Mutant KRAS peptide–MHC complex

The **mutant KRAS peptide–MHC complex** is a composite molecular target formed when peptides derived from oncogenic KRAS mutations (such as G12C, G12V, or G12D) are processed and presented by tumor cells in the groove of a major histocompatibility complex (MHC) class I molecule (commonly referred to as human leukocyte antigen, HLA, in humans)[1][2][4]. These complexes act as tumor-specific neoantigens, recognizable by specialized T cell receptors (TCRs), engineered TCRs, bispecific antibodies, or CAR T cells, thereby enabling selective immune targeting of cancer cells harboring KRAS mutations[2][4][5]. The complex’s formation and immune visibility are influenced both by the presenting HLA allele and the specific mutant KRAS peptide sequence, with certain mutations and HLA combinations (e.g., KRAS G12V 9-mer with HLA-A*11:01) providing highly selective, stable targets[2][4]. Emerging immunotherapies exploit this neoantigen presentation, including cell therapies, bispecific T cell engagers, and agents that enhance immune recognition (e.g., covalent inhibitors like ARS-1620 which create a haptenated peptide–MHC ligand)[1][2][4]. The primary therapeutic rationale is to trigger potent anti-tumor T cell responses or cytolytic activity against cancer cells while minimizing effects on normal tissues. Challenges include HLA restriction, tumor heterogeneity, and risk of immune toxicity[2][3][4].

Other names

Mutant KRAS neoantigen–MHC complexmKRAS–MHC complexKRAS mutant peptide–HLA complexMutant KRAS pHLA complex

Targeting of mutant KRAS peptide–MHC complexes by TCR-mimic or CAR T cells leads to T cell–mediated lysis of tumor cells presenting the neoantigen[2][4][5]; Bispecific antibodies (BiTEs) direct effector T cells to tumor cells bearing the complex[1][4]; Covalent KRAS G12C inhibitors (e.g., ARS-1620) create uniquely haptenated peptides for targeted immune recognition[1]