Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) neoantigen-HLA complex (mKRAS-HLA)

Mutant KRAS-derived neoantigen peptides presented by Human Leukocyte Antigen (HLA) molecules represent a critical class of tumor-specific targets for cancer immunotherapy. KRAS is one of the most frequently mutated oncogenes in human cancers, particularly in pancreatic, colorectal, and lung adenocarcinomas, where mutations at codon 12 (e.g., G12D, G12V, G12C) drive oncogenesis. These intracellular mutations are processed by the proteasome into short peptides, which are then loaded onto HLA class I or II molecules and displayed on the cell surface. This peptide-HLA (pMHC) complex serves as a "non-self" signal that can be specifically recognized by T-cell receptors (TCRs), distinguishing malignant cells from healthy tissue. Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, cancer vaccines like ELI-002, and bispecific T-cell engagers. While highly specific, challenges include the requirement for specific HLA genotypes (HLA restriction) and potential immune escape through HLA downregulation or loss. Additionally, ensuring the absence of cross-reactivity with wild-type KRAS or other self-peptides is paramount for clinical safety.

Other names

KRAS mutant peptide-MHC complexKRAS neoepitope-HLA complexKRAS-mutant pMHCMutant KRAS-HLA complexKRAS G12D/V/C/R neoantigen-HLA complex

T-cell receptor (TCR) mediated recognition of the peptide-HLA complex, leading to T-cell activation, secretion of cytotoxic granules (perforin, granzymes), and induction of apoptosis in the target tumor cell.