T细胞受体
主要组织相容性复合体
抗原
癌症免疫疗法
单克隆抗体
MHC限制
肽
生物
嵌合抗原受体
免疫疗法
T细胞
抗体
MHC I级
分子生物学
计算生物学
免疫学
免疫系统
生物化学
作者
Xinbo Yang,Daisuke Nishimiya,Sara Löchte,Kevin Jude,Marta Borowska,Christina S Savvides,Michael Dougan,Leon Su,Zhao Xiang,Jacob Piehler,K. Christopher Garcia
标识
DOI:10.1038/s41587-022-01567-w
摘要
Abstract Monoclonal antibodies (Abs) that recognize major histocompatability complex (MHC)-presented tumor antigens in a manner similar to T cell receptors (TCRs) have great potential as cancer immunotherapeutics. However, isolation of ‘TCR-mimic’ (TCRm) Abs is laborious because Abs have not evolved the structurally nuanced peptide–MHC restriction of αβ-TCRs. Here, we present a strategy for rapid isolation of highly peptide-specific and ‘MHC-restricted’ Abs by re-engineering preselected Abs that engage peptide–MHC in a manner structurally similar to that of conventional αβ-TCRs. We created structure-based libraries focused on the peptide-interacting residues of TCRm Ab complementarity-determining region (CDR) loops, and rapidly generated MHC-restricted Abs to both mouse and human tumor antigens that specifically killed target cells when formatted as IgG, bispecific T cell engager (BiTE) and chimeric antigen receptor-T (CAR-T). Crystallographic analysis of one selected pMHC-restricted Ab revealed highly peptide-specific recognition, validating the engineering strategy. This approach can yield tumor antigen-specific antibodies in several weeks, potentially enabling rapid clinical translation.
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