9NFB

Structure of the cross-HLA supertype antibody R302 bound to a class I MHC presenting a divarasib-modified KRAS-G12C peptide on HLA-A*02

This is a non-PDB format compatible entry.

Summary for 9NFB

• Entry DOI: 10.2210/pdb9nfb/pdb
• EMDB information: 49361
• Descriptor: MHC class I antigen, Beta-2-microglobulin, GTPase KRas, ... (6 entities in total)
• Functional Keywords: antibody, cancer-neoantigen, complex, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 96990.19

Authors

Maso, L. (deposition date: 2025-02-21, release date: 2025-10-08, Last modification date: 2025-12-31)

Primary citation

Maso, L.,Mosure, S.A.,Rodriguez-Aponte, S.A.,Pizzo, A.,Mensah, D.N.,Southard, M.,Sze, S.,Ahmed, T.,Vash, B.,Hattori, T.,Rajak, E.,Koide, A.,Neel, B.G.,Koide, S.,Liu, W.,Toenjes, S.T.,Jardine, P.D.S.,Chopra, R.,Rader, C.,Stopfer, L.E.
Engineered antibodies that stabilize drug-modified KRAS G12C neoantigens enable selective and potent cross-HLA immunotherapy.
Nat Commun, 16:11264-11264, 2025

PubMed 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-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 peptides presented by three HLA-A3 supertype alleles. AETX-R114 dramatically increases the half-life and thereby the number of presented p*MHCs, enabling selective and potent killing of resistant cancer cells both in vitro and in vivo. To broaden the therapeutic potential of creating and targeting synthetic neoantigens, we further develop AETX-R302, which recognizes divarasib-modified KRAS peptides presented on alleles from the HLA-A2 and A3 supertypes. Cryo-EM structure determination reveals the molecular basis for breaking HLA supertype restriction. Collectively, our study illustrates how engineered antibodies can transform synthetic neoantigens into actionable cancer immunotherapy targets.

PubMed: 41408054
DOI: 10.1038/s41467-025-66132-w

Experimental method

ELECTRON MICROSCOPY (3.23 Å)