靶向TROP2的双载荷抗体药物偶联物：靶向正交细胞杀伤机制的Multi-Payload Conjugates™

Introduction: Antibody-Drug Conjugates (ADCs) have a tremendous impact on patient outcomes in breast and other cancers. Dato-DXd, for example, is a 2 nd -line therapy for stage IV, HR+/HER2 negative metastatic breast cancer and EGFR mutant non-small cell lung cancer (NSCLC). Sacituzumab govitecan (SG), is approved as a 3 rd line therapy in metastatic HER2 negative breast cancer. Many patients fail to respond or relapse after treatment with these ADCs due to tumor heterogeneity and resistance to the mono payload ADC. Dosing in patients is further limited by off-target toxicity due to instability of the maleimide bond between the antibody and linker. Combination therapies have historically outperformed monotherapies across most solid tumors, pointing to a potential for improvement of ADC efficacy. CatenaBio is developing next generation Multi-Payload Conjugates™ (MPCs™) with dual payloads and a more stable C-Y bond, that deliver targeted combination chemotherapies within a single molecule with reduced toxicities 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 replacing the unstable maleimide bond with a more stable C-Y bond. Results: Catena's lead TROP2 targeting dual payload MPC, CATB-101, features an optimized combination and ratio of tubulin and TOP1 inhibitors. CATB-101 demonstrates superior tumor growth inhibition and excellent tolerability in multiple TROP2 expressing CDX and PDX models of TNBC, gastric, and lung cancers. In head-to-head comparisons, CATB-101 outperforms T-DXd, SG and Dato-DXd with full tumor elimination at low doses. CATB-101 eliminates tumors in models following progression on SG treatment, demonstrating potential in ADC relapsed patients. Non-GLP non-human primate (NHP) toxicology trials with CATB-101 demonstrate a remarkable safety profile, by eliminating or reducing off-target toxicity. Conclusion: 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 next generation multi-payload conjugates. Catena's MPCs™ offer a next step in ADC design and allow for targeted delivery of multiple mechanisms of action with a single MPC™ while reducing off-target toxicity. CATB-101 is highly efficacious at eliminating tumors across multiple CDX and PDX models of cancer that display a range of target surface expression. Validated in early NHP toxicology studies with a significantly enhanced therapeutic window, these molecules offer the potential to circumvent tumor resistance pathways to deliver more durable patient responses.