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TitleEngineered antibodies that stabilize drug-modified KRAS neoantigens enable selective and potent cross-HLA immunotherapy.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 11264, Year 2025
Publish dateDec 17, 2025
AuthorsLorenzo Maso / Sarah A Mosure / Sergio A Rodriguez-Aponte / Angelina Pizzo / Diamond N Mensah / Matthew Southard / Samantha Sze / Tanvir Ahmed / Brian Vash / Takamitsu Hattori / Epsa Rajak / Akiko Koide / Benjamin G Neel / Shohei Koide / Weifeng Liu / Sean T Toenjes / Paul Da Silva Jardine / Rajesh Chopra / Christoph Rader / Lauren E Stopfer /
PubMed AbstractCovalent 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 ...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.
External linksNat Commun / PubMed:41408054 / PubMed Central
MethodsEM (single particle)
Resolution2.58 - 3.23 Å
Structure data

49361

9nfb

EMDB-49361, PDB-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
Method: EM (single particle) / Resolution: 3.23 Å

49362

9nfc

EMDB-49362, PDB-9nfc:
Structure of the cross-HLA supertype antibody R302 bound to a class I MHC presenting a divarasib-modified KRAS-G12C peptide on HLA-A*03
Method: EM (single particle) / Resolution: 2.58 Å

Chemicals

PDB-1awr:
CYPA COMPLEXED WITH HAGPIA

Source
  • homo sapiens (human)
KeywordsPROTEIN BINDING / Antibody / Cancer-neoantigen / complex

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