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Antibody dependent cellular phagocytosis by macrophages is a novel mechanism of action of elotuzumab.
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2018-04-13 , DOI: 10.1158/1535-7163.mct-17-0998
Ahmed T. Kurdi , Siobhan V. Glavey , Natalie A. Bezman , Amy Jhatakia , Jennifer L. Guerriero , Salomon Manier , Michele Moschetta , Yuji Mishima , Aldo Roccaro , Alexandre Detappe , Chia-Jen Liu , Antonio Sacco , Daisy Huynh , Yu-Tzu Tai , Michael D. Robbins , Jamil Azzi , Irene M. Ghobrial

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.

中文翻译:

巨噬细胞的抗体依赖性细胞吞噬作用是 elotuzumab 的一种新作用机制。

Elotuzumab 是最近批准用于治疗多发性骨髓瘤的抗体,已被证明可刺激自然杀伤 (NK) 细胞对 Fcγ 受体 (FcγR) 介导的抗体依赖性细胞毒性。然而,elotuzumab 对肿瘤微环境中其他效应细胞的调节作用尚未得到充分探索。抗体依赖性细胞吞噬作用 (ADCP) 是巨噬细胞有助于单克隆抗体抗肿瘤效力的一种机制。在此,我们使用缺乏 NK 和适应性免疫细胞的异种移植肿瘤模型研究了 elotuzumab 对肿瘤相关巨噬细胞的 NK 细胞独立作用。我们证明了单药 elotuzumab 在免疫功能低下的多发性骨髓瘤异种移植模型中的显着抗肿瘤功效,这部分是由 Elotuzumab 与巨噬细胞的 Fc-FcγR 相互作用介导的。该研究显示 Elotuzumab 在体内诱导巨噬细胞的表型激活,并通过 FcγR 依赖性方式在体外介导骨髓瘤细胞的 ADCP。总之,这些发现提出了一种新的免疫介导机制,通过该机制,elotuzumab 发挥抗骨髓瘤活性,并有助于为可以增强巨噬细胞活性的联合疗法提供理论依据。摩尔癌症治疗; 17(7); 1454-63。©2018 AACR。这些发现提出了一种新的免疫介导机制,通过该机制,elotuzumab 发挥抗骨髓瘤活性,并有助于为可以增强巨噬细胞活性的联合疗法提供理论依据。摩尔癌症治疗; 17(7); 1454-63。©2018 AACR。这些发现提出了一种新的免疫介导机制,通过该机制,elotuzumab 发挥抗骨髓瘤活性,并有助于为可以增强巨噬细胞活性的联合疗法提供理论依据。摩尔癌症治疗; 17(7); 1454-63。©2018 AACR。
更新日期:2018-04-13
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