Fig. 1. Structure-based strategy for isolation of peptide–MHC-restricted antibodies.

a, T cell receptors (TCRs) bind to peptide–MHC in ‘canonical’ MHC-restricted TCR docking topologies, whereby TCRs CDR1 and CDR2 are generally focused on the MHC helices while CDR3 is focused on the bound peptide antigen (PDB:2CKB). b, Crystal structures of TCRm Abs show that they can recognize pMHC in both noncanonical (PDB: 4WUU and 1W72) and canonical binding modes (PDB: 3CVH). c, In the strategy we describe, TCRm antibodies exhibiting canonical TCR-like docking footprints on the pMHC were chosen to serve as a starting template for re-engineering. Only peptide-contacting residues were randomized, but MHC-contacting residues were preserved. d, The peptide-focused TCRm library was selected against different peptide antigens presented by the same MHC.