Abstract 5797: Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing

Abstract Introduction: ADCs have had tremendous impact on patient outcomes in breast cancer and are now second line therapy for stage IV HER2 positive metastatic breast cancer. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and resistance to ADC payloads. We are developing next generation ADCs that deliver targeted combination chemotherapies with a single molecule. Method: CatenaBio has developed a novel system capable of attaching distinct payloads at different sites to the same antibody, enabling the production of highly stable single-molecule targeted combination therapies, Multi-Payload-Conjugates (MPCs), with a well-defined drug-antibody ratio (DAR). Results: We screened combinations of different payloads targeting several different mechanisms of cell division attached to trastuzumab at different DARs to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in both HER2 high and low tumor cell lines. Additionally, these novel MPCs show potent inhibition of tumor growth in a HER2+ xenograft model of cancer. Conclusion: Antibody Drug Conjugates have revolutionized the treatment of high HER2 positive breast cancer. More recently advances have been made in the design of ADCs to expand indications to include HER2 low as well as HER2 negative patients. Multi-payload Conjugates® offer the next step in ADC design and allow for the combination of multiple mechanisms of action in a single MPC that are highly effective across multiple breast cancer cell lines and HER2 expression levels. These molecules offer the potential to circumvent tumor resistance pathways and deliver deeper and more durable responses. Citation Format: Richard L. Kendall, Marco Lobba, Saurabh Johri, Chanez Symister, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Andrew Lau, Matthew B. Francis. Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5797.