Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United States.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States.
Front Immunol. 2018 Nov 5;9:2551. doi: 10.3389/fimmu.2018.02551. eCollection 2018.
Multiple myeloma (MM) is a bone marrow plasma cell neoplasm and is the second most-common hematologic malignancy. Despite advances in therapy, MM remains largely incurable. Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7, which is highly expressed on myeloma cells, and the antibody is approved for the treatment of relapsed and/or refractory (RR) MM in combination with lenalidomide and dexamethasone. Elotuzumab can stimulate robust antibody-dependent cellular cytotoxicity (ADCC) through engaging with FcγRIIIA (CD16) on NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Interestingly, SLAMF7 is also expressed on cytolytic NK cells, which also express the requisite adaptor protein, EAT-2, to mediate activation signaling. Accumulating evidence indicates that antibody crosslinking of SLAMF7 on human and mouse NK cells can stimulate EAT-2-dependent activation of PLCγ, ERK, and intracellular calcium mobilization. The binding of SLAMF7 by elotuzumab can directly induce signal transduction in human NK cells, including co-stimulation of the calcium signaling triggered through other surface receptors, such as NKp46 and NKG2D. In RRMM patients, elotuzumab monotherapy did not produce objective responses, but did enhance the activity of approved standard of care therapies, including lenalidomide or bortezomib, which are known to enhance anti-tumor responses by NK cells. Taken together, these preclinical results and accumulating experience in the clinic provide compelling evidence that the mechanism of action of elotuzumab in MM patients involves the activation of NK cells through both CD16-mediated ADCC and direct co-stimulation via engagement with SLAMF7, as well as promoting ADCP by macrophages. We review the current understanding of how elotuzumab utilizes multiple mechanisms to facilitate immune-mediated attack of myeloma cells, as well as outline goals for future research.
多发性骨髓瘤（MM）是一种骨髓浆细胞肿瘤，是第二大常见的血液系统恶性肿瘤。尽管治疗取得了进展，但 MM 仍然基本上无法治愈。依洛珠单抗是一种针对 SLAMF7 的人源化 IgG1 单克隆抗体，SLAMF7 在骨髓瘤细胞上高度表达，该抗体已被批准与来那度胺和地塞米松联合用于治疗复发和/或难治性（RR）MM。依洛珠单抗可通过与 NK 细胞上的 FcγRIIIA（CD16）结合以及巨噬细胞的抗体依赖性细胞吞噬作用（ADCP）来刺激强大的抗体依赖性细胞细胞毒性（ADCC）。有趣的是，SLAMF7 也在细胞毒性 NK 细胞上表达，NK 细胞也表达必需的衔接蛋白 EAT-2，以介导激活信号。越来越多的证据表明，SLAMF7 在人和小鼠 NK 细胞上的抗体交联可刺激 EAT-2 依赖性 PLCγ、ERK 和细胞内钙动员的激活信号。依洛珠单抗与 SLAMF7 的结合可直接诱导人 NK 细胞中的信号转导，包括通过其他表面受体（如 NKp46 和 NKG2D）触发的钙信号的共刺激。在 RRMM 患者中，依洛珠单抗单药治疗未产生客观反应，但增强了已批准的标准治疗药物的活性，包括来那度胺或硼替佐米，这些药物已知可通过 NK 细胞增强抗肿瘤反应。综上所述，这些临床前结果和临床积累的经验提供了令人信服的证据，表明依洛珠单抗在 MM 患者中的作用机制涉及通过 CD16 介导的 ADCC 和与 SLAMF7 结合的直接共刺激激活 NK 细胞，以及通过巨噬细胞促进 ADCP。我们回顾了目前对依洛珠单抗如何利用多种机制促进对骨髓瘤细胞的免疫介导攻击的理解，并概述了未来研究的目标。
