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Petersen, Mark E; Brant, Michael G; Lasalle, Manuel; Das, Samir; Duan, Renee; Wong, Jodi; Ding, Tong; Wu, Kaylee J; Siddappa, Dayananda; Fang, Chen; Zhang, Wen; Wu, Alex M L; Hirkala-Schaefer, Truman; Garnett, Graham A E; Fung, Vincent; Yang, Luying; Hernandez Rojas, Andrea; Lawn, Samuel O; Barnscher, Stuart D; Rich, Jamie R; Colombo, Raffaele
Molecular cancer therapeutics, 05/2024, Volume: 23, Issue: 5Journal Article
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.
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