T细胞受体
主要组织相容性复合体
抗原
受体
T细胞
化学
亲缘关系
细胞生物学
突变体
过继性细胞移植
交叉反应性
生物
体外
计算生物学
细胞毒性T细胞
免疫学
生物化学
免疫系统
基因
交叉反应
作者
Xiang Zhao,Elizabeth Motunrayo 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 García
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2022-04-07
卷期号:376 (6589)
被引量:80
标识
DOI:10.1126/science.abl5282
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI