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整

嵌合抗原受体 (CAR) T 细胞疗法依赖于由合成受体引导的 T 细胞靶向和裂解癌细胞。CAR 通过 scFv（结合剂）与细胞表面抗原结合，其亲和力是决定 CAR T 细胞功能和治疗成功的关键。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并获得美国食品和药物管理局 (FDA) 批准的细胞。我们报告了 CD19 抗原与结合剂 FMC63 的冷冻电镜结构，结合剂 FMC63 用于四种 FDA 批准的 CAR T 细胞疗法（Kymriah、Yescarta、Tecartus 和 Breyanzi），结合剂 SJ25C1 也广泛用于多种治疗临床试验。我们将这些结构用于分子动力学模拟，这指导了较低或较高亲和力结合物的产生，并最终产生了具有独特肿瘤识别敏感性的 CAR T 细胞。CAR T 细胞表现出不同的抗原密度要求以触发细胞溶解，并且它们在接触肿瘤细胞后促进胞吞作用的倾向也不同。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。