A splicing neoantigen mutant targeting KRAS G12V, its screening method and application

CN122145603APending Publication Date: 2026-06-05ZHEJIANG UNIV

Patent Information

Authority / Receiving Office: CN · China
Patent Type: Applications(China)
Current Assignee / Owner: ZHEJIANG UNIV
Filing Date: 2026-02-06
Publication Date: 2026-06-05

AI Technical Summary

Technical Problem

Existing immunotherapeutic targets targeting KRAS G12V mutations have insufficient affinity and lack effective rational design methods, which limits their application in cancer vaccines and TCR-T therapies.

Method used

High-affinity spliced neoantigen mutants were screened using molecular dynamics simulations and free energy perturbation calculations. The binding stability with HLA-A*02:01 was enhanced by introducing hydrophobic or large side-chain amino acids at positions 3 and 6 of the KRAS G12V splice peptide. The candidate mutants were verified by pre-loaded peptide-HLA-A*02:01 tetramer substitution experiment and peptide pulse experiment.

Benefits of technology

It significantly improves the binding ability of spliced neoantigen mutants to HLA-A*02:01, enhances immunogenic potential, and is suitable for the treatment of pancreatic cancer, colorectal cancer, or non-small cell lung cancer expressing HLA-A*02:01.

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Abstract

This invention discloses a spliced neoantigen mutant targeting KRAS G12V, its screening method, and its applications. Based on all-atom molecular dynamics simulations, this invention elucidates the HLA-A... * The molecular mechanism of superior conformational rigidity and lower binding entropy penalty in the 02:01 presentation was investigated. Based on this, key secondary anchoring sites of the splicing peptide were rationally designed using free energy perturbation calculations, resulting in a series of high-affinity mutants. These mutants introduced more hydrophobic or larger side-chain amino acids at positions 3 and / or 6 than the original amino acid, significantly enhancing the binding stability with HLA and the surface stability of the complex. Experiments confirmed that the peptide provided in this invention is effective for pre-loaded peptide-HLA-A. * 02:01 The tetramer replacement efficiency and binding stability on the T2 cell surface are significantly better than those of natural splice peptides, making it a potential target for tumor vaccines or TCR-T therapy to treat malignant tumors with KRAS G12V mutations.

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