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Engineered antibodies that stabilize drug-modified KRASG12C neoantigens enable selective and potent cross-HLA immunotherapy

ABSTRACT: Covalent inhibitors of the oncoprotein KRAS have significant initial efficacy, but responses lack durability. Covalent inhibitor-modified oncoproteins are presented as MHC-restricted hapten-peptides (p*MHC) on the cancer cell surface, creating an opportunity to combine targeted therapy with immunotherapy to overcome drug resistance. Building on previous indirect evidence of KRASG12C-derived p*MHCs, we used immunopeptidomics to identify and directly quantify these synthetic neoantigens. Prompted by their low copy number, we developed AETX-R114, a T cell engaging bispecific antibody with picomolar affinity for MHC-restricted sotorasib-modified KRASG12C peptides presented by three alleles belonging to the HLA-A3 supertype. AETX-R114 dramatically increases the half-life and thereby the number of presented p*MHCs, enabling selective and potent killing of resistant cancer cells in vitro and in vivo. To broaden the therapeutic potential of creating and targeting synthetic neoantigens we developed AETX-R302, which recognizes divarasib-modified KRASG12C peptides presented on alleles from the HLA-A2 and HLA-A3 supertypes. Cryo-EM structure determination revealed the molecular basis for breaking HLA supertype restriction. Collectively, our study illustrates how engineered antibodies can transform synthetic neoantigens into actionable, specific-cancer immunotherapy targets.

INSTRUMENT(S): Orbitrap Ascend

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Lauren Stopfer

PROVIDER: MSV000097193 | MassIVE | Fri Feb 21 16:33:00 GMT 2025

REPOSITORIES: MassIVE

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