Synthesis and biological evaluation of novel quaternary ammonium antibody drug conjugates based on camptothecin derivatives

by Yifan Zhang, Mengyuan Ding, Lei Wang, Sicheng Yin, Liang Zhang, Xuemei Cao, Zhiyang Chen, Weinan Li, Qingsong Guo, Shulei Zhu, Wei Lu, Tong Yang

Antibody drug conjugates (ADCs) have emerged as a highly promising class of cancer therapeutics, comprising antibodies, effector molecules, and linkers. Among them, DS-8201a with DXd as the effector molecule, has shown remarkable anti-tumor efficacy against solid tumors, sparking a surge of interest in ADCs with camptothecin derivatives as ADC effector molecules. In this study, we introduced and successfully constructed quaternary ammonium ADCs utilizing camptothecin derivatives WL-14 and CPTS-1 for the first time. All four ADCs displayed excellent stability under physiological conditions and in plasma, facilitating their prolonged circulation in vivo. Moreover, the four ADCs, employing Val-Cit or Val-Ala dipeptide linkers effectively achieved complete release of the effector molecules via cathepsin B. Although, the in vitro antitumor activity of these ADCs was comparatively limited, the development of quaternary ammonium ADCs based on novel camptothecin derivatives as effector molecules is still a viable and promising strategy. Significantly, our study provides valuable insights into the crucial role of linker optimization in ADCs design.