title: Synthesis, characterization and targeting chemotherapy for ovarian cancer of trastuzumab-SN-38 conjugates.
abstract: Antibody-drug conjugates (ADCs), combining monoclonal antibody with high cytotoxicity chemotherapeutic drug (warhead), have been successfully applied for clinical cancer therapy. Linker technology to select and design linker connecting warhead with antibody, is critical to the success of therapeutic ADCs. In this study, three kinds of linkers were designed to connect SN-38, the bioactive metabolite of the anticancer drug irinotecan (CPT-11), which is 100-1000 times more potent than CPT-11, with the anti-HER2 antibody trastuzumab to prepare three different ADC conjugates (T-SN38 A, B and C). Meanwhile, we compared the anti-ovarian cancer effect of these three T-SN38 conjugates with trastuzumab in vitro and in vivo. Our in vitro results showed that T-SN38 A, B and C (drug-to-antibody ratio, DAR=3.7, 3.2, 3.4) were 2 to 3 times as cytotoxic as SN-38, and the IC50 for these three conjugates on SKOV-3 cell line at 72 h were 5.2 ± 0.3, 4.4 ± 0.7, and 5.1 ± 0.4 nM respectively. In our in vivo studies, T-SN38 conjugates had well targeting ability for tumor tissue and all three of them had much higher anti-ovarian cancer potency than trastuzumab. Among of them, T-SN38 B, which coupled SN-38 with trastuzumab by a carbonate bond, has the best anti-ovarian cancer potency. In conclusion, the novel HER2-targeting ADCs T-SN38 have great potential for HER2-positive ovarian cancer. Moreover, the SN-38-Linkers designed in this study can also be used to connect with other antibodies for the therapy of other cancers.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China; Research Center for Public Health and Preventive Medicine, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, PR China; Guangdong Zhongsheng Pharmaceutical Co., Ltd., PR China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Su
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Yangpin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Xiangzheng
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Guangdong Zhongsheng Pharmaceutical Co., Ltd., PR China.
authors.forename: Xian
authors.initials: X
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Rundong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Lantu
authors.initials: L
authors.lastname: Gou
authors.affiliation: Guangdong Zhongsheng Pharmaceutical Co., Ltd., PR China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: xieym@scu.edu.cn.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Gastrointestinal Surgery, West China Hostpital, Sichuan University, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Pharmacology & Pharmaceutical Sciences School of Medicine/ Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, PR China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China. Electronic address: jinliangyang@scu.edu.cn.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002166:Camptothecin; D018796:Immunoconjugates; D000077146:Irinotecan; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: 10-hydroxycamptothecin (PubChem CID: 97,226); 4-dimethylaminopyridine (PubChem CID:14,284); 7-ethyl-10-hydroxycamptothecin (PubChem CID:104,842); Antibody-drug conjugates (ADCs); Bi-function linker; N-hydroxysuccinimide (PubChem CID:80,170); Ovarian cancer; PEG4 (PubChem CID:21,896,924); SN-38; Targeting chemotherapy; Trastuzumab; dicyclohexylcarbodiimide (PubChem CID:10,868); dithiothreitol (PubChem CID:19,001); ethyldiisopropylamine (PubChem CID:81,531); mercaptoacetic acid (PubChem CID:1133); triphosgene (PubChem CID:94,429)