Mutant KRAS peptide-MHC complex (mKRAS-MHC)

Mutant KRAS peptide-MHC complexes represent a class of tumor-specific neoantigens generated from the intracellular processing of mutated KRAS proteins, such as the G12D, G12V, and G12C variants [1, 3]. These mutations, which are prevalent in pancreatic, colorectal, and lung cancers, result in the presentation of unique peptide sequences on the cell surface via Major Histocompatibility Complex (MHC) molecules, specifically Human Leukocyte Antigens (HLA) [3, 8]. Because KRAS is an intracellular signaling protein, these peptide-MHC (pMHC) complexes provide the primary mechanism for the adaptive immune system to recognize and target cells harboring these oncogenic drivers [4, 11]. Therapeutic approaches leveraging this target include T-cell receptor-engineered T-cell (TCR-T) therapies, neoantigen vaccines, and TCR-mimic (TCRm) bispecific antibodies [4, 9, 15]. These modalities aim to trigger potent T-cell mediated cytotoxicity against tumor cells while sparing healthy tissues that express only wild-type KRAS [11, 13]. However, clinical development faces challenges such as HLA restriction, where a therapy is only effective in patients with specific HLA genotypes, and the low density of these complexes on the tumor cell surface [7, 8]. Recent research has also explored "haptenated" neoantigens, where covalent inhibitors like sotorasib modify the KRAS peptide within the MHC groove to create a distinct, drug-induced target for immunotherapy [5, 16].

Other names

Mutant KRAS neoantigenmKRAS peptide-HLA complexKRAS neoepitopeKRAS G12D/V/C peptide-MHCmKRAS-pMHCKRAS-derived T-cell epitope

Drugs targeting these complexes typically function by engaging the adaptive immune system, either through T-cell receptor (TCR) recognition in engineered T-cell therapies (TCR-T), priming the immune system via neoantigen vaccines, or using TCR-mimic (TCRm) bispecific antibodies to recruit and activate T-cells directly at the tumor site [3, 4, 11].