Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

• Published in: mAbs Vol. 7; no. 2; pp. 311 - 320
• Main Authors: Overdijk, Marije B, Verploegen, Sandra, Bögels, Marijn, van Egmond, Marjolein, van Bueren, Jeroen J Lammerts, Mutis, Tuna, Groen, Richard WJ, Breij, Esther, Martens, Anton CM, Bleeker, Wim K, Parren, Paul WHI
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 04.03.2015
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Neoplasm - pharmacology; Burkitt's lymphoma; CD38; Cell Line, Tumor; Cytophagocytosis - drug effects; daratumumab; Humans; Lymphoma - drug therapy; Lymphoma - immunology; Lymphoma - pathology; macrophage; Macrophages - immunology; Mice; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Multiple Myeloma - pathology; phagocytosis; therapeutic antibody; Xenograft Model Antitumor Assays; phagocytosis; multiple myeloma; CCS, cosmic calf serum; PBMC, peripheral blood mononuclear cells; mAb, monoclonal antibody; MNC, mononuclear cells; Mϕ, macrophage; macrophage; MM, multiple myeloma; ADCC, antibody-dependent cellular cytotoxicity; E:T, effector to target ratio; BL, Burkitt's lymphoma; BM, bone marrow; Burkitt's lymphoma; FcγR, Fc-gamma receptor; DP, double positive; therapeutic antibody; CD38; DARA, daratumumab; daratumumab; CDC, complement-dependent cytotoxicity; IMiD, immunomodulatory drug
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2015.1007813

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.