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

Overdijk, Marije B ; Jansen, J H Marco ; Nederend, Maaike ; Lammerts van Bueren, Jeroen J ; Groen, Richard W J ; Parren, Paul W H I ; Leusen, Jeanette H W ; Boross, Peter

The Journal of immunology (1950), 2016-08, Vol.197 (3), p.807-813 [Periódico revisado por pares]

United States

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Título:
The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor-Mediated Cross-Linking
Autor: Overdijk, Marije B ; Jansen, J H Marco ; Nederend, Maaike ; Lammerts van Bueren, Jeroen J ; Groen, Richard W J ; Parren, Paul W H I ; Leusen, Jeanette H W ; Boross, Peter
Assuntos: 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
É parte de: The Journal of immunology (1950), 2016-08, Vol.197 (3), p.807-813
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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.
Editor: United States
Idioma: Inglês

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

Overdijk, Marije B ; Jansen, J H Marco ; Nederend, Maaike ; Lammerts van Bueren, Jeroen J ; Groen, Richard W J ; Parren, Paul W H I ; Leusen, Jeanette H W ; Boross, Peter

United States

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