Chimeric antigen receptor (CAR) T cell therapy relies on T cells that are guided by synthetic receptors to target and lyse cancer cells. CARs bind to cell surface antigens through an scFv (binder), the affinity of which is central to determining CAR T cell function and therapeutic success. CAR T cells targeting CD19 were the first to achieve marked clinical responses in patients with relapsed/refractory B cell malignancies and to be approved by the U.S. Food and Drug Administration (FDA). We report cryo-EM structures of CD19 antigen with the binder FMC63, which is used in four FDA-approved CAR T cell therapies (Kymriah, Yescarta, Tecartus, and Breyanzi), and the binder SJ25C1, which has also been used extensively in multiple clinical trials. We used these structures for molecular dynamics simulations, which guided creation of lower- or higher-affinity binders, and ultimately produced CAR T cells endowed with distinct tumor recognition sensitivities. The CAR T cells exhibited different antigen density requirements to trigger cytolysis and differed in their propensity to prompt trogocytosis upon contacting tumor cells. Our work shows how structural information can be applied to tune CAR T cell performance to specific target antigen densities.

中文翻译：

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CD19 CAR 抗原结合机制和亲和力调节


嵌合抗原受体 (CAR) T 细胞疗法依赖于合成受体引导的 T 细胞来靶向并裂解癌细胞。 CAR 通过 scFv（结合剂）与细胞表面抗原结合，其亲和力对于决定 CAR T 细胞功能和治疗成功至关重要。靶向 CD19 的 CAR T 细胞是第一个在复发/难治性 B 细胞恶性肿瘤患者中取得显着临床反应的细胞，并获得美国食品和药物管理局 (FDA) 的批准。我们报告了 CD19 抗原与结合剂 FMC63 和结合剂 SJ25C1 的冷冻电镜结构，FMC63 用于 FDA 批准的四种 CAR T 细胞疗法（Kymriah、Yescarta、Tecartus 和 Breyanzi），而结合剂 SJ25C1 也广泛用于多种治疗临床试验。我们使用这些结构进行分子动力学模拟，指导创建较低或较高亲和力的结合物，并最终产生具有独特肿瘤识别敏感性的 CAR T 细胞。 CAR T 细胞表现出不同的触发细胞溶解的抗原密度要求，并且在接触肿瘤细胞时促进吞噬作用的倾向也不同。我们的工作展示了如何应用结构信息来调整 CAR T 细胞的性能以适应特定的靶抗原密度。