KRAS G12D-derived peptide-HLA class I complex (KRAS G12D-pHLA)

The KRAS G12D-derived peptide-HLA class I complex is a tumor-specific neoantigen formed when the mutant KRAS protein is processed by the intracellular proteasome and its resulting peptides are presented on the cell surface by specific Human Leukocyte Antigen (HLA) molecules (Simanshu et al., 2017). KRAS G12D is a predominant driver mutation in several lethal malignancies, including pancreatic ductal adenocarcinoma and colorectal cancer, where a single amino acid substitution (glycine to aspartic acid) creates a unique epitope not found in normal tissues (Leidner et al., 2022). This complex serves as a critical target for advanced immunotherapies, such as T-cell receptor-engineered T-cell (TCR-T) therapy and neoantigen vaccines, which aim to exploit the high specificity of the mutant peptide for selective tumor destruction. The effectiveness of these therapies is strictly restricted by the patient's HLA genotype, with common alleles of interest including HLA-C*08:02 and HLA-A*11:01 (Bear et al., 2021). While targeting this complex minimizes off-tumor toxicity due to the absence of the mutation in healthy cells, therapeutic challenges include the potential for tumor immune escape through HLA downregulation or loss of heterozygosity. Current clinical development focuses on identifying high-affinity TCRs and optimizing vaccine delivery to overcome the immunosuppressive tumor microenvironment.

Other names

KRAS G12D neoantigenKRAS G12D-MHC complexKRAS G12D-HLA complexMutant KRAS G12D peptide-HLA complexKRAS G12D-HLA-C*08:02KRAS G12D-HLA-A*11:01

T-cell receptor (TCR) mediated recognition of the mutant peptide-HLA complex, leading to T-cell activation and cytotoxic lysis of the target tumor cell (Leidner et al., 2022).