MassIVE MSV000097193

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

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Description

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. [doi:10.25345/C5C53FD11] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: HLA ; MHC ; Immunopeptidomics ; KRAS ; Hapten ; SureQuant ; Neoantigen ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Lauren Stopfer, Aethon Therapeutics, USA
Submitting User: lstopfer2
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