Abstract 2887: Next generation antibody drug conjugates targeting HER2 and TROP2: Multi-Payload ConjugatesTM targeting orthogonal mechanisms of cell killing
Authors: Richard L. Kendall, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Derek Garcia-Almedina, Saurabh Johri, Matthew Francis, Marco Lobba
Journal: Cancer Research (2025)

Abstract Introduction: Antibody-Drug Conjugates (ADCs) have had tremendous impact on patient outcomes in breast and other cancers. T-DXd, for example, is second-line therapy for stage IV, HER2 positive metastatic breast cancer as well as HER2 low expressing tumors. Sacituzumab govitecan, a TROP2 targeted ADC, has been approved as a 3rd line therapy in locally advanced or metastatic HER2 negative breast cancer. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and eventual resistance to the ADC payload. 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 novel, highly stable, single-molecule targeted combination therapies, MPCs™, 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 MPCs show superior inhibition and excellent tolerability in mouse models of tumor growth in HER2 high and HER2 low/TROP2 expressing xenograft models including models of TNBC (triple negative breast cancer). In head-to-head comparisons MPCs out-perform current standards of care T-DXd and sacituzumab govitecan, demonstrating tumor elimination at low mg/kg doses. To produce the MPCs, combinations of different payloads targeting orthogonal mechanisms of cell division attached to trastuzumab as well as sacituzumab were screened at different DARs and payload ratios to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in multiple cell lines containing high and low expression of HER2 and TROP2, as well as a T-DXd resistant cell line. 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 conjugate modalities. Multi-payload Conjugates™ offer the next step in ADC design and allow for the targeted combination of multiple mechanisms of action with a single MPC™ that are highly efficacious at eliminating tumors across multiple cell line derived xenograft models with a range of target expression. Successfully constructed with a variety of targeting antibodies, these molecules offer the potential to circumvent tumor resistance pathways to deliver deeper and more durable patient responses. Citation Format: Richard L. Kendall, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Derek Garcia-Almedina, Saurabh Johri, Matthew Francis, Marco Lobba. Next generation antibody drug conjugates targeting HER and TROP: Multi-Payload ConjugatesTM targeting orthogonal mechanisms of cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2887.