Genentech Research and Early Development, Genentech Inc., South San Francisco, California.
Roche Global IT Solution Centre, Warsaw, Poland.
Cancer Immunol Res. 2024 Jan 3;12(1):60-71. doi: 10.1158/2326-6066.CIR-23-0072.
T cell-retargeting therapies have transformed the therapeutic landscape for hematologic diseases. T cell-dependent bispecific antibodies (TDB) function as conditional agonists that induce a polyclonal T-cell response, resulting in target cell destruction and cytokine release. The relationship between this response and its effects on surrounding innate immune populations has not been fully explored. Here we show that treatment with mosunetuzumab in patients results in natural killer (NK) cell activation in the peripheral blood. We modeled this phenomenon in vitro and found that TDB-mediated killing activated NK cells, increasing NK function and antibody-dependent cellular cytotoxicity (ADCC), and enhanced the capability of macrophages to perform antibody-dependent cellular phagocytosis (ADCP). This enhancement was triggered by cytokines released through TDB treatment, with IL2 and IFNγ being major drivers for increased ADCC and ADCP, respectively. Surprisingly, cytolytic ability could be further augmented through neutralization of IL10 for NK cells and TNFα for macrophages. Finally, we showed that TDB treatment enhanced the efficacy of Fc-driven killing to an orthogonal solid tumor target in vivo. These results provide rationale for novel antibody therapy combinations that take advantage of both adaptive and innate immune responses.
T 细胞重定向疗法改变了血液疾病的治疗格局。T 细胞依赖性双特异性抗体（TDB）作为条件激动剂发挥作用，诱导多克隆 T 细胞反应，导致靶细胞破坏和细胞因子释放。这种反应及其对周围固有免疫群体的影响尚未得到充分探索。在这里，我们表明，在患者中使用 mosunetuzumab 治疗会导致外周血中自然杀伤（NK）细胞的激活。我们在体外对这种现象进行了建模，发现 TDB 介导的杀伤激活了 NK 细胞，增强了 NK 功能和抗体依赖性细胞毒性（ADCC），并增强了巨噬细胞进行抗体依赖性细胞吞噬（ADCP）的能力。这种增强是通过 TDB 治疗释放的细胞因子触发的，其中 IL2 和 IFNγ 分别是增强 ADCC 和 ADCP 的主要驱动因素。令人惊讶的是，通过中和 NK 细胞的 IL10 和巨噬细胞的 TNFα，可以进一步增强细胞毒性能力。最后，我们表明，TDB 治疗增强了 Fc 驱动的杀伤对体内正交实体肿瘤靶标的疗效。这些结果为利用适应性和固有免疫反应的新型抗体治疗组合提供了依据。
