FZ-AD005, a Novel DLL3-Targeted Antibody-Drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models.

Autor:	Guo Q; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Gao B; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Song R; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Li W; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Zhu S; School of Pharmacy, East China Normal University, Shanghai, China., Xie Q; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Lou S; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Wang L; School of Pharmacy, East China Normal University, Shanghai, China., Shen J; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Zhao T; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Zhang Y; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Wu J; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China., Lu W; School of Pharmacy, East China Normal University, Shanghai, China., Yang T; Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd., Shanghai, China.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Oct 01; Vol. 23 (10), pp. 1367-1377.
DOI:	10.1158/1535-7163.MCT-23-0701
Abstrakt:	Delta-like ligand 3 (DLL3) is overexpressed in small cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with rovalpituzumab tesirine. In this study, we developed a novel DLL3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody, FZ-A038, and a valine-alanine (Val-Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line-derived xenograft and patient-derived xenograft models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable, and the highest nonseverely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of patients with SCLC. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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