T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.

中文翻译：

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TriTAC，一类新型 T 细胞接合蛋白结构，设计用于治疗实体瘤


T 细胞具有消除癌细胞和对抗恶性肿瘤的独特能力。癌细胞采用了多种旨在抑制 T 细胞的免疫逃避机制。通过对 T 细胞进行基因重编程、阻断癌细胞对 T 细胞的抑制或将 T 细胞与癌细胞短暂连接以进行重定向裂解的疗法，已显着改善了患者的治疗效果。最后一种方式基于结合癌细胞表面抗原和 T 细胞受体不变成分的抗体构建体。尽管在血液系统癌症患者中观察到针对 CD19、CD20 或 BCMA 特异性的 T 细胞接合剂的高反应率，但实体瘤的治疗却不太成功。在这里，我们开发并表征了一种新型 T 细胞接合器格式，称为 TriTAC（三特异性 T 细胞激活构建体）。 TriTAC 的设计具有提高患者安全性和实体瘤活性的特性，包括高稳定性、小尺寸、灵活的接头、长血清半衰期以及高度特异性和有效的重定向裂解。本研究建立了 TriTAC 的结构/活性关系，并描述了 HPN424 的开发，HPN424 是一种针对转移性去势抵抗性前列腺癌患者的 TriTAC 靶向 PSMA-（FOLH1-）的临床开发。