Abstract 5605: Advanced dual payload antibody-drug conjugates for targeted chemoimmunotherapy

Abstract Antibody drug conjugates (ADCs) represent an effective therapeutic strategy for cancers, leveraging cancer-targeting monoclonal antibodies linked to potent payloads. Here, we report several novel conjugation platforms for dual-payload ADCs (DualADCs) that harness antibodies to co-deliver a chemotherapeutic agent, such as microtubule or topoisomerase I inhibitors, for direct tumor cell killing, alongside a toll like receptor agonist to enhance tumoral immunity. Aggressive triple-negative breast cancer was used as the model cancer for evaluating and comparing our DualADCs. Specifically, we developed advanced cysteine and lysine-based coconjugation technologies by linking chemotherapy and immunotherapy with one antibody, designing and optimizing linkers, increasing homogeneity, and refining reaction formulations to increase conjugation rate. The chemo-immunotherapy conjugation was validated with HPLC, and the drug to antibody ratios and drug to drug ratio were quantitated using advanced UPLC MS. The robustness and scalability of our optimal conjugation procedure was validated using spinner flask based reaction. In vitro characterizations revealed high cancer binding via flow cytometry, strong cancer specificity with minimal off target in normal human tissues, appropriate binding affinity, efficient drug internalization as revealed by confocal microscopy, and high cytotoxicity in cancer cell lines. In vivo evaluations demonstrated favorable tumor biodistribution, high plasma stability, low systemic toxicity, promising therapeutic efficacy in multiple xenograft mouse models, and immune modulation in tumor microenvironment. Collectively, this study establishes advanced dual-payload ADCs and innovative conjugation procedures for targeted chemo-immunotherapy of cancers. Citation Format: X. Margaret Liu, Zhuoxin “Zora” Zhou. Advanced dual payload antibody-drug conjugates for targeted chemoimmunotherapy 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 5605.