-linking (22). Recent studies have revealed previously unknown immunomodulatory effects of DARA where CD38-expressing immunosuppressive regulatory T and B cells, and myeloid-derived suppressor cells are highly sensitive to DARA treatment (23).…”