Abstract 5796: A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations

Abstract HER3 activation, via NRG1 ligand-dependent and -independent heterodimerization with HER2 or EGFR, has been associated with tumor progression and acquired resistance to therapies in multiple indications. HER3 mutations, detected in around 3% of cancer cases, may drive oncogenic signaling, leading to rapid tumor growth. Currently, there are no approved targeted therapies for HER3 mutations. Through analysis of real-world data and structural modelling of HER3 heterodimers, we identified four common HER3 mutations located within or close to the dimerization interface of HER3, suggesting a potential impact on HER3 heterodimerization. Immunoprecipitation assays confirmed that all four mutations increased the heterodimerization of HER3 with both HER2 and EGFR. Further, conversion of an endogenous HER3 mutation to wild type via CRISPR editing significantly reduced the growth of KYSE-150, a HER3 mutant cell line. HMBD-001 is a clinical-stage anti-HER3 antibody rationally developed to uniquely block the HER3 dimerization interface to potently inhibit HER3 heterodimerization. Through structural analysis and FACS binding on HER3 mutation cell lines, we confirmed that the binding epitope of HMBD-001 does not overlap with the selected HER3 mutations and therefore may be a good therapeutic option for patients with HER3 mutations. In vitro, HMBD-001 suppressed HER3 mutation-driven PI3K/AKT signaling, as demonstrated by the reduction of phosphorylated HER3 and AKT levels. In multiple cell- and patient-derived xenograft models with HER3 mutations HMBD-001 response achieved 80% tumor growth inhibition. Based on this encouraging preclinical data, a Phase Ib clinical trial (NCT05919537) has been initiated, evaluating HMBD-001 in patients with aberrant HER3 signaling, including HER3 mutations. Citation Format: Weiyi Toy, Dipti Thakkar, Roberto Magallanes, Sharon Wu, Ming Poi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup. A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5796.