Abstract Dual-payload antibody drug conjugates (ADCs) have gained increasing attention due to their potential to overcome limitations of single-payload ADCs. Depending on the combination strategy, dual-payload formats have been reported in order to mitigate tumor heterogeneity or to address resistance that may develop with single payload ADCs. Our dual-payload approach is differentiated from these approaches by aiming to identify two distinct payloads that could provide synergistic anti-tumor activities while minimizing overlapping unwanted side effects. Through extensive combination screening campaigns, we have discovered payload pairs that synergize each other by ZIP score experiments. TROP2 is a perfect target antigen to validate our dual-payload ADC format since it is a clinically validated. Although there are two FDA-approved ADCs, Trodelvy and Datroway, anti-tumor efficacy from these TROP2 ADCs have been subpar due to dose-limiting toxicities. We have developed a novel TROP2-targeting dual-payload ADC (AD2C) by using MMAE-based dual-payload combination to address this unmet need. The presentation highlights advantages of the synergistic dual-payload TROP2 ADC over known single-payload ADCs or other dual-payload ADC formats by demonstrating, (1) in vitro cytotoxicity for cancer cells having different TROP2 expression levels (2) in vivo efficacy in various CDX(cancer-cell derived xenograft) models (3) in vivo ADC stability in rats and monkeys by PK(pharmacokinetics) studies, and (4) preliminary toxicity studies conducted in mice and monkeys.In due course, we are currently in preparation of PDX efficacy studies for further confirming its in vivo efficacy over various patient-derived tumor cells, and IND-enabling toxicology studies in order to quickly move forward the dual-payload TROP2 ADC(AD2C) into clinical study. Citation Format: Myeong Joo Kim, Soyeon Lim, Dahyun Kim, Han ah Kim, Jaebeom Park, Eunseok Choi, Da wo Jeong, Ji Eun Choi, Young Sang Kim, Seung Chan Kim, Hyo Jin Kang, Chang-Sun Lee. A novel synergistic dual-payload TROP2 ADC (CTPH-03) delivering enhanced safety by increased MTD 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 4438.
Kim et al. (2026) studied this question.