Engineered antibodies that stabilize drug-modified KRAS^G12C neoantigens enable selective and potent cross-HLA immunotherapy.

ABSTRACT: Covalent inhibitors of oncoprotein KRAS have initial efficacy, but responses lack durability. Covalently modified oncoproteins are presented as MHC-restricted hapten-peptides (p*MHC) on the cancer cell surface, enabling combination of targeted therapy with immunotherapy to overcome drug resistance. Building on indirect evidence of KRAS^G12C-derived p*MHCs, we use immunopeptidomics to identify and directly quantify these synthetic neoantigens. To address challenges by their low copy number, we develop AETX-R114, a T cell engaging bispecific antibody with picomolar affinity for MHC-restricted sotorasib-modified KRAS^G12C peptides presented by three HLA-A3 supertype alleles. AETX-R114 dramatically increases the half-life and thereby the number of presented p*MHCs, enabling

SUBMITTER: Maso L 

PROVIDER: S-EPMC12717047 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature