小柯机器人

美国斯坦福大学医学院K. Christopher Garcia研究组报道，肽主要组织相容性复合体(MHC)限制抗体可用于癌症免疫治疗。该研究于2023年1月2日发表于国际一流学术期刊《自然—生物技术》杂志上。

他们提出了一种快速分离高度肽特异性和“MHC限制”抗体的策略，通过重新设计预选抗体，使其以结构类似于传统αβ- T细胞受体(TCRs)的方式与肽-MHC接合。他们创建了基于结构的文库，专注于“TCR-mimic”(TCRm)单克隆抗体(Abs)互补决定区(CDR)环的肽相互作用残基，并快速生成针对小鼠和人类肿瘤抗原的MHC限制性抗体，当它们被格式为IgG、双特异性T细胞接合子(BiTE)和嵌合抗原受体-T (CAR-T)时，这些抗体可特异性杀死靶细胞。对一个pMHC限制性Ab的晶体学分析显示出高度的肽特异性识别，验证了工程策略。这种方法可以在几周内产生肿瘤抗原特异性抗体，有可能实现快速临床转译。

据了解，Abs以类似于TCR的方式识别MHC呈递的肿瘤抗原，具有作为癌症免疫疗法的巨大潜力。然而，分离TCRm抗体是很困难的，因为抗体没有进化出αβ-TCRs结构上细微的肽- MHC限制。

附：英文原文

Title: Facile repurposing of peptide–MHC-restricted antibodies for cancer immunotherapy

Author: Yang, Xinbo, Nishimiya, Daisuke, Lchte, Sara, Jude, Kevin M., Borowska, Marta, Savvides, Christina S., Dougan, Michael, Su, Leon, Zhao, Xiang, Piehler, Jacob, Garcia, K. Christopher

Issue&Volume: 2023-01-02

Abstract: Monoclonal antibodies (Abs) that recognize major histocompatability complex (MHC)-presented tumor antigens in a manner similar to Tcell 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.

DOI: 10.1038/s41587-022-01567-w

Source: https://www.nature.com/articles/s41587-022-01567-w

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex