Novel Hydrophilic Linker To Improve Stability And In Vitro Activity Of Antibody-Drug Conjugates

By Kern H. Chang, Hana Yu, Myunghoe Heo, Nahmju Kim, Seonhwa Lee, Enhyung Chang, Jinyoung Kim, Yeejin Jeon, Anna Jang, Donggeon Kim, and Byuoung chul Lee

Antibody–drug conjugate performance is influenced by molecular design factors beyond target selection. Hydrophilic design elements are evaluated for their impact on ADC behavior across tumor models expressing clinically relevant targets, including EGFR, TROP2, tissue factor, and HER2. Comparative in vitro analyses demonstrate how hydrophilic and non‑hydrophilic ADC variants differ in potency, selectivity, and effects on cell viability. Observed trends in target‑dependent activity, off‑target effects, and dose–response behavior across multiple cell lines provide insight into how linker and payload chemistry contribute to therapeutic window optimization. Evaluation of both targeting and non‑targeting controls further emphasizes the role of early molecular design decisions in shaping functional performance during ADC development.