Antibody-Dependent Cellular Phagocytosis by Macrophages is a Novel Mechanism of Action of Elotuzumab
| Autor: | Irene M. Ghobrial, Natalie Bezman, Michele Moschetta, Antonio Sacco, Aldo M. Roccaro, Yu-Tzu Tai, Daisy Huynh, Siobhan Glavey, Yuji Mishima, Alexandre Detappe, Jamil Azzi, Jennifer L. Guerriero, Ahmed T. Kurdi, Amy Jhatakia, Chia Jen Liu, Michael Robbins, Salomon Manier |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class Antibodies Monoclonal Humanized Monoclonal antibody Article Mice 03 medical and health sciences 0302 clinical medicine Immune system Phagocytosis Cell Line Tumor Tumor Microenvironment medicine Animals Humans Macrophage Elotuzumab Cell Proliferation Antibody-dependent cell-mediated cytotoxicity Tumor microenvironment biology Chemistry Macrophages Antibody-Dependent Cell Cytotoxicity Antibodies Monoclonal Xenograft Model Antitumor Assays Killer Cells Natural 030104 developmental biology Oncology 030220 oncology & carcinogenesis Monoclonal Cancer research biology.protein Antibody Multiple Myeloma medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 17:1454-1463 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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