Kirsten rat sarcoma virus oncogene homolog G12D (KRAS G12D) mutant peptide presented by Human Leukocyte Antigen C*08:02 (HLA-C*08:02) (KRAS G12D/HLA-C*08:02)

The KRAS G12D mutant peptide presented by HLA-C*08:02 is a tumor-specific neoantigen complex that serves as a high-precision target for cancer immunotherapy. KRAS is a GTPase that, when mutated at the glycine-12 position to aspartic acid (G12D), drives constitutive signaling for cell proliferation and survival in several aggressive malignancies, most notably pancreatic ductal adenocarcinoma and colorectal cancer (Tran et al., 2016, NEJM). This specific mutant peptide is processed intracellularly and presented on the cell surface by the HLA-C*08:02 major histocompatibility complex (MHC) class I molecule. Because the G12D mutation is absent in healthy tissues, the resulting peptide-MHC complex provides a unique signature for the immune system to distinguish malignant cells from normal ones. Therapeutic strategies targeting this complex primarily involve adoptive T-cell therapy using T-cell receptors (TCR-T) engineered to recognize this specific pMHC combination. Clinical proof-of-concept has been established in landmark studies where patients with metastatic pancreatic and colorectal cancers experienced significant tumor regression following the infusion of HLA-C*08:02-restricted KRAS G12D-specific T cells (Leidner et al., 2022, NEJM).

Other names

KRAS G12D neoantigen presented by HLA-C*08:02HLA-C*08:02-restricted KRAS G12DKRAS G12D 9-mer peptide (GADGVGKSA) presented by HLA-C*08:02pMHC complex KRAS G12D:HLA-C*08:02

The target is recognized by engineered or endogenous T-cell receptors (TCRs) that specifically bind the mutant KRAS G12D peptide in the context of the HLA-C*08:02 molecule, triggering T-cell activation, cytokine release, and cytotoxic lysis of the tumor cell (Leidner et al., 2022, NEJM).