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Mol Cancer Ther. 2018 Jul;17(7):1454-1463. doi: 10.1158/1535-7163.MCT-17-0998. Epub 2018 Apr 13.

Antibody-Dependent Cellular Phagocytosis by Macrophages is a Novel Mechanism of Action of Elotuzumab.

Author information

1
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
2
Bristol-Myers Squibb, Princeton, New Jersey.
3
ASST Spedali Civili di Brescia, Clinical Research Development and Phase I Unit, Laboratorio CREA, Brescia, BS, Italy.
4
Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Boston, Massachusetts. Irene_ghobrial@dfci.harvard.edu jazzi@rics.bwh.harvard.edu.
5
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Irene_ghobrial@dfci.harvard.edu jazzi@rics.bwh.harvard.edu.
#
Contributed equally

Abstract

Elotuzumab, a recently approved antibody for the treatment of multiple myeloma, has been shown to stimulate Fcγ receptor (FcγR)-mediated antibody-dependent cellular cytotoxicity by natural killer (NK) cells toward myeloma cells. The modulatory effects of elotuzumab on other effector cells in the tumor microenvironment, however, has not been fully explored. Antibody-dependent cellular phagocytosis (ADCP) is a mechanism by which macrophages contribute to antitumor potency of monoclonal antibodies. Herein, we studied the NK cell independent effect of elotuzumab on tumor-associated macrophages using a xenograft tumor model deficient in NK and adaptive immune cells. We demonstrate significant antitumor efficacy of single-agent elotuzumab in immunocompromised xenograft models of multiple myeloma, which is in part mediated by Fc-FcγR interaction of elotuzumab with macrophages. Elotuzumab is shown in this study to induce phenotypic activation of macrophages in vivo and mediates ADCP of myeloma cells though a FcγR-dependent manner in vitro Together, these findings propose a novel immune-mediated mechanism by which elotuzumab exerts anti-myeloma activity and helps to provide rationale for combination therapies that can enhance macrophage activity. Mol Cancer Ther; 17(7); 1454-63. ©2018 AACR.

PMID:
29654064
PMCID:
PMC6030488
DOI:
10.1158/1535-7163.MCT-17-0998
[Indexed for MEDLINE]
Free PMC Article

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