RAS neoantigen-derived peptide–Major Histocompatibility Complex (RAS pMHC)

RAS neoantigen-derived peptide–Major Histocompatibility Complex (pMHC) complexes are cell-surface markers formed when mutated RAS proteins, such as KRAS G12D, G12V, or G12C, are processed by the proteasome and presented by MHC Class I molecules (NIH, 2021). These complexes are highly tumor-specific because the underlying mutations are absent in normal tissues, making them ideal targets for precision immunotherapy (NIH, 2024). While naturally occurring RAS pMHCs often exist at extremely low densities—typically fewer than 10 copies per cell—they can be targeted by high-affinity T-cell receptors (TCRs) or TCR-like antibodies (Nature Communications, 2024). A novel therapeutic strategy, known as the HapImmune platform, utilizes covalent RAS inhibitors to create "synthetic neoantigens" where the drug remains attached to the peptide within the MHC groove, significantly enhancing target distinctiveness (PNAS, 2023). This approach enables the development of bispecific T-cell engagers, such as AETX-R114 and AETX-R302, which selectively eliminate drug-resistant tumor cells (Aethon Therapeutics, 2025). Despite their potential, challenges include the high degree of HLA polymorphism, which restricts individual therapies to specific patient subsets, and the potential for tumor immune escape through the downregulation of MHC expression (NIH, 2003).

Other names

Mutant RAS peptide-MHC complexmRAS p/HLA complexRAS neoantigen pMHCHaptenated RAS peptide-MHCKRAS G12D/V/C neoantigen MHC

T-cell engagement via bispecific antibodies, TCR-mediated cytotoxicity, and stabilization of low-abundance peptide-MHC complexes to trigger immune-mediated cell killing.