HER2-targeted antibody drug conjugates for ovarian cancer therapy

doi:10.1016/j.ejps.2016.08.015

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	HER2-targeted antibody drug conjugates for ovarian cancer therapy
	Jiang, Jing 5; Dong, Lihou 2; Wang, Lei 3; Wang, Ling 1; Zhang, Jing 5; Chen, Fang 2; Zhang, Xiuli 5; Huang, Min1 ; Li, Shenjun 1; Ma, Weiwei 1
刊名	EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
	2016-10-10
卷号	93 页码:274-286
关键词	Ovarian cancer Antibody drug conjugates (ADCs) HER2/ErbB2 Monomethyl auristatin E (MMAE)
ISSN号	0928-0987
DOI	10.1016/j.ejps.2016.08.015
文献子类	Article
英文摘要	HER2 targeted delivery of ovarian cancer therapy has been beneficial for some patients, although, its efficacy is yet to be confirmed in large populations. We generated a novel anti-HER2 humanized antibody (Hertuzumab) and conjugated it to a microtubule-disrupting drug monomethyl auristatin E conjugate (MMAE) with a lysosomal protease-cleavable valine-citrulline linker. The average drug to antibody ratio (DAR) of Hertuzumab-vc-MMAE was varied by conjugating Hertuzumab antibodies with increasing linker-drugs (LDs) from D0-D8. The resulting conjugates were tested for kinetic affinity for soluble HER2-ECD, cytotoxicity,, and in vivo pharmacokinetics. The kinetic binding constant values (Kt)) were obtained by the bio-layer interference (BLI) method. The half time (t(1/2)) and clearance (Cl) results of the pharmacokinetic profile in rats were DAR-dependent. Hertuzumab-vc-MMAE with DAR4 Was selected for further evaluation. Both Hertuzumab and Hertuzumab conjugates could bind to HER2 antigen, and exhibited significant cytotoxicity on HER2 positive tumor cells after internalization by receptor-mediated endocytosis. Hence, Hertuzumab-vc-MMAE conjugates were significantly selective both in vitro and in vivo as compared to other ovarian cancer clinical therapies that are currently used. Cell signal transduction and cell cycle were also affected, as shown by down regulation of PI3K/AKT pathway and arrested mitosis in the G2/M phase. The pharmacokinetics and pharmacodynamics (PK-PD) of the conjugates in nude mouse xenograft model demonstrated a correlation between efficacy and drug concentration. These results show that Hertuzumab-vc-MMAE is a potential therapeutic agent for HER2 positive ovarian cancer. (C) 2016 Published by Elsevier B.V.
资助项目	National Science and Technology Major Project of China[2014ZX09508004001] ; National Science and Technology Major Project of China[2013ZX09401002]
WOS关键词	PRIMARY PERITONEAL CARCINOMA ; TRASTUZUMAB EMTANSINE T-DM1 ; 2-POSITIVE BREAST-CANCER ; MONOCLONAL-ANTIBODY ; EPITHELIAL OVARIAN ; ANTITUMOR-ACTIVITY ; GASTRIC-CANCER ; LUNG-CANCER ; HER2 ; PERTUZUMAB
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000384853200030
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275860]
专题	药理学第一研究室
通讯作者	Fang, Jianmin; Wang, Chunhua
作者单位	1.RemeGen Ltd, Yantai 264000, Shandong, Peoples R China; 2.Beijing Inst Radiat Med, Dept Pharmacol & Toxicol, Beijing 100850, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 4.Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China 5.Binzhou Med Univ, Dept Pharmacol, Yantai 256603, Shandong, Peoples R China;
推荐引用方式 GB/T 7714	Jiang, Jing,Dong, Lihou,Wang, Lei,et al. HER2-targeted antibody drug conjugates for ovarian cancer therapy[J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,2016,93:274-286.
APA	Jiang, Jing.,Dong, Lihou.,Wang, Lei.,Wang, Ling.,Zhang, Jing.,...&Wang, Chunhua.(2016).HER2-targeted antibody drug conjugates for ovarian cancer therapy.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,93,274-286.
MLA	Jiang, Jing,et al."HER2-targeted antibody drug conjugates for ovarian cancer therapy".EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 93(2016):274-286.