title: Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma.
abstract: Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA's mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt's lymphoma cell lines. Phagocytosis contributed to DARA's anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.
authors.affiliation: a Genmab ; Utrecht , The Netherlands.
authors.forename: Marije B
authors.initials: MB
authors.lastname: Overdijk
authors.forename: Sandra
authors.initials: S
authors.lastname: Verploegen
authors.forename: Marijn
authors.initials: M
authors.lastname: Bögels
authors.forename: Marjolein
authors.initials: M
authors.lastname: van Egmond
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: Lammerts van Bueren
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.forename: Esther
authors.initials: E
authors.lastname: Breij
authors.forename: Anton C M
authors.initials: AC
authors.lastname: Martens
authors.forename: Wim K
authors.initials: WK
authors.lastname: Bleeker
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057899:Cytophagocytosis / Q000187:drug effects*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; C556306:daratumumab
keywords: ADCC, antibody-dependent cellular cytotoxicity; BL, Burkitt's lymphoma; BM, bone marrow; Burkitt's lymphoma; CCS, cosmic calf serum; CD38; CDC, complement-dependent cytotoxicity; DARA, daratumumab; DP, double positive; E:T, effector to target ratio; FcγR, Fc-gamma receptor; IMiD, immunomodulatory drug; MM, multiple myeloma; MNC, mononuclear cells; Mϕ, macrophage; PBMC, peripheral blood mononuclear cells; daratumumab; mAb, monoclonal antibody; macrophage; multiple myeloma; phagocytosis; therapeutic antibody