Blood Adv. 2021 Mar 9;5(5):1291-1304. doi: 10.1182/bloodadvances.2020002736.
CD3-engaging bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells are potent therapeutic approaches for redirecting patient T cells to recognize and kill tumors. Here we describe a fully human bsAb (REGN5458) that binds to B-cell maturation antigen (BCMA) and CD3, and compare its antitumor activities vs those of anti-BCMA CAR T cells to identify differences in efficacy and mechanism of action. In vitro, BCMAxCD3 bsAb efficiently induced polyclonal T-cell killing of primary human plasma cells and multiple myeloma (MM) cell lines expressing a range of BCMA cell surface densities. In vivo, BCMAxCD3 bsAb suppressed the growth of human MM tumors in murine xenogeneic models and showed potent combinatorial efficacy with programmed cell death protein 1 blockade. BCMAxCD3 bsAb administration to cynomolgus monkeys was well tolerated, resulting in the depletion of BCMA+ cells and mild inflammatory responses characterized by transient increases in C-reactive protein and serum cytokines. The antitumor efficacy of BCMAxCD3 bsAb was compared with BCMA-specific CAR T cells containing a BCMA-binding single-chain variable fragment derived from REGN5458. Both BCMAxCD3 bsAb and anti-BCMA CAR T cells showed similar targeted cytotoxicity of MM cell lines and primary MM cells in vitro. In head-to-head in vivo studies, BCMAxCD3 bsAb rapidly cleared established systemic MM tumors, whereas CAR T cells cleared tumors with slower kinetics. Thus, using the same BCMA-binding domain, these results suggest that BCMAxCD3 bsAb rapidly exerts its therapeutic effects by engaging T cells already in place at the tumor site, whereas anti-BCMA CAR T cells require time to traffic to the tumor site, activate, and numerically expand before exerting antitumor effects.
CD3 结合双特异性抗体（bsAbs）和嵌合抗原受体（CAR）T 细胞是一种将患者 T 细胞重新定向识别和杀伤肿瘤的有效治疗方法。在这里，我们描述了一种完全人源的 bsAb（REGN5458），它与 B 细胞成熟抗原（BCMA）和 CD3 结合，并比较其抗肿瘤活性与抗 BCMA CAR T 细胞的活性，以确定疗效和作用机制的差异。在体外，BCMAxCD3 bsAb 有效地诱导多克隆 T 细胞杀伤原代人浆细胞和多种表达不同 BCMA 细胞表面密度的骨髓瘤（MM）细胞系。在体内，BCMAxCD3 bsAb 抑制了人 MM 肿瘤在小鼠异种移植模型中的生长，并与程序性细胞死亡蛋白 1 阻断显示出强大的组合疗效。BCMAxCD3 bsAb 在食蟹猴中的给药耐受性良好，导致 BCMA+细胞耗竭，并伴有短暂的 C 反应蛋白和血清细胞因子升高的轻度炎症反应。BCMAxCD3 bsAb 的抗肿瘤疗效与含有源自 REGN5458 的 BCMA 结合单链可变片段的 BCMA 特异性 CAR T 细胞进行了比较。BCMAxCD3 bsAb 和抗 BCMA CAR T 细胞在体外均显示出对 MM 细胞系和原代 MM 细胞的相似靶向细胞毒性。在头对头的体内研究中，BCMAxCD3 bsAb 迅速清除已建立的全身性 MM 肿瘤，而 CAR T 细胞则以较慢的动力学清除肿瘤。因此，使用相同的 BCMA 结合结构域，这些结果表明，BCMAxCD3 bsAb 通过结合已经存在于肿瘤部位的 T 细胞迅速发挥其治疗作用，而抗 BCMA CAR T 细胞需要时间到达肿瘤部位，激活并在发挥抗肿瘤作用之前进行数量上的扩增。
