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A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy

Immunotargeting of tumor-specific antigens is a powerful therapeutic strategy. Immunotherapies directed at MHC-I complexes have expanded the scope of antigens and enabled the direct targeting of intracellular oncoproteins at the cell surface. We asked whether covalent drugs that alkylate mutated residues on oncoproteins could act as haptens to generate unique MHC-I-restricted neoantigens. Here, we report that KRAS G12C mutant cells treated with the covalent inhibitor ARS1620 present ARS1620-modified peptides in MHC-I complexes. Using ARS1620-specific antibodies identified by phage display, we show that these haptenated MHC-I complexes can serve as tumor-specific neoantigens and that a bispecific T cell engager construct based on a hapten-specific antibody elicits a cytotoxic T cell response against KRAS G12C cells, including those resistant to direct KRAS G12C inhibition. With multiple K-RAS G12C inhibitors in clinical use or undergoing clinical trials, our results present a strategy to enhance their efficacy and overcome the rapidly arising tumor resistance.

 

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The article describes a study on the use of covalent drugs that alkylate mutated residues on oncoproteins to generate unique MHC-I-restricted neoantigens. The researchers investigated whether treatment with the covalent inhibitor ARS1620 could lead to the presentation of ARS1620-modified peptides in MHC-I complexes in KRAS G12C mutant cells. They found that this was indeed the case, and that the haptenated MHC-I complexes could serve as tumor-specific neoantigens.

The researchers then developed a bispecific T cell engager construct based on a hapten-specific antibody that could elicit a cytotoxic T cell response against KRAS G12C cells, including those resistant to direct KRAS G12C inhibition. This suggests that targeting neoantigens generated by covalent drugs that alkylate mutated residues on oncoproteins may be a powerful therapeutic strategy for cancer.

The study has important implications for the development of immunotherapies for cancer, particularly in the context of K-RAS G12C inhibitors, which are currently in clinical use or undergoing clinical trials. The findings suggest that this approach could enhance the efficacy of K-RAS G12C inhibitors and overcome the rapidly arising tumor resistance that often occurs with these types of drugs.

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S7332 K-Ras(G12C) inhibitor 9 K-Ras(G12C) inhibitor 9 is an allosteric inhibitor of oncogenic K-Ras(G12C).

Related Targets

Ras