Kirsten rat sarcoma viral oncogene homolog (KRAS) G12V peptide–Human leukocyte antigen (HLA) A*02:01 complex (KRAS G12V/HLA-A*02:01)

The Kirsten rat sarcoma viral oncogene homolog (KRAS) G12V peptide–Human leukocyte antigen (HLA) A*02:01 complex is a tumor-specific neoantigen target formed by the presentation of a mutated KRAS fragment on the cell surface. KRAS is a GTPase involved in cell signaling, and the G12V mutation (glycine to valine at position 12) is a frequent oncogenic driver in solid tumors such as pancreatic, colorectal, and lung cancers (Leidner et al., 2022, NEJM). In patients carrying the HLA-A*02:01 allele, the intracellularly processed G12V mutant peptide is loaded onto the Major Histocompatibility Complex (MHC) Class I molecule and transported to the plasma membrane (Wang et al., 2016, Cancer Immunology Research). This complex is a primary target for T-cell receptor (TCR) based immunotherapies, including TCR-engineered T-cells (TCR-T) and TCR-like bispecific antibodies. These therapies aim to exploit the high specificity of the neoantigen to minimize off-target effects on healthy tissues that lack the mutation (Sim et al., 2020, Protein Science). Unlike direct KRAS inhibitors, these immunotherapies rely on the immune system's ability to recognize the peptide-HLA interface to induce apoptosis in malignant cells. Clinical development focuses on overcoming challenges such as HLA downregulation and the requirement for specific patient HLA typing (Bear et al., 2020, Cancer Immunology Research). The complex represents a personalized medicine approach, as it requires both the presence of the specific mutation and the matching HLA allele in the patient.

Other names

KRAS G12V neoantigen-HLA complexHLA-A*02:01/KRAS(G12V)pMHC complex KRAS G12VKRAS G12V-HLA-A2 complex

T-cell receptor binding and subsequent T-cell mediated cytotoxicity