TriTACs, a Novel Class of T-Cell-Engaging Protein Constructs Designed for the Treatment of Solid Tumors
TriTACs, a Novel Class of T-Cell-Engaging Protein Constructs Designed for the Treatment of Solid Tumors
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DOI：
10.1158/1535-7163.mct-20-0061
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发表时间：
2021-01-01
影响因子：
5.7
通讯作者：
Wesche, Holger
中科院分区：
文献类型：
--
作者：
Austin, Richard J.;Lemon, Bryan D.;Wesche, Holger
T细胞具有消除癌细胞和对抗恶性肿瘤的独特能力。癌细胞采用多种免疫逃避机制，旨在抑制T细胞。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细胞与癌细胞瞬时连接以进行重定向裂解的疗法，已经实现了显著改善的患者结果。最后一种模式是基于抗体构建体，其结合癌细胞上的表面抗原和T细胞受体的不变组分。尽管在血液系统癌症患者中观察到对CD 19、CD 20或BCMA具有特异性的T细胞增殖剂的高应答率，但实体瘤的治疗不太成功。在这里，我们开发并表征了一种新的T细胞活化剂形式，称为TriTAC（用于三特异性T细胞活化构建体）。TriTAC被设计成具有改善患者安全性和实体瘤活性的特征，包括高稳定性、小尺寸、柔性接头、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HPN 424的开发，HPN 424是一种PSMA-（FOLH 1-）靶向TriTAC，用于转移性去势抵抗性前列腺癌患者的临床开发。
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.