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

J Immunol. 2016 Aug 1;197(3):807-13. doi: 10.4049/jimmunol.1501351. Epub 2016 Jun 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Myeloma / immunology*
  • Receptors, IgG / drug effects
  • Receptors, IgG / immunology*
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Receptors, IgG
  • daratumumab
  • ADP-ribosyl Cyclase 1