New Publication in Nature Communications Demonstrates the Therapeutic Utility of Targeting Synthetic Neoantigens Generated by KRAS G12C Inhibitors
Findings shared in article co-authored by Aethon Therapeutics scientists and NYU researchers support the hypothesis that combining covalent inhibitors and T cell engagers can overcome drug resistance in KRAS-mutated cancers
New York, New York — December 19, 2025 — Aethon Therapeutics today announced the publication of a new study, “Engineered antibodies that stabilize drug-modified KRASG12C neoantigens enable selective and potent cross-HLA immunotherapy,” in Nature Communications. The work described in the publication was performed by Aethon scientists in collaboration with researchers at New York University (NYU).
KRASG12C inhibitors such as sotorasib, adagrasib, and divarasib generate synthetic neoantigens are drug-modified peptides (p*) that are presented on cancer cells by major histocompatibility complex (MHC) molecules as p*MHCs. Although these antigens exist at extremely low copy number, they present a uniquely tumor-specific signature.
Using targeted immunopeptidomics, the study authors directly identify and quantify these KRASG12C haptenated peptides for the first time. Through further detailed characterization—including their abundance, HLA allele coverage, and intrinsic instability—the Aethon team generated key insights that guided a tailored antibody engineering strategy.
The resulting bispecific T cell engagers, AETX-R114 (sotorasib companion) and AETX-R302 (divarasib companion), bind drug-modified KRASG12C p*MHCs with high specificity and affinity across multiple HLA supertypes. This binding increases the stability, and thus the effective surface density of these ultra-low-abundance antigens, enabling potent and selective T-cell–mediated killing of KRASG12C inhibitor–resistant cancer cells in vitro and in vivo.
Overall, the study highlights how high-affinity, high-specificity antibodies targeting hapten-modified KRASG12C peptides can bypass historic limitations of pMHC-directed therapeutics—particularly low antigen density and HLA restriction. The findings advance Aethon’s HapImmune™ platform and support ongoing work through its strategic collaboration with Revolution Medicines. The full article is available open access in Nature Communications.
Link: https://www.nature.com/articles/s41467-025-66132-w