Kirsten rat sarcoma virus oncogene homolog G12D mutant peptide–Major Histocompatibility Complex class I complex (KRAS G12D–MHC I complex)

The KRAS G12D mutant peptide–MHC class I complex is a tumor-specific neoantigen presented on the surface of cancer cells harboring the G12D mutation (Leidner et al., 2022, NEJM). This complex consists of a processed 9- or 10-amino acid peptide derived from the mutant KRAS protein, where the glycine at position 12 is replaced by aspartic acid, bound to a Major Histocompatibility Complex (MHC) class I molecule such as HLA-A*11:01 or HLA-C*08:02 (Wang et al., 2021, Science Immunology). KRAS is a GTPase that regulates cell growth, and the G12D mutation is a primary driver in pancreatic, colorectal, and lung cancers (Simanshu et al., 2017, Cell). Because this specific peptide-MHC configuration is absent in normal tissues, it serves as an ideal target for precision immunotherapies, including TCR-engineered T-cell (TCR-T) therapies and bispecific T-cell engagers (Bear et al., 2023, Cancer Discovery). These therapeutic agents are designed to recognize the mutant epitope with high specificity, triggering a cytotoxic T-cell response that leads to the selective destruction of malignant cells while minimizing damage to healthy tissue. Clinical efficacy of targeting this complex depends on both the presence of the KRAS G12D mutation and the expression of the specific HLA allele required for presentation.

Other names

KRAS G12D neoantigen-HLA complexKRAS G12D-HLA-A*11:01 complexKRAS G12D-HLA-C*08:02 complexMutant KRAS-MHC I complex

T-cell receptor (TCR) mediated recognition of the mutant peptide-MHC complex leading to the formation of an immunological synapse and subsequent cytotoxic T-lymphocyte activation and tumor cell apoptosis.