Abstract 6932: BCG045: A first-in-class bispecific ADC targeting TROP2 and MUC1 demonstrates promising tumor efficacy and potentially reduced toxicity in preclinical studies

Abstract Although TROP2 ADCs provide clinical benefits, they face challenges with on-target toxicity and resistance. MUC1 is another crucial biomarker in oncology. In cancer cells, MUC1 loses its normal polarity and redistributes across the cell surface and cytoplasm. It consists of two subunits: the transmembrane domain (MUC1-C), which activates key oncogenic signaling pathways, and the extracellular domain (MUC1-N), which can be shed into circulation. Both TROP2 and MUC1 are overexpressed in various epithelial tumors and are linked to poor prognosis. Furthermore, the induction of TROP2 expression can occur through the binding of galectin-3 to MUC1. In this study, we developed a bispecific ADC that targets both TROP2 and MUC1, aiming to enhance efficacy while reducing target-related toxicity. To minimize the on-target toxicity associated with TROP2, we identified a TROP2 binder designed to reduce its internalization in a monovalent format with low affinity. To prevent the neutralization of antibodies/ADC by circulating shed MUC1, thereby affecting efficacy and pharmacokinetics, we developed a MUC1 binder that specifically recognizes the MUC1-N/C junction of membrane-bound MUC1 on tumor cells. This membrane-bound MUC1 binder demonstrated high specificity for MUC1 and robust affinity for both human and monkey MUC1. In tumor-bearing mouse models, the MUC1 binder exhibited an improved pharmacokinetic profile compared to benchmark antibodies, as well as strong anti-tumor efficacy. Notably, the performance of the MUC1 binder was unaffected by the presence of shed MUC1, suggesting its potential for effective therapeutic use in targeting MUC1-overexpressing tumors. The TROP2×MUC1 bispecific antibody (bsAb) demonstrated broad binding capabilities across a range of tumor cell lines with varying expressions of TROP2 and MUC1. Notably, the bsAb exhibited efficient internalization in tumor cells, while also showing reduced internalization activity in TROP2 single-positive cells, which is an important feature for minimizing on-target toxicity. When conjugated with a TOP1 inhibitor (TOP1i) linker-payload, designated as BLD1102, to form BCG045, the bispecific ADC displayed potent efficacy in various patient-derived xenograft (PDX) models. BCG045 outperformed the benchmark ADCs in certain models, indicating its enhanced therapeutic potential. Overall, the data suggest that BCG045 could be a promising new treatment option for multiple tumors, offering improved efficacy and safety. Citation Format: Jeremy Lee, Yifu Zhang, Chengzhang Shang, Yi Yang, . BCG045: A first-in-class bispecific ADC targeting TROP2 and MUC1 demonstrates promising tumor efficacy and potentially reduced toxicity in preclinical studies 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 6932.