Kirsten rat sarcoma virus oncogene homolog G12V peptide–Human leukocyte antigen complex (KRAS G12V–HLA complex)

The KRAS G12V peptide–Human leukocyte antigen (HLA) complex is a tumor-specific neoantigen target formed when the mutated Kirsten rat sarcoma virus oncogene homolog (KRAS) protein is intracellularly processed and its G12V-containing peptide fragment is presented on the cell surface by HLA molecules (Wang et al., 2016, PMID: 26437913). KRAS is a small GTPase that acts as a molecular switch in signaling pathways like MAPK/ERK, and the G12V mutation leads to constitutive activation and uncontrolled cell proliferation (Simanshu et al., 2017, PMID: 28843286). This mutation is highly prevalent in several aggressive malignancies, including pancreatic ductal adenocarcinoma and colorectal cancer. Because the G12V mutant peptide is only presented by cells harboring the somatic mutation, the complex provides a unique window for highly specific immunotherapy. Therapeutic approaches targeting this complex include T-cell receptor-engineered T-cell (TCR-T) therapies, such as AFNT-211, and TCR-mimetic bispecific antibodies (Affini-T Therapeutics, 2024; Dou et al., 2021, PMID: 33649112). These agents are designed to recognize the specific spatial configuration of the mutant peptide nestled within the HLA groove, typically restricted to specific alleles like HLA-A*11:01 or HLA-A*03:01. Upon binding, these therapies trigger T-cell activation and the subsequent lysis of the cancer cell. A significant challenge in targeting this complex is the potential for tumor immune escape through the loss of HLA expression or the heterogeneity of KRAS mutations within a single patient.

Other names

KRAS G12V-MHC complexKRAS G12V neoantigen-HLA complexKRAS G12V peptide-MHC class I complexMutant KRAS G12V-HLA-A*11:01 complex

Recognition of the mutant KRAS G12V peptide presented by specific HLA molecules by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies, leading to directed T-cell mediated lysis of tumor cells.