Abstract 1818: Overcoming resistance with OBI-902: Preclinical evaluation of a next-generation TROP2 ADC.

Abstract Trophoblast cell surface antigen 2 (TROP2) is a clinically validated target. However, existing TROP2 ADCs show distinct toxicities, such as myelosuppression (sacituzumab govitecan) and stomatitis/interstitial lung disease (datopotumab deruxtecan). These toxicities underscore the need for safer ADCs. OBI-902 is a novel, site-specific ADC designed to address this gap. It consists of a humanized anti-TROP2 antibody conjugated to a topoisomerase I inhibitor via glycan-based site-specific platform, which generates a highly stable and homogeneous ADC optimized for enhanced antitumor activities and reduced systemic toxicity. This study investigates the exposure-response relationships to further characterize its pharmacologic and therapeutic profile. A comprehensive preclinical data package was generated for OBI-902. The pharmacokinetic-pharmacodynamic (PK-PD) relationship was characterized to define exposure-response parameters in non-small cell lung cancer (NSCLC) xenograft models. Antitumor efficacy was evaluated across multiple dosing regimens in NSCLC models, patient-derived xenografts (PDX) from various cancer types, and cell line-derived xenografts (CDX) engineered for TROP2 resistance. The safety profile was formally established in a GLP-compliant toxicology study in non-human primates, supporting further development. In an NSCLC xenograft model, OBI-902 exhibited a predictable and dose-proportional PK profile at doses ≥3 mg/kg, establishing a clear exposure-response relationship. This translated to durable anti-tumor activity at extended dosing intervals (3 mg/kg): the Q3W regimen induced complete regressions (CRs) in 2/5 animals by day 35, while both Q4W and Q6W regimens achieved sustained tumor stasis through day 62. OBI-902 demonstrated robust tumor growth inhibition, including regressions, across a diverse panel of ten PDX models encompassing NSCLC, triple-negative breast cancer (TNBC), and gastric cancer. To address acquired resistance, In TOP1 ADC-resistant NSCLC and TNBC CDX models, OBI-902 demonstrated superior efficacy, yielding 3-fold and 2-fold smaller mean tumor volumes, respectively, compared to the TOP1 inhibitor-based ADCs, highlighting its potential to overcome resistance. In a GLP-compliant toxicology study in cynomolgus monkeys, OBI-902 was well-tolerated with a NOAEL of 30 mg/kg, supporting a wide therapeutic index for clinical development. OBI-902 exhibits broad and potent antitumor activity across multiple cancer models, including those resistant to prior TOP1 ADCs, along with a favorable safety profile. Taken together, these preclinical results support the clinical development of OBI-902, which is currently being evaluated in a Phase 1/2 clinical trial as a potential best-in-class TROP2-targeted ADC. Citation Format: Ren-Yu Hsu, Chi-Huan Lu, Chi-Sheng Shia, Jing-Rong Huang, Hsin-Shan Wu, Lu-Tzu Chen, Jhih-Jie Yang, Tzu-Min Yen, Jyy-Shiuan Tu, Yu-Hsuan Tsao, Ya-Chi Chen. Overcoming resistance with OBI-902: Preclinical evaluation of a next-generation TROP2 ADC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1818.