Kirsten rat sarcoma virus oncogene homolog G12V mutant peptide presented by Human Leukocyte Antigen A*11:01 (KRAS G12V/HLA-A*11:01)

The Kirsten rat sarcoma virus oncogene homolog (KRAS) G12V mutant peptide presented by Human Leukocyte Antigen (HLA) A*11:01 is a tumor-specific neoantigen complex. KRAS is a small GTPase that functions as a molecular switch in signaling pathways such as MAPK and PI3K, regulating cell growth and survival (PubMed: 33035207). The G12V mutation, a glycine-to-valine substitution at codon 12, results in constitutive activation of the protein, driving oncogenesis in various malignancies, most notably pancreatic ductal adenocarcinoma and colorectal cancer (PubMed: 26491474). Intracellular processing of the mutant KRAS protein generates specific peptides that are loaded onto HLA-A*11:01 molecules and displayed on the cell surface. This peptide-MHC complex is a critical target for immunotherapy, as it is absent in healthy tissues, providing a high degree of tumor specificity. Therapeutic approaches include T-cell receptor (TCR) engineered T-cells and bispecific molecules designed to recognize the unique structural interface of the mutant peptide within the HLA groove (Affini-T Therapeutics, 2024). Clinical success depends on the dual presence of the KRAS G12V mutation and the HLA-A*11:01 allele in the patient's tumor (PubMed: 35613030). These therapies aim to induce T-cell mediated lysis of cancer cells while avoiding healthy tissue. Challenges include potential HLA downregulation by tumors and the need for high TCR specificity to avoid cross-reactivity.

Other names

KRAS G12V/HLA-A*11:01KRAS G12V neoantigenHLA-A*11:01-restricted KRAS G12V peptideKRAS G12V/A*11:01 complex

T-cell receptor (TCR) mediated recognition of the mutant peptide-HLA complex, leading to T-cell activation, secretion of cytotoxic granules, and direct lysis of the target cancer cell.