Mutant Kirsten rat sarcoma virus oncogene homolog-derived peptide-Major Histocompatibility Complex (KRAS-pMHC)

Mutant KRAS-derived peptide antigens presented on MHC molecules (KRAS-pMHC) are highly specific tumor neoantigens that result from the intracellular processing of oncogenic KRAS proteins. KRAS is a small GTPase that, when mutated at hotspot residues such as G12D, G12V, or G12C, drives the development of aggressive cancers including pancreatic, colorectal, and non-small cell lung cancer [1.2.3, 1.3.4]. Although the KRAS protein is located within the cytoplasm, mutant variants are degraded by the proteasome into short peptides, which are then transported to the endoplasmic reticulum, loaded onto Major Histocompatibility Complex (MHC) Class I molecules, and displayed on the cell surface for immune surveillance [1.1.1, 1.3.1]. These complexes are considered "public" neoantigens because the same KRAS mutations are shared across many patients, though their therapeutic targeting is restricted by the specific Human Leukocyte Antigen (HLA) alleles of the individual [1.3.1, 1.4.3]. Current therapeutic approaches targeting KRAS-pMHC include T-cell receptor-engineered T-cell (TCR-T) therapies, TCR-mimic (TCRm) antibodies, and peptide-based vaccines, all designed to induce a selective cytotoxic T-cell response against malignant cells while minimizing damage to healthy tissues [1.1.3, 1.2.3]. Additionally, novel "HapImmune" strategies utilize covalent KRAS inhibitors to create drug-modified synthetic neoantigens that can be targeted by bispecific T-cell engagers to overcome resistance to direct KRAS inhibition [1.2.1, 1.3.3].

Other names

KRAS neoantigen-MHC complexKRAS mutant peptide-HLA complexKRAS-pMHCHaptenated KRAS-MHCKRAS G12D peptide-HLA-C*08:02KRAS G12V peptide-HLA-A*11:01

T-cell receptor-mediated cytotoxicity, T-cell recruitment via bispecific engagers, and active immunization via neoantigen vaccines.