HLA-A*11:01–KRAS G12V 9-mer peptide complex (HLA-A*11:01/KRAS-G12V)

The HLA-A*11:01–KRAS G12V 9-mer peptide complex is a neoantigenic target formed by the presentation of a mutated fragment of the KRAS protein on the surface of tumor cells. KRAS is a GTPase that acts as a molecular switch in cell signaling; mutations at codon 12, such as G12V (glycine to valine), lead to constitutive activation and uncontrolled cell proliferation [PubMed: 33462234]. In individuals carrying the HLA-A*11:01 allele—which is highly prevalent in East Asian populations—the mutated protein is processed into a 9-mer peptide (typically VVGAVGVGK) and displayed by the Major Histocompatibility Complex (MHC) Class I molecule [Nature Communications, 2021]. This specific peptide-MHC complex is recognized as foreign by the immune system, making it a highly selective target for immunotherapies like TCR-engineered T-cell (TCR-T) therapy [NEJM, 2022]. By targeting this complex, therapies aim to eliminate KRAS-mutant cancer cells while sparing healthy tissues that lack the mutation. This approach is currently being evaluated in clinical trials for pancreatic, colorectal, and lung cancers, providing a potential solution for patients with KRAS-driven tumors that are resistant to conventional therapies [Affini-T Therapeutics, 2024].

Other names

HLA-A*11:01/KRAS G12V complexKRAS G12V neoantigen-MHC complexA11/G12V 9-mer complexHLA-A*11:01-restricted KRAS G12V epitope

The mechanism involves the specific recognition of the HLA-A*11:01–KRAS G12V complex by engineered T-cell receptors (TCRs) on the surface of therapeutic T cells. This binding event triggers T-cell activation, leading to the secretion of cytotoxic cytokines (e.g., IFN-gamma, TNF-alpha) and the release of perforin and granzymes, which induce targeted apoptosis in the cancer cells expressing the complex [Nature Communications, 2021; NEJM, 2022].