KRAS G12D mutant peptide–HLA class I complex (KRAS G12D-HLA complex)

The KRAS G12D mutant peptide–HLA class I complex is a tumor-specific neoantigen presented on the surface of cancer cells harboring the G12D mutation in the KRAS oncogene (Waters & Der, 2018, Cold Spring Harb Perspect Med). This complex is formed when the intracellular mutant KRAS protein is degraded by the proteasome into short peptides, which are then loaded onto Major Histocompatibility Complex (MHC) class I molecules and transported to the plasma membrane (Leidner et al., 2022, N Engl J Med). KRAS G12D is a predominant driver mutation in several lethal malignancies, including over 90% of pancreatic ductal adenocarcinomas and a significant portion of colorectal and lung cancers (Waters & Der, 2018, Cold Spring Harb Perspect Med). Because the G12D substitution creates a unique amino acid sequence not found in the human proteome, the resulting peptide-HLA complex serves as a highly specific target for immunotherapy (Sim et al., 2020, Sci Immunol). Therapeutic strategies targeting this complex include T-cell receptor (TCR) engineered T-cell therapies (TCR-T) and TCR-like bispecific antibodies, which aim to bypass the immune system's natural tolerance to tumors (Leidner et al., 2022, N Engl J Med; Affini-T Therapeutics, 2023). These therapies are restricted by the patient's HLA type, as the mutant peptide must be presented by specific alleles such as HLA-A*11:01 or HLA-C*08:02 to be recognized (Leidner et al., 2022, N Engl J Med; Sim et al., 2020, Sci Immunol). Clinical trials have demonstrated that targeting this complex can induce significant tumor regression in patients with advanced solid tumors (Leidner et al., 2022, N Engl J Med).

Other names

KRAS G12D neoantigenKRAS G12D-MHC class I complexKRAS G12D-HLA-A*11:01KRAS G12D-HLA-C*08:02KRAS G12D pMHC

Recognition by engineered T-cell receptors (TCRs) or TCR-like antibodies, leading to T-cell mediated cytotoxicity against cells presenting the mutant peptide.