Abstract LB044: Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region

Abstract Oncogenic mutations of HER2 have been identified in HER2-low tumors. Such mutations in the extracellular region could serve as tumor-specific antigens that are accessible to antibody therapeutics. Although multiple antibody therapeutics have been successfully developed against cancers that overexpress wild-type HER2, none is specifically applicable to treating tumors driven by HER2 mutants expressed at a low level. Here, we developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 extracellular region. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimic the dimerization arm of HER and inhibit HER2 dimerization. These antibodies as T-cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro and in a mouse xenograft model. These results validate HER2 extracellular region mutations as actionable therapeutic targets and offer promising candidates toward clinical development. More generally, they suggest that point mutations in the extracellular region of cell-surface receptors as actionable targets for anti-cancer therapy. Citation Format: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide. Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB044.