The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor–Mediated Cross-Linking
Copyright policy )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.
- University of Southern Denmark Denmark
- Amsterdam UMC Netherlands
- Genmab (United States) United States
- Amsterdam University Medical Centers Netherlands
- Amsterdam UMC, location VUmc Netherlands
Knockout, Antineoplastic Agents, Apoptosis, Antibody-Dependent Cell Cytotoxicity/immunology, Inbred C57BL, Antibodies, Mice, Multiple Myeloma/immunology, Receptors, Journal Article, Tumor Cells, Cultured, Animals, Humans, Mice, Knockout, Cultured, IgG/drug effects, Animal, Apoptosis/drug effects, Receptors, IgG, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, ADP-ribosyl Cyclase 1, Antibodies, Monoclonal/pharmacology, Monoclonal/pharmacology, Tumor Cells, Receptors, IgG/drug effects, Mice, Inbred C57BL, Disease Models, Animal, Disease Models, Multiple Myeloma, Antineoplastic Agents/pharmacology
Knockout, Antineoplastic Agents, Apoptosis, Antibody-Dependent Cell Cytotoxicity/immunology, Inbred C57BL, Antibodies, Mice, Multiple Myeloma/immunology, Receptors, Journal Article, Tumor Cells, Cultured, Animals, Humans, Mice, Knockout, Cultured, IgG/drug effects, Animal, Apoptosis/drug effects, Receptors, IgG, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, ADP-ribosyl Cyclase 1, Antibodies, Monoclonal/pharmacology, Monoclonal/pharmacology, Tumor Cells, Receptors, IgG/drug effects, Mice, Inbred C57BL, Disease Models, Animal, Disease Models, Multiple Myeloma, Antineoplastic Agents/pharmacology
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