Abstract A038: Selective therapeutic antibodies against oncogenic mutations of HER2 ectodomain

Abstract Dysregulation of HER2 is a well-established mechanism of oncogenesis. Small molecule drugs targeting its kinase domain, and antibody-based drugs such as trastuzumab and pertuzumab targeting its ectodomain have shown efficacy against HER2-overexpression tumors. Separately from HER2 overexpression, oncogenic mutations in the ectodomain in HER2 have been identified in several tumors. As disease drivers that are readily accessible to biologics, these mutants are potentially attractive but still unvalidated therapeutic targets. Current anti-HER2 therapeutic antibodies are indiscriminatory of the mutational state of HER2 and their cross-reactivity to wild-type HER2 can cause toxicity. Here, we have developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 ectodomain. These antibodies bound to both HER2 S310F/Y with >100-fold selectivity over the wild-type. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies mimic the dimerization arm of HER2 and inhibit dimerization. The developed antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro. These results establish the feasibility of targeted therapy against S310F/Y-driven cancers and offer promising candidates toward clinical development. 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 HER2 ectodomain [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A038.