AETX-R114 / Aethon Therap - LARVOL DELTA

Engineered antibodies that stabilize drug-modified KRASG12C neoantigens enable selective and potent cross-HLA immunotherapy. (PubMed, Nat Commun) - "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 KRASG12C peptides presented by three HLA-A3 supertype alleles...To broaden the therapeutic potential of creating and targeting synthetic neoantigens, we further develop AETX-R302, which recognizes divarasib-modified KRASG12C 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."

Journal • Oncology • KRAS

Cross-HLA targeting of synthetic neoepitopes with T cell engagers to eradicate sotorasib-resistant, KRAS-G12C mutant cancer (AACR 2025) - "Here, we present the development of AETX-R114, a TCE targeting sotorasib-p*MHCs presented on 3 different HLA-A3 supertype alleles, A*03:01, A*11:01, and A*68:01, which is not competed by free drug and demonstrates in vitro and in vivo tumor cell-specific potency. Although we previously provided indirect evidence of p*MHCs (PMID 36250888), here we use immunopeptidomics to directly identify sotorasib, divarasib, and adagrasib-modified p*MHCs presented on the cell surface of inhibitor-resistant cells...The unique properties of drug-modified HLA peptides provide new opportunities in anti-MHC targeting immunotherapies. Taken together, our approach unites targeted, mutation-specific therapy with immunotherapy to enable cancer specific, immune-mediated cell killing."

IO biomarker • Oncology • KRAS • PRAME

Deciphering the molecular basis for pan-HLA recognition of divarasib-modified pMHCs by newly discovered hit-to-lead antibody AETX-R302 (AACR 2025) - "The potential of exploiting synthetic neoantigens is well demonstrated by antibody AETX-R114, which recognizes multiple hapten-peptides (sotorasib-conjugated KRASG12C peptides) presented by different HLAs. Collectively, the cryo-EM structures explain AETX-R302's unprecedented A2/A3 supertype cross-reactivity and its high specificity and affinity. This information will be exploited to develop TCEs that engage tumor-specific synthetic neoantigen targets with pan-HLA recognition."

Oncology • KRAS