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

作者：Xinbo Yang, Daisuke Nishimiya, Sara Löchte, Kevin M. Jude, Marta Borowska, Christina S. Savvides, Michael Dougan, Leon Su, Xiang Zhao, Jacob Piehler, K. Christopher García · 发表于：Nature Biotechnology · 年份：2023 · DOI：10.1038/s41587-022-01567-w · 被引用次数：58 · 研究领域：Immunotherapy and Immune Responses、Monoclonal and Polyclonal Antibodies Research、Immune Cell Function and Interaction

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.