The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor-Mediated Cross-Linking.
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.
Genmab, 3584 CM Utrecht, the Netherlands;
Marije B
MB
Overdijk
Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center, 3584 CX Utrecht, the Netherlands;
J H Marco
JH
Jansen
Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center, 3584 CX Utrecht, the Netherlands;
Maaike
M
Nederend
Genmab, 3584 CM Utrecht, the Netherlands;
Jeroen J
JJ
Lammerts van Bueren
Department of Cell Biology, University Medical Center, 3584 CX Utrecht, the Netherlands;
Richard W J
RW
Groen
Genmab, 3584 CM Utrecht, the Netherlands; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; and Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Paul W H I
0000-0002-4365-3859
PW
Parren
Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center, 3584 CX Utrecht, the Netherlands; jleusen@umcutrecht.nl.
Jeanette H W
JH
Leusen
Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center, 3584 CX Utrecht, the Netherlands;
Peter
P
Boross
D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000276:immunology*; D017452:Receptors, IgG / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017452:Receptors, IgG; C556306:daratumumab; D051997:ADP-ribosyl Cyclase 1