Abstract Background: While Enhertu® has delivered meaningful clinical benefits in HER2-positive and HER2-low cancers, many patients still experience suboptimal outcomes, particularly in HER2-low tumors that account for over 50% of the HER2-positive pan cancer population. Resistance to HER2-targeted therapies remains a critical challenge, including HER2 downregulation or loss, which diminishes antibody binding and payload delivery. OBI Pharma is the first to discover that TROP2 and HER2 form heterodimers (Data not published) in cancer cells. This TROP2 and HER2 crosstalk provides a strong rationale for dual targeting. In response, we developed OBI-201—a bispecific antibody-drug conjugate (ADC) engineered to simultaneously engage both TROP2 and HER2, aiming to enhance tumor specificity and overcome resistance associated with single-target therapies. Method: OBI-201 is a next-generation bispecific ADC that co-targets HER2 and TROP2, using site-specific GlycOBI® glycan-based conjugation technology to attach an exatecan payload at a DAR of 4 for precise delivery. To assess the efficiency of internalization, pHAb-labeled OBI-201 was applied to HER2/TROP2 co-expressing cells by quantifying fluorescence signals. To evaluate its antitumor activity, OBI-201 was tested in both cell line-derived xenograft (CDX) models and patient-derived xenograft (PDX) models. Results: The bispecific ADC format of OBI-201 was designed to enhance tumor targeting and promote efficient internalization, which was confirmed by strong internalization signals observed in cells co-expressing HER2 and TROP2. OBI-201 demonstrated superior antitumor activity compared to Enhertu®, Datroway®, and Trodelvy® in HER2-low colorectal, pancreatic, and NSCLC models, as well as in Enhertu-resistant NSCLC CDX models. Remarkably, in a HER2-low TNBC PDX model with established multi-drug resistance, including resistance to Trodelvy®, OBI-201 achieved complete tumor regression in 3 out of 6 mice, highlighting its potential to overcome treatment resistance and address unmet needs in difficult-to-treat tumors. Conclusion: OBI-201 is a next-generation bispecific ADC targeting HER2 and TROP2, designed to overcome the limitations of single-target therapies. Its dual-targeting approach, enabled by GlycOBI®, proprietary ADC enabling technologies for precise payload delivery, offers strong potential to overcome HER2-low expression and resistance, addressing significant unmet needs across a broad spectrum of solid tumors. Citation Format: C. Lu, S. Wang, Y. Chen, Y. Wu, T. Huang, W. Chan, L. Chen, H. Wu, C. Wei. Obi-201: a bispecific trop2 × her2 antibody-drug conjugate to expand therapeutic reach beyond her2-low limitations abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-08.
Lu et al. (Tue,) studied this question.
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