美国斯坦福大学医学院K. Christopher Garcia课题组的最新研究通过捕获键改造增强了T细胞受体(TCR)的敏感性。相关论文于2022年4月8日发表在《科学》杂志上。

研究人员研发了一种替代策略来分离TCR突变体，这些突变体具有高激活信号以及通过获取捕获键与低亲和力肽-主要组织相容性复合物(pMHC)结合。与临床测试的与心脏抗原具有致命性交叉反应的高亲和力TCR相比，肿瘤抗原MAGE-A3特异性TCR工程类似物保持了生理亲和力，同时表现出增强的靶杀伤效力和极低的交叉反应性。捕获键改造是一种基于生物物理的策略，以提高用于T细胞治疗TCR的高灵敏度，降低潜在的不良交叉反应。

研究人员表示，工程化T细胞受体过继细胞疗法是一种靶向癌症抗原的潜在治疗方法，但肿瘤反应性TCR通常对其目标配体、pMHC的反应较弱。高亲和力TCR可以增强TCR-T细胞治疗的功效，但也可以与脱靶抗原发生交叉反应，导致器官免疫。

附：英文原文

Title: Tuning T cell receptor sensitivity through catch bond engineering

Author: Xiang Zhao, Elizabeth M. Kolawole, Waipan Chan, Yinnian Feng, Xinbo Yang, Marvin H. Gee, Kevin M. Jude, Leah V. Sibener, Polly M. Fordyce, Ronald N. Germain, Brian D. Evavold, K. Christopher Garcia

Issue&Volume: 2022-04-08

Abstract: Adoptive cell therapy using engineered T cell receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide–major histocompatibility complexes (pMHCs). Affinity-matured TCRs can enhance the efficacy of TCR–T cell therapy but can also cross-react with off-target antigens, resulting in organ immunopathology. We developed an alternative strategy to isolate TCR mutants that exhibited high activation signals coupled with low-affinity pMHC binding through the acquisition of catch bonds. Engineered analogs of a tumor antigen MAGE-A3–specific TCR maintained physiological affinities while exhibiting enhanced target killing potency and undetectable cross-reactivity, compared with a high-affinity clinically tested TCR that exhibited lethal cross-reactivity with a cardiac antigen. Catch bond engineering is a biophysically based strategy to tune high-sensitivity TCRs for T cell therapy with reduced potential for adverse cross-reactivity.

DOI: abl5282

Source: https://www.science.org/doi/10.1126/science.abl5282