Article(id=1209792474298576932, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1209792462298674131, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2021-0789, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1621872000000, receivedDateStr=2021-05-25, revisedDate=1634572800000, revisedDateStr=2021-10-19, acceptedDate=null, acceptedDateStr=null, onlineDate=1766366602729, onlineDateStr=2025-12-22, pubDate=1647014400000, pubDateStr=2022-03-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766366602729, onlineIssueDateStr=2025-12-22, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766366602729, creator=13701087609, updateTime=1766366602729, updator=13701087609, issue=Issue{id=1209792462298674131, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='3', pageStart='547', pageEnd='844', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766366599868, creator=13701087609, updateTime=1766370620295, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1209809325250450301, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1209792462298674131, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1209809325250450302, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1209792462298674131, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=695, endPage=699, ext={EN=ArticleExt(id=1209792476282482756, articleId=1209792474298576932, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Anti-tumor activity of novel targeting HER2 antibody-drug conjugates, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=
Antibody-drug conjugates (ADCs) are widely used in cancer treatment. Human epidermal growth factor receptor-2 (HER2) is overexpressed in various types of solid tumors and is a validated therapeutic target for cancers. To develop a more effective therapy, we generated a novel anti-HER2 humanized monoclonal antibody MIL40 and MIL40 drug conjugates as novel cancer therapies. The MIL40 was conjugated with small molecule cytotoxic agents DM1 [emtansine, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] or monomethylauristatin E (MMAE) to generate ADCs, which were evaluated for their in vitro and in vivo anti-cancer activities. Experimental results show that MIL40-DM1 and MIL40-MMAE can effectively identify and bind to HER2-positive tumor cells. The binding capabilities of MIL40-DM1 and MIL40-MMAE with HER2 extracellular domain (ECD) antigens were not different after conjugation with DM1 or MMAE. The ADCs showed potent cytotoxicity in HER2-positive ovarian cancer cells SKOV3, breast cancer cells SKBR3 and stomach cancer cells N87 in vitro. MIL40-DM1 can effectively inhibit the volume and weight growth of SKOV3 transplant tumors in mice. The mice in this study were used and treated by following the international guidelines for the care and use of laboratory animals, and approved by Animal Ethics Committee of Institute of Military Cognitive and Brain Sciences.
, correspAuthors=Xin-ying LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jing GENG, Yue-mei YANG, Xin-ying LI), CN=ArticleExt(id=1209792480669724893, articleId=1209792474298576932, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=新型靶向HER2抗体MIL40偶联药物的抗肿瘤活性研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=
抗体偶联药物(antibody-drug conjugates, ADCs) 目前已被广泛应用于肿瘤治疗。人表皮生长因子受体2 (human epidermal growth factor receptor 2, HER2) 在包括乳腺癌、胃癌和卵巢癌在内的多种实体瘤中均呈特异性高表达, 被视为理想的肿瘤治疗靶点。本研究在一种靶向HER2的新型抗体—MIL40的基础上, 成功构建靶向HER2的ADCs (MIL40-DM1和MIL40-MMAE), 并研究其抗肿瘤活性。实验结果表明, MIL40-DM1和MIL40-MMAE能够有效识别并结合HER2阳性肿瘤细胞。偶联DM1和MMAE后, MIL40-DM1和MIL40-MMAE与HER2-ECD抗原的结合能力并未受到影响。两者在体外均能有效杀伤HER2阳性SKOV3卵巢癌细胞、SKBR3乳腺癌细胞和N87胃癌细胞。MIL40-DM1能够有效抑制小鼠SKOV3移植瘤的体积以及重量的增长(本研究中的小鼠按照国际实验室动物护理和使用准则进行使用和治疗, 并得到了军事医学科学院军事认知与脑科学研究所动物伦理委员会的批准)。
, correspAuthors=李新颖, authorNote=null, correspAuthorsNote=
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The binding activity of MIL40-DM1 and MIL40-MMAE with HER2 ECD by ELISA. HER2: Human epidermal growth factor receptor-2; DM1: Emtansine, <i>N</i><sup>2</sup>'-deacetyl-<i>N</i><sup>2</sup>'-(3-mercapto-1-oxopropyl)-maytansine; MMAE: Monomethylauristatin E; ECD: Extracellular domain. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \stackrel{-}{x} $</span> ± <i>s</i> , figureFileSmall=t9hCrWGvQw0cJVh+yhycNw==, figureFileBig=rtY0yf0H68mU+lyY7pJDdg==, tableContent=null), ArticleFig(id=1209809074175218297, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=EN, label=null, caption=null, figureFileSmall=fq6sobPz5ZcjfHLS8W11qw==, figureFileBig=QIYeTf1jqZWVFw9lzkMmgw==, tableContent=null), ArticleFig(id=1209809074296853117, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=CN, label=Figure 2, caption=
Binding activity of HER2 positive SKOV3 (A), SKBR3 (B) and N87 (C) treated with different concentration of MIL40-DM1 and MIL40-MMAE by FACS. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \stackrel{-}{x} $</span> ± <i>s</i> , figureFileSmall=fq6sobPz5ZcjfHLS8W11qw==, figureFileBig=QIYeTf1jqZWVFw9lzkMmgw==, tableContent=null), ArticleFig(id=1209809074422682252, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=EN, label=null, caption=null, figureFileSmall=nELfh6w9BuFu8zdWeQAi1A==, figureFileBig=Z3kEUbNx4eHHnwSq8CiS1A==, tableContent=null), ArticleFig(id=1209809074519151259, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=CN, label=Figure 3, caption=
Cytotoxicity of different concentration of MIL40-DM1 and MIL40-MMAE in SKOV3 (A), SKBR3 (B) and N87 (C) cells by CCK8. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \stackrel{-}{x} $</span> ± <i>s</i> , figureFileSmall=nELfh6w9BuFu8zdWeQAi1A==, figureFileBig=Z3kEUbNx4eHHnwSq8CiS1A==, tableContent=null), ArticleFig(id=1209809074632397482, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=EN, label=null, caption=null, figureFileSmall=3h5Rch9EWbPCItHe2hF/cg==, figureFileBig=Qr6TAEIdXILBEVMYXsyP6w==, tableContent=null), ArticleFig(id=1209809074779198138, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=CN, label=Figure 4, caption=
<i>In vivo</i> anti-tumor efficacy of MIL40-DM1 against SKOV3 cell xenograft tumors. A: The tumor growth curves of tumor-bearing mice after treatment with different drugs (NS was negative control, Herceptin and MIL40 was positive control); B: The body weight shifting in tumor bearing mice. <i>n</i> = 7, <span class="mag-xml-inline-formula">$ \stackrel{-}{x} $</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05 , figureFileSmall=3h5Rch9EWbPCItHe2hF/cg==, figureFileBig=Qr6TAEIdXILBEVMYXsyP6w==, tableContent=null), ArticleFig(id=1209809074959553225, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=EN, label=null, caption=null, figureFileSmall=UBvWK8HJMX1LtpsOKl9LFA==, figureFileBig=3sMbsi8jw3eleLq+DpzOoA==, tableContent=null), ArticleFig(id=1209809075093770971, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209792474298576932, language=CN, label=Figure 5, caption=
<i>In vivo</i> anti-tumor efficacy of MIL40-DM1 against SKOV33 cell xenograft tumors. 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