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

• Published in: Nature biotechnology Vol. 41; no. 7; pp. 932 - 943
• Main Authors: Yang, Xinbo, Nishimiya, Daisuke, Löchte, Sara, Jude, Kevin M., Borowska, Marta, Savvides, Christina S., Dougan, Michael, Su, Leon, Zhao, Xiang, Piehler, Jacob, Garcia, K. Christopher
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2023; Nature Publishing Group
• Subjects: 631/535/1266; 631/61/24; Agriculture; Animals; Antibodies; Antibodies, Monoclonal - therapeutic use; Antigen (tumor-associated); Antigens; Antigens, Neoplasm; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cancer; Cancer immunotherapy; Chimeric antigen receptors; Complementarity-determining region; Crystallography; Humans; Identification methods; Immunoglobulin G; Immunotherapy; Life Sciences; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice; Monoclonal antibodies; Neoplasms - therapy; Peptides; Peptides - chemistry; Receptors; Receptors, Antigen, T-Cell; T cell receptors; Tumors
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/s41587-022-01567-w

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.
A method to identify antibodies against peptide–MHC complexes could enable patient-specific cancer immunotherapeutics.