Article open access publication

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

mAbs, Taylor & Francis, ISSN 1942-0870

Volume 7, 2, 2015

DOI:10.1080/19420862.2015.1007813, Dimensions: pub.1058413271, PMC: PMC4622648, PMID: 25760767,

Affiliations

Organisations

  1. (1) Genmab (Netherlands), grid.466767.2
  2. (2) VU University Medical Center, grid.16872.3a
  3. (3) Department of Clinical Chemistry and Hematology; University Medical Center, ; Utrecht, The Netherlands
  4. (4) Department of Cell Biology; University Medical Center, ; Utrecht, The Netherlands
  5. (5) Department of Immunology; University Medical Center, ; Utrecht, The Netherlands
  6. (6) Leiden University Medical Center, grid.10419.3d
  7. (7) University of Southern Denmark, grid.10825.3e, SDU

Countries

Netherlands

Denmark

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Europe

Description

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.

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University of Southern Denmark

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2015: Unused

Research area: Medicine

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Times Cited: 208

Field Citation Ratio (FCR): 39.67

Relative Citation ratio (RCR): 9.15

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