Kirsten rat sarcoma virus oncogene homolog G12V peptide-Human Leukocyte Antigen A*02:01 complex (KRAS G12V/HLA-A*02:01)

The Kirsten rat sarcoma virus oncogene homolog (KRAS) G12V peptide-Human Leukocyte Antigen (HLA) A*02:01 complex is a tumor-specific neoantigen presented on the surface of cancer cells [1, 8]. It consists of a peptide derived from the KRAS protein with a glycine-to-valine mutation at position 12, bound to the MHC Class I molecule HLA-A*02:01 [11, 14]. KRAS mutations are among the most common drivers in human cancers, particularly in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer [1, 11]. Since the G12V mutation is absent in healthy tissues, this complex provides a highly specific target for immunotherapy, minimizing the risk of on-target, off-tumor toxicity [1, 11]. Therapeutic approaches targeting this complex include T-cell receptor-engineered T-cell (TCR-T) therapies, bispecific T-cell engagers (BiTEs), and TCR-mimic (TCRm) chimeric antigen receptor (CAR) T-cells [2, 3, 4]. These agents are designed to recognize the specific peptide-HLA configuration and trigger a potent T-cell-mediated cytotoxic response against the tumor [2, 12]. However, clinical development faces challenges such as the low density of the complex on the cell surface and the potential for immune evasion through the loss of HLA expression or HLA loss of heterozygosity (LOH) [4, 11, 12].

Other names

KRAS G12V-HLA-A*02:01 complexKRAS G12V-HLA-A2 complexKRAS G12V neoantigen-MHC complexKRAS G12V pMHC

T-cell receptor-mediated recognition of the peptide-MHC complex followed by T-cell activation and targeted tumor cell lysis