1. Facile repurposing of peptide-MHC-restricted antibodies for cancer immunotherapy.
- Author
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Yang X, Nishimiya D, Löchte S, Jude KM, Borowska M, Savvides CS, Dougan M, Su L, Zhao X, Piehler J, and Garcia KC
- Subjects
- Mice, Animals, Humans, Receptors, Antigen, T-Cell, Immunotherapy, Antibodies, Monoclonal therapeutic use, Antigens, Neoplasm, Peptides chemistry, Neoplasms therapy
- 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., (© 2023. The Author(s).)
- Published
- 2023
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