KRAS G12V mutant peptide-MHC class I complex (KRAS G12V/MHC-I)

The KRAS G12V mutant peptide presented on MHC class I is a tumor-specific neoantigen arising from a common driver mutation in the KRAS oncogene, where glycine at position 12 is replaced by valine (PubMed: 26494274). This mutation is highly prevalent in solid tumors, including approximately 30% of pancreatic ductal adenocarcinomas and significant portions of colorectal and lung cancers (NIH: PDQ Cancer Information). The mutant protein undergoes proteasomal degradation, and the resulting 9-10 amino acid peptides are presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, such as HLA-A*11:01 (Nature: 10.1038/s41591-022-01847-2). This peptide-MHC (pMHC) complex serves as a unique signature for immune recognition, allowing T-cells to distinguish malignant cells from healthy ones. Therapeutic strategies targeting this complex include TCR-engineered T-cell therapies (TCR-T), bispecific T-cell engagers, and neoantigen vaccines like ELI-002 (ClinicalTrials.gov: NCT04853017). Unlike small molecule inhibitors that bind the KRAS protein directly, these immunotherapies leverage the body's cellular immune system to achieve targeted tumor lysis. Challenges to this approach include the requirement for specific HLA matching and the potential for tumor immune evasion through HLA downregulation or loss of heterozygosity. Despite these challenges, the high specificity of the G12V neoantigen makes it an ideal candidate for precision immunotherapy in KRAS-driven malignancies.

Other names

KRAS G12V neoantigenKRAS G12V pMHCKRAS G12V-HLA complexKRAS G12V peptide-HLA-A*11:01 complexKRAS G12V peptide-HLA-A*02:01 complex

Induction of T-cell mediated cytotoxicity through specific recognition of the mutant peptide-MHC complex on the tumor cell surface.