Mutant Kirsten rat sarcoma virus oncogene homolog-derived peptide-Human Leukocyte Antigen complex (Mutant KRAS-pHLA)

Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS)-derived peptides bound to patient Human Leukocyte Antigen (HLA) molecules constitute a critical class of tumor-specific neoantigens. KRAS is a small GTPase that, when mutated at specific hotspots like G12D, G12V, or G12C, drives uncontrolled cell proliferation in various malignancies, including pancreatic and colorectal cancers (Simanshu et al., 2017). These intracellular mutant proteins are degraded by the proteasome into short peptide fragments, which are then transported to the endoplasmic reticulum and loaded onto HLA molecules for surface presentation (Bear et al., 2021). Because these mutant sequences are not present in the normal human genome, the resulting peptide-HLA (pHLA) complexes are recognized as foreign by the immune system, specifically by T-cell receptors (TCRs). This high degree of tumor specificity makes the KRAS-pHLA complex an ideal target for precision immunotherapies, such as TCR-engineered T-cell (TCR-T) therapies and neoantigen vaccines (Leidner et al., 2022). Drugs targeting these complexes, like ELI-002, aim to expand the population of endogenous T-cells capable of recognizing these specific markers (Pant et al., 2024). However, the effectiveness of such therapies is often restricted by the patient's specific HLA haplotype, as different HLA alleles present different sets of peptides. Therapeutic development focuses on identifying the most common KRAS mutations and the HLA alleles that most effectively present them to ensure broad patient applicability.

Other names

KRAS neoantigen-HLA complexKRAS mutant peptide-MHC complexKRAS G12D-HLA complexKRAS G12V-HLA complexKRAS G12C-HLA complex

Recognition of the specific mutant peptide-HLA complex by T-cell receptors (TCRs) or TCR-like antibodies, leading to T-cell activation and subsequent cytotoxic lysis of the tumor cell.