KRAS G12D mutant peptide presented by HLA-A*11:01 (KRAS G12D/HLA-A*11:01)

The KRAS G12D mutant peptide presented by HLA-A*11:01 is a tumor-specific neoantigen complex that serves as a critical target for precision immunotherapy. KRAS is a GTPase involved in signal transduction; the G12D mutation (glycine to aspartic acid at position 12) results in constitutive activation, driving oncogenesis in a high percentage of pancreatic, colorectal, and lung cancers (Wang et al., 2016, Science). In individuals carrying the HLA-A*11:01 allele, which is particularly prevalent in East Asian populations, the mutated protein is processed into a specific 10-mer peptide (VVVGADGVGK) and displayed on the cell surface via the MHC Class I molecule (Sim et al., 2020, Journal for ImmunoTherapy of Cancer). Because this specific peptide-MHC complex is absent on healthy cells, it provides a narrow therapeutic window for T-cell receptor (TCR) engineered T-cell therapies and neoantigen vaccines like ELI-002 (Elicio Therapeutics, 2023). Therapeutic strategies aim to bypass the immune system's natural tolerance by providing high-affinity TCRs that recognize the structural interface of the G12D mutation within the HLA-A*11:01 binding groove. Successful targeting leads to the selective destruction of malignant cells while sparing normal tissue, although clinical efficacy can be limited by the immunosuppressive tumor microenvironment and mechanisms of antigen loss.

Other names

KRAS G12D-HLA-A*11:01 complexHLA-A*11:01-restricted KRAS G12D neoantigenKRAS G12D 7-16 peptide-MHC complexVVVGADGVGK-HLA-A*11:01

Recognition of the specific mutant peptide-MHC complex by engineered T-cell receptors (TCRs) or vaccines, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of tumor cells expressing the KRAS G12D mutation in the context of the HLA-A*11:01 allele.