KRAS G12D peptide–HLA-A*11:01 complex

The KRAS G12D peptide–HLA-A*11:01 complex is a peptide–MHC class I (pMHC) target in which the KRAS G12D neoantigen decamer peptide (sequence VVVGADGVGK) is presented by the human leukocyte antigen HLA-A*11:01 on tumor cells, enabling selective recognition by KRAS G12D–specific T-cell receptors. Crystallographic studies resolved the HLA-A*11:01 complexed with the KRAS G12D peptide and showed that the Asp at position 6 (resulting from the G12D mutation) is buried in the HLA groove and forms a salt bridge with HLA residue R114 (stabilized by D116) and a hydrogen bond to Q70, creating distinct electrostatic features that underpin higher-affinity binding by engineered TCRs compared with the wild-type KRAS peptide complex. Functionally, this pMHC is exploited by engineered TCR therapies and ImmTAC bispecifics to redirect T cells to kill KRAS G12D, HLA-A*11:01–positive cancer cells with high specificity, guided by the unique mutation-dependent peptide–HLA interactions and associated energetic/structural determinants. The epitope is a decamer distinct from related 9-mer/10-mer KRAS mutant peptides that show limited cross-recognition, underscoring epitope specificity within HLA-A*11:01 presentations. Recent work identified additional HLA-A*11:01–restricted KRAS G12D–specific TCRs and engineered variants to mitigate off-target reactivity, highlighting both therapeutic promise and the need for stringent safety engineering.

Other names

HLA-A*11:01–KRAS G12D peptide complexHLA-A*11–KRAS G12D pHLAKRAS G12D pHLA-A*11HLA-A*11:01–VVVGADGVGK (KRAS G12D) complex

TCR-mimetic or soluble TCR binds specifically to the KRAS G12D decamer peptide (VVVGADGVGK) presented by HLA-A*11:01, forming a high-affinity interaction that redirects T cells (via ImmTAC CD3-engagement or TCR-transduced T cells) to lyse tumor cells expressing KRAS G12D and HLA-A*11:01. Selectivity arises from mutation-dependent peptide–HLA interactions (e.g., Asp at peptide position 6 forming salt bridge with HLA R114 and stabilized by D116; altered electrostatics enhance TCR affinity for the G12D complex vs wild type).