Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates
Mark E. Petersen, Michael G. Brant, Manuel Lasalle, Samir Das, Renee Duan, Jodi Wong, Tong Ding, Kaylee J. Wu, Dayananda Siddappa, Chen Fang, Wen Zhang, Alex M. L. Wu, Truman Hirkala-Schaefer, Graham A. E. Garnett, Vincent Fung, Luying Yang, Andrea Hernández Rojas, Samuel O. Lawn, Stuart D. Barnscher, Jamie R. Rich, Raffaele Colombo
Abstract
In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present the development of a novel camptothecin ZD06519 (FD1), which has been specifically designed for its application as an ADC payload. A panel of camptothecin analogs with different substituents at the C-7 and C-10 positions of the camptothecin core was prepared and tested in vitro. Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug-linkers, conjugated to trastuzumab, and evaluated in vitro and in vivo. ZD06519 was selected on the basis of its favorable properties as a free molecule and as an antibody conjugate, which include moderate free payload potency (∼1 nmol/L), low hydrophobicity, strong bystander activity, robust plasma stability, and high-monomeric ADC content. When conjugated to different antibodies using a clinically validated MC-GGFG-based linker, ZD06519 demonstrated impressive efficacy in multiple cell line-derived xenograft models and noteworthy tolerability in healthy mice, rats, and non-human primates.