Abstract PS4-06-12: Dual-payload TROP2 targeted antibody drug conjugate: Multi-Payload Conjugates™ deliver orthogonal mechanisms of cell killing

Abstract Introduction: Antibody-Drug Conjugates (ADCs) have a tremendous impact on patient outcomes in breast and other cancers. Dato-DXd, for example, is second-line therapy for stage IV, HR positive/HER2 negative metastatic breast cancer. Sacituzumab govitecan (SG), a TROP2 targeted ADC, is approved as a 3rd line therapy in locally advanced or metastatic HER2 negative breast cancer, and in combination with pembrolizumab, is likely to see approval in 1st line therapy for PD-L1 positive tumors. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and eventual resistance to the ADC payload. Combination therapies have historically outperformed mono chemo approaches across most solid tumors to date, pointing to a potential avenue for improvement of ADC efficacy. We are developing next generation Multi-Payload Conjugates™ (MPCs™) that deliver targeted combination chemotherapies within a single molecule to address shortcomings in current ADCs. Method: CatenaBio has developed highly stable, dual-payload ADC combination therapies, with tunable payload ratios. Our selective conjugation platform allows the attachment of distinct payloads targeting different mechanisms of action at three unique sites on antibody scaffolds. Results: Catena’s lead TROP2 targeting MPC, CATB-101, features an optimized combination and ratio of tubulin and Topo1 inhibitors. CATB-101 demonstrates superior inhibition and excellent tolerability in mouse models of tumor growth in TROP2 expressing xenograft models including multiple CDX and PDX models of TNBC (triple negative breast cancer). In head-to-head comparisons with T-DXd, SG and Dato-DXd, MPCs out-perform the current approved ADCs in breast cancer and demonstrate full tumor elimination at low mg/kg doses. Furthermore, CATB-101 rescues CDX models after progression on SG treatment, demonstrating potential applications in late-line treatment. Non-GLP Non-Human Primate (NHP) toxicology trials with CATB101 demonstrate remarkable safety profile, surpassing benchmark mono-payload ADCs in tolerability. Conclusion: While advances have been made in the design of ADCs to expand to previously unaddressed populations, high patient relapse and the failure of recent mono-payload ADCs in late-stage trials indicate a need for novel multi-payload conjugates. Catena’s MPCs™ offer the next step in ADC design and allow for the targeted delivery of multiple mechanisms of action with a single MPC™ are highly efficacious at eliminating tumors across multiple CDX and PDX xenograft models with a range of target expression. Now validated in early NHP toxicology studies with a significantly enhanced therapeutic window, these molecules offer the potential to circumvent tumor resistance pathways to deliver deeper and more durable patient responses. Citation Format: M. Lobba, D. Trinter, M. Nguyen, S. Brady, C. Symister, A. Lau, D. Garcia-Almedina, S. Johri, F. Matthew, R. Kendall. Dual-payload TROP2 targeted antibody drug conjugate: Multi-Payload Conjugates™ deliver orthogonal mechanisms of cell killing 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 PS4-06-12.