Abstract 5734: Advancing ADC discovery with a highly versatile linker-camptothecin library

Abstract Camptothecin derivatives have gained prominence as payloads in investigational antibody-drug conjugates (ADCs), exemplified by the clinical success of Trodelvy and Enhertu. The precise design of these linker-camptothecins has been instrumental in achieving optimal safety and efficacy for specific therapeutic indications. Growing evidence suggests that a single linker-payload design cannot accommodate the diverse requirements of various therapeutic targets. For instance, while the linker-payload of Enhertu (GGFG-DXd) has shown exceptional efficacy in HER2-targeted therapies, its performance is less promising in TROP2- and HER3-targeted indications. This highlights the critical need for linker-camptothecin systems with greater diversity in drug release mechanisms, kinetics, and payload potency to address varying therapeutic needs. To address the limitations of existing linker-camptothecin designs, including issues with stability, release efficiency, and specificity, we have developed a comprehensive library of linker-camptothecins with enhanced molecular diversity. Our design strategy incorporates a range of stimuli-responsive release mechanisms, such as cathepsin-, legumain-, and glucuronidase-mediated cleavage, as well as pH-sensitive linkers. Multiple camptothecin derivatives, including SN38, Exatecan, and TopoIx, were selected based on their distinct pharmacological properties—such as antitumor efficacy, lipophilicity, and half-life—and were conjugated to various linkers, creating a versatile library with broad applicability. This molecular diversity facilitates optimized release profiles and payload activities, tailored to specific therapeutic scenarios. Leveraging this library, we constructed a series of highly refined ADCs targeting different antigens and evaluated them systematically in both in vitro and in vivo preclinical models. These studies revealed that the ADCs incorporating the novel linker-camptothecin designs demonstrated significantly enhanced therapeutic efficacy and improved safety profiles compared to conventional linker-payload systems. In summary, we have established a novel linker-camptothecin library with diverse release behaviors optimized for specific therapeutic contexts. This approach facilitates the discovery and development of potent ADC candidates with superior efficacy and safety profiles, providing a robust platform for precision drug development targeting diverse indications. Citation Format: Meijun Xiong, Qingsong Wu, Yanchun Li, Chong Liu, Yajun Sun, Zengyan Mu, Xinju Gao, Yanwen Feng, Haibo He, Paul H. Song, Gang Qin. Advancing ADC discovery with a highly versatile linker-camptothecin library [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 5734.