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MAbs. 2015;7(2):311-21. doi: 10.1080/19420862.2015.1007813.

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

Author information

1
a Genmab ; Utrecht , The Netherlands.

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.

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

PMID:
25760767
PMCID:
PMC4622648
DOI:
10.1080/19420862.2015.1007813
[Indexed for MEDLINE]
Free PMC Article

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