Article open access publication

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

The Journal of Immunology, The American Association of Immunologists, ISSN 0022-1767

Volume 197, 3, 2016

DOI:10.4049/jimmunol.1501351, Dimensions: pub.1079287282, PMID: 27316683,

Affiliations

Organisations

  1. (1) Genmab (Netherlands), grid.466767.2
  2. (2) Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center, 3584 CX Utrecht, the Netherlands;
  3. (3) Department of Cell Biology, University Medical Center, 3584 CX Utrecht, the Netherlands;
  4. (4) Leiden University Medical Center, grid.10419.3d
  5. (5) University of Southern Denmark, grid.10825.3e, SDU
  6. (6) Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center, 3584 CX Utrecht, the Netherlands; jleusen@umcutrecht.nl.

Countries

Netherlands

Denmark

Continents

Europe

Description

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.

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University of Southern Denmark

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Times Cited: 97

Field Citation Ratio (FCR): 18.34

Relative Citation ratio (RCR): 5.48

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