药学学报

以TROP2为靶点的新型抗体偶联药物hIMB1636-MMAE对人表皮癌A431的抗肿瘤活性研究

PDF下载

朱诗雨 , 吴小凡 , 周玉洁 , 徐晓睿 , 孙丽平 , 高瑞娟 , 李卓荣 , 苗庆芳 ^* , 周丹丹 ^*

药学学报 | 研究论文 2026,61(7): 2479-2486

收起

药学学报 |研究论文 2026 , 61 (7) : 2479 -2486

以TROP2为靶点的新型抗体偶联药物hIMB1636-MMAE对人表皮癌A431的抗肿瘤活性研究

全屏

[Author(id=1308841931950617093, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841932072251911, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841931950617093, language=EN, stringName=Shi-yu ZHU, firstName=Shi-yu, middleName=null, lastName=ZHU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841932244218376, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841931950617093, language=CN, stringName=朱诗雨, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841932302938634, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841932382630412, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841932302938634, language=EN, stringName=Xiao-fan WU, firstName=Xiao-fan, middleName=null, lastName=WU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841932613317133, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841932302938634, language=CN, stringName=吴小凡, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841932718174735, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841933020164625, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841932718174735, language=EN, stringName=Yu-jie ZHOU, firstName=Yu-jie, middleName=null, lastName=ZHOU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841933099856402, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841932718174735, language=CN, stringName=周玉洁, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841933158576660, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841933221491222, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933158576660, language=EN, stringName=Xiao-rui XU, firstName=Xiao-rui, middleName=null, lastName=XU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841933288600087, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933158576660, language=CN, stringName=徐晓睿, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841933372486169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=4, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841933447983643, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933372486169, language=EN, stringName=Li-ping SUN, firstName=Li-ping, middleName=null, lastName=SUN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841933519286812, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933372486169, language=CN, stringName=孙丽平, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841933603172894, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=5, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841933687058976, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933603172894, language=EN, stringName=Rui-juan GAO, firstName=Rui-juan, middleName=null, lastName=GAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841933779333665, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933603172894, language=CN, stringName=高瑞娟, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841933854831139, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=6, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308841933926134309, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933854831139, language=EN, stringName=Zhuo-rong LI, firstName=Zhuo-rong, middleName=null, lastName=LI, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841933993243174, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841933854831139, language=CN, stringName=李卓荣, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841935700324904, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=7, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=miaoqf@imb.pumc.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1308841935788405290, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841935700324904, language=EN, stringName=Qing-fang MIAO, firstName=Qing-fang, middleName=null, lastName=MIAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841935863902763, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841935700324904, language=CN, stringName=苗庆芳, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])]), Author(id=1308841935922623021, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, orderNo=8, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=zhdd0080@163.com, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1308841936006509103, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841935922623021, language=EN, stringName=Dan-dan ZHOU, firstName=Dan-dan, middleName=null, lastName=ZHOU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308841936082006576, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, authorId=1308841935922623021, language=CN, stringName=周丹丹, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308841931870925313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, xref=null, ext=[AuthorCompanyExt(id=1308841931879313922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308841931887702531, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841928481927663, companyId=1308841931870925313, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050)])])]

朱诗雨, 吴小凡, 周玉洁, 徐晓睿, 孙丽平, 高瑞娟, 李卓荣, 苗庆芳^*, 周丹丹^*

作者信息

中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050

通讯作者:

苗庆芳, Tel: 13691504102, E-mail: miaoqf@imb.pumc.edu.cn

周丹丹, Tel: 17810259269, E-mail: zhdd0080@163.com

作者简介:

作者贡献:

苗庆芳、周丹丹负责论文构思和指导; 朱诗雨负责实验操作和论文撰写; 吴小凡负责本实验使用的抗体偶联药物合成; 周玉洁和徐晓睿负责实验数据处理及作图; 孙丽平负责动物实验操作; 苗庆芳、周丹丹、李卓荣、高瑞娟负责论文修改。

Antitumor efficacy of a TROP2-targeting ADC hIMB1636-MMAE against human epidermal carcinoma A431 cells

Shi-yu ZHU, Xiao-fan WU, Yu-jie ZHOU, Xiao-rui XU, Li-ping SUN, Rui-juan GAO, Zhuo-rong LI, Qing-fang MIAO^*, Dan-dan ZHOU^*

Affiliations

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

出版时间: 2026-07-12 doi: 10.16438/j.0513-4870.2025-1315

文章导航

摘要

收起

为评估新型抗体偶联药物hIMB1636-MMAE对人滋养层细胞表面抗原2 (trophoblast cell surface antigen 2, TROP2) 高表达的人表皮癌的疗效, 本研究系统评估了其对人表皮癌细胞A431体内外抗肿瘤疗效及作用机制。通过Western blot检测A431细胞中TROP2的表达情况; 通过流式细胞术检测hIMB1636-MMAE与A431细胞的结合特性及其对细胞周期和凋亡的影响; 利用激光共聚焦显微镜观察其被肿瘤细胞内吞的过程, 并利用CCK-8法评估其体外杀细胞活性; 进一步构建A431细胞裸鼠异种移植瘤模型, 以评价hIMB1636-MMAE的体内抗肿瘤效果。实验结果显示, A431细胞表达高水平的TROP2, hIMB1636-MMAE能特异性结合该细胞, 能够被其有效内吞并运送至溶酶体。hIMB1636-MMAE在体外可选择性杀伤A431细胞(IC₅₀为1.49 ± 0.22 nmol·L^-1), 可诱导G2/M期细胞周期阻滞和细胞凋亡, 在体内10 mg·kg^-1对A431裸鼠移植瘤的抑制率为93.89% (实验得到中国医学科学院医药生物技术研究所动物护理与使用委员会批准, 编号: IMB-20220210D₂03)。综上所述, hIMB1636-MMAE在体内外显示出良好的抗皮肤癌潜力, 为TROP2阳性皮肤癌患者提供了潜在候选药物。

关键词

hIMB1636-MMAE / A431 / 皮肤癌 / 抗体偶联药物 / 增殖 / 凋亡 / 周期

Abstract

收起

To evaluate the antitumor activity of the novel antibody-drug conjugate (ADC) hIMB1636-MMAE against human epidermal carcinoma, this study systematically investigated its therapeutic efficacy and mechanism of action in A431 cells. Trophoblast cell surface antigen 2 (TROP2) expression in A431 cells was confirmed by Western blot. Flow cytometry was used to analyze the binding characteristics of hIMB1636-MMAE to A431 cells and its effects on cell cycle arrest and apoptosis. The internalization process of the ADC was visualized using confocal laser scanning microscopy, while cytotoxicity in vitro was assessed via the CCK-8 assay. Moreover, an A431 cell-derived xenograft model was established in nude mice to evaluate the in vivo antitumor efficacy of hIMB1636-MMAE. Results showed that A431 cells exhibited high TROP2 expression. hIMB1636-MMAE could specifically bind to A431 cells, and was effectively internalized and transported to lysosomes. Furthermore, hIMB1636-MMAE specifically killed cancer cells with IC₅₀ value of 1.49 ± 0.22 nmol·L^-1, and induced G2/M phase cell cycle arrest and apoptosis. In A431 cell-derived xenografts, hIMB1636-MMAE at 10 mg·kg^-1 exhibited a significant antitumor effect, achieving a tumor inhibition rate of 93.89% (all animal protocols were approved by the Animal Care and Use Committee at the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, No. IMB-20220210D₂03). In conclusion, hIMB1636-MMAE demonstrates promising potential against skin cancer and may serve as a candidate therapeutic for TROP2-positive cutaneous malignancies.

Key words

hIMB1636-MMAE / A431 / skin cancer / antibody-drug conjugate / proliferation / apoptosis / cell cycle

引用本文

朱诗雨, 吴小凡, 周玉洁, 徐晓睿, 孙丽平, 高瑞娟, 李卓荣, 苗庆芳, 周丹丹. 以TROP2为靶点的新型抗体偶联药物hIMB1636-MMAE对人表皮癌A431的抗肿瘤活性研究. 药学学报, 2026 , 61 (7) : 2479 -2486 . DOI: 10.16438/j.0513-4870.2025-1315

Shi-yu ZHU, Xiao-fan WU, Yu-jie ZHOU, Xiao-rui XU, Li-ping SUN, Rui-juan GAO, Zhuo-rong LI, Qing-fang MIAO, Dan-dan ZHOU. Antitumor efficacy of a TROP2-targeting ADC hIMB1636-MMAE against human epidermal carcinoma A431 cells[J]. Acta Pharmaceutica Sinica, 2026 , 61 (7) : 2479 -2486 . DOI: 10.16438/j.0513-4870.2025-1315

正文

收起

皮肤癌是全球范围内最常见的恶性肿瘤之一, 其发病率和死亡率持续攀升, 尤其在老年人群中构成了严峻的公共卫生挑战^[1]。根据肿瘤细胞来源及生物学行为, 皮肤癌主要分为非黑色素瘤皮肤癌(non-melanoma skin cancer, NMSC) 和黑色素瘤两大类, 其中NMSC又包括基底细胞癌和鳞状细胞癌^[2]。GLOBOCAN 2022的数据显示, 2022年全球新发NMSC病例达1 234 533例, 相关死亡人数约为69 416人^[3]。目前, 手术治疗作为皮肤癌常用的治疗手段之一, 只适用于早期和局部进展期的患者, 且术后可能伴发感染、积液等并发症, 若肿瘤切除不彻底还可能有复发风险^[4]。对于晚期或转移性皮肤癌, 细胞毒性化疗是首选疗法, 但其毒副作用较为显著^[5], 因此, 临床亟需开发更高效且安全的治疗策略。

抗体疗法作为生物医药领域最具革命性的突破之一, 以其高特异性、低毒性和广泛的治疗潜力, 已成为全球制药市场增长最迅速的细分领域^[6]。目前, 该疗法已被广泛应用到癌症、自身免疫性疾病、感染性疾病及血液系统疾病等多种重大疾病的治疗中^[7]。根据结构与功能的不同, 抗体药物可被分为裸抗体、抗体偶联药物(antibody-drug conjugates, ADCs) 和小分子抗体片段等类型^[8]。其中, ADC凭借其在肿瘤治疗中展现出的卓越潜力而备受关注。ADC是由单克隆抗体和细胞毒性药物通过连接子共价结合而成, 这种设计巧妙融合了抗体对靶点的特异性识别能力和细胞毒素的强大杀伤活性, 使其与传统化疗药物相比, 系统性毒性更低, 较常规抗体类药物具有更好的疗效^{[9, 10]}。

人滋养层细胞表面抗原2 (trophoblast cell surface antigen 2, TROP2) 是一种由细胞外结构域、跨膜结构域和胞质尾部组成的单次跨膜糖蛋。在健康组织中, TROP2呈低水平表达, 并在生理状态下参与调控细胞增殖与分化、胚胎发育以及组织稳态与屏障功能的维持^[11]。然而, TROP2在乳腺癌、胰腺癌、卵巢癌、前列腺癌、胃癌、结直肠癌、皮肤癌等多种实体瘤中异常高表达^[12-18], 这种高表达与肿瘤的侵袭、转移和不良预后密切相关^{[17, 19]}。基于其表达的特异性和在肿瘤发生发展中的关键作用, TROP2已成为癌症诊断与治疗领域的重要靶点。尽管目前已有部分研究探索了抗体干预在皮肤癌治疗中的应用, 但针对TROP2的靶向治疗在皮肤癌中的研究仍相对有限。

hIMB1636-MMAE是课题组与本所化学室李卓荣教授合作研发的一种新型ADC^[20], 由抗TROP2单克隆抗体hIMB1636与微管蛋白抑制剂单甲基澳瑞他汀E (monomethyl auristatin E, MMAE) 通过valine-citrulline可裂解连接子(VC连接子) 组合而成。前期研究表明, hIMB1636-MMAE在胰腺癌肿瘤模型中显示出显著的抗肿瘤活性。本研究通过系统评估其与人表皮癌细胞A431的结合能力、内吞效应、体外细胞毒性及体内药效, 并初步探索其作用机制, 以揭示hIMB1636-MMAE在皮肤癌中的抗肿瘤潜力, 为皮肤癌的药物治疗提供新的候选策略与实验证据。

材料与方法

收起

细胞系 人表皮癌细胞A431由本实验室保存, 人皮肤成纤维细胞NHDF由本所王璐璐教授惠赠。

实验动物与试剂 DMEM高糖培养基(1002C-500 mL) 与胎牛血清(U16001DC) 购自北京中生奥邦生物科技有限公司; 胰酶(BL512A)、4%多聚甲醛通用型组织固定液(BL539A) 和Cell Counting Kit-8 (CCK-8) (BS350B) 购自白鲨生物; Annexin V-FITC/PI细胞凋亡检测试剂盒(AP101) 和PI细胞周期检测试剂盒(CCS012) 购自联科生物; LAMP-1抗体(9091S) 购自Cell Signaling Technology; Alexa Fluor® 647标记山羊抗人IgG (H+L) (CSA3802) 购自佰奥瑞科技有限公司; FITC标记羊抗人IgG (A0556) 和Alexa Fluor® 555标记驴抗兔IgG (H+L) (A0453) 均购自碧云天生物技术有限公司; PBS缓冲液(G4202) 购自武汉塞维尔科技有限公司; Triton X-100 (T8200) 购自北京索莱宝科技有限公司; Sacituzumab Govitecan (IMMU-132) 购自北京圆心新特大药房。BALB/c裸鼠(18~20 g) 由北京华阜康公司提供, 实验动物生产许可证号为SCXK (京) 2024-0003, 动物实验批准编号: IMB-20220210D₂03。hIMB1636-MMAE由本所李卓荣教授课题组合成。

仪器流式细胞仪(CSIM 110, 安捷伦科技公司); 激光共聚焦扫描显微镜(Sunny CSIM 110, 普迈SUNNY公司); CO₂细胞培养箱(HERAce11150i, Thermo公司); 酶标仪[Spectramax i3x, 美谷分子仪器(上海) 公司]; 化学发光成像仪(ChemiDoc, Bio-Rad公司)。

细胞复苏和培养 将冻存的A431细胞和NHDF细胞从液氮中取出后快速置于37 ℃恒温水浴锅中解冻, 随后转移至含2 mL DMEM培养基的离心管中, 1 000 r·min^-1离心3 min。弃去上清液, 将细胞沉淀重悬于含10%胎牛血清的DMEM培养基中, 置于5% CO₂恒温细胞培养箱中培养, 每2~3天传代一次。

Western blot检测TROP2表达情况 A431细胞与NHDF细胞胰酶消化并收集至1.5 mL离心管, 加入含PMSF的裂解液, 冰上裂解20 min后, 在12 000 r·min^-1、4 ℃条件下离心20 min。吸取含蛋白的上清液至新的离心管中, BCA法检测蛋白浓度后, 每管样品加入5×loading buffer煮沸10 min。通过SDS-PAGE对蛋白进行电泳分离并采用“湿转法”将蛋白转移至PVDF膜上。将膜用5%脱脂牛奶室温封闭2 h后, 用靶向TROP2的兔抗在4 ℃孵育过夜。次日PBST洗膜3次, 每次10 min, 用HRP标记的抗兔IgG二抗稀释液室温孵育2 h。PBST洗涤3次后, 用ECL发光液在化学发光成像仪中采集图像。

流式细胞术检测亲和活性 A431细胞和NHDF细胞经胰酶消化后收集于1.5 mL离心管中, 1 000 r·min^-1离心3 min, 弃去上清液。细胞用PBS重悬后3 000 r·min^-1离心3 min进行洗涤, 重复3次。将细胞分别重悬于稀释至0.01、0.1、1 μg·mL^-1 hIMB1636-MMAE溶液中(对照组细胞不作处理), 室温条件下孵育2 h。随后采用相同的操作流程, 用PBS洗涤细胞3次。将细胞重悬于1∶200稀释的Alexa Fluor 647标记的山羊抗人IgG (H+L) 二抗溶液中, 室温避光孵育1 h。PBS洗涤3次后将细胞重悬, 并过300目筛网以得到单细胞悬液, 最后使用流式细胞仪检测细胞表面荧光强度。

共聚焦显微镜检测内吞活性 将圆形玻片用75%乙醇浸泡10 min灭菌, 晾干后放置于六孔板中。收集对数生长期的A431细胞, 按4×10⁵个/孔的密度接种至含爬片的六孔板内, 在37 ℃、5% CO₂条件下过夜培养。次日, 细胞用浓度为10 μg·mL^-1 hIMB1636-MMAE分别于37和4 ℃条件下孵育0和4 h。孵育结束后, 弃去培养基, 用PBS洗涤3次, 随后加入4%多聚甲醛室温固定10 min。弃去固定液, PBS洗涤3次, 每孔加入500 μL 0.5% Triton X-100溶液透化10 min。PBS洗涤3次, 接着用2% BSA室温封闭2 h, 之后将1∶200稀释的兔抗溶酶体相关膜蛋白1 (LAMP1) 抗体滴加在细胞表面, 4 ℃孵育过夜。次日用PBS洗涤3次后, 加入1∶200稀释的Alexa Fluor 555标记的驴抗兔IgG (H+L) 抗体和Alexa Fluor 488标记的羊抗人IgG (H+L) 抗体的混合液, 室温避光孵育1 h。PBS洗去多余二抗后, 用含DAPI的封片剂对细胞核进行染色, 最后通过激光共聚焦显微镜观察捕获荧光图像。

CCK-8检测ADC的杀伤活性 取对数生长期的A431和NHDF细胞以3 000个/孔的密度接种至96孔板, 放于37 ℃、5% CO₂孵箱培养24 h。待细胞完全贴壁后, 弃去原培养液, 替换为含系列浓度hIMB1636-MMAE、MMAE、hIMB1636和IMMU-132 (浓度梯度设置为300、100、30、10、3、1、0.3、0.1、0.03 nmol·L^-1) 的DMEM完全培养基。继续培养48 h后, 96孔板每孔加入10 μL CCK-8检测试剂, 于37 ℃避光孵育。每隔30 min将板子放于酶标仪中, 在450 nm波长处检测吸光度并绘制细胞增殖抑制曲线。

流式细胞术测定细胞周期和细胞凋亡 在细胞周期实验中, 将A431细胞以3×10⁵个/孔的密度接种至六孔板中, 培养过夜。细胞贴壁后, 分别用0、5、10、20 nmol·L^-1 hIMB1636-MMAE处理24 h, 之后收集细胞于1.5 mL离心管中。细胞用PBS洗涤3次(3 000 r·min^-1, 3 min), 每管加入500 μL含破膜剂的碘化丙啶(PI) 染色液, 室温避光染色30 min。将细胞重悬并过300目筛网后, 用流式细胞仪检测并分析细胞周期分布。在细胞凋亡实验中, 将每毫升细胞数为2×10⁵个的A431细胞接种至六孔板中, 培养过夜。用浓度为0、5、10、30 nmol·L^-1 hIMB1636-MMAE处理48 h后, 收集细胞至1.5 mL离心管, PBS洗涤3次(3 000 r·min^-1 3 min)。随后用1×binding buffer重悬细胞, 每管依次加入5 μL Annexin V-FITC和10 μL的PI染色液, 混匀后室温避光孵育10 min。反应结束后将细胞重悬并过300目筛网, 立即通过流式细胞仪检测凋亡细胞百分比。

体内抗肿瘤药效评价 收集生长状态良好的A431细胞, 经PBS洗涤2次后重悬, 调整每毫升细胞数至5×10⁷个。取100 μL细胞悬液(含5×10⁶个细胞) 接种于6~8周龄雌性BALB/c裸鼠右侧腋下。待肿瘤体积生长至100~200 mm³时, 将荷瘤小鼠随机分为对照组和实验组(每组6只)。实验组小鼠通过尾静脉给予10 mg·kg^-1 hIMB1636-MMAE, 对照组尾静脉注射等体积的PBS。给药频率为每4天一次, 共给药5次。期间每4天测量并记录一次小鼠体重和肿瘤体积, 肿瘤体积按公式V = 0.5×长×宽²计算。当小鼠肿瘤体积达到2 000 mm³时, 采用CO₂吸入法对小鼠实施安乐死。

统计学方法 实验数据采用GraphPad Prism 10和Adobe Illustrator分析并作图, 实验数据以平均数±标准差(x ± s) 表示。组间比较采用t检验, P < 0.05具有统计学意义。

结果

收起

1　TROP2在A431细胞中高表达

Western blot的分析结果显示, 在人表皮癌A431细胞中可明确检测到TROP2蛋白的表达, 在约36 kDa处有清晰的免疫反应条带。而作为阴性对照的正常人皮肤成纤维细胞NHDF则未观察到相应条带(图1)。该结果证明TROP2在A431细胞中呈高表达状态。

2　hIMB1636-MMAE与A431细胞表面的TROP2抗原特异性结合

ADC与靶点阳性肿瘤细胞的特异性结合是其发挥药效的基础, 因此, 本研究首先通过流式细胞术评估了hIMB1636-MMAE与高表达TROP2的人表皮癌细胞A431的亲和活性。结果显示使用浓度为0、0.01、0.1、1 μg·mL^-1 hMB1636-MMAE对A431细胞进行孵育, 细胞群的荧光强度呈现明显的浓度依赖性右移, 表明该ADC以浓度依赖性的方式与A431细胞结合(图2)。作为对照, 使用不同浓度hMB1636-MMAE孵育并未引起TROP2阴性细胞NHDF的荧光信号偏移, 进一步证明了hIMB1636-MMAE能够与细胞表面TROP2抗原特异性结合。

3　hIMB1636-MMAE在A431细胞中的内吞活性

ADC被肿瘤细胞内化并转运至溶酶体是有效载荷释放的前提, 通过共聚焦显微镜可以直接观察抗体偶联物被细胞内化的过程。如图3A所示, 在4 ℃条件下(膜转运被抑制), 绿色荧光标记的hMB1636-MMAE初加入时(即第0 h), 视野中只观察到细胞核与溶酶体染色; 孵育4 h后, 绿色荧光聚集在A431细胞表面, 证明ADC能与膜上的TROP2抗原结合。在37 ℃条件下(图3B), 第0 h仅有溶酶体与细胞核染色, 孵育4 h后, 绿色荧光信号进入细胞内, 并且与红色荧光标记的溶酶体存在共定位(黄色荧光), 说明在生理条件下ADC能被TROP2阳性的A431细胞内吞并运输至溶酶体。

4　hIMB1636-MMAE对A431细胞的杀伤作用

为评估hIMB1636-MMAE的抗肿瘤效果和靶向能力, 本研究采用CCK-8法比较了不同浓度hIMB1636-MMAE、裸抗体hIMB1636和游离毒素MMAE在TROP2高表达细胞系A431和低表达细胞系NHDF中的体外杀伤活性。结果如图4所示, 在阳性细胞A431中, hIMB1636-MMAE表现出浓度依赖性的杀伤作用, 基于3次独立重复实验数据拟合的增殖抑制曲线, 计算得到该ADC对A431细胞的半数抑制浓度(IC₅₀) 为1.49 ± 0.22 nmol·L^-1, 说明hIMB1636-MMAE对A431细胞保留了MMAE的强效细胞毒性(IC₅₀ = 0.26 ± 0.09 nmol·L^-1)。而在阴性细胞NHDF中, hIMB1636-MMAE未引起明显的细胞活性下降, 相比之下, 游离MMAE的IC₅₀值为0.77 ± 0.15 nmol·L^-1, 这是由于其可通过扩散作用直接穿透细胞膜进入肿瘤细胞所致。以上结果说明, hIMB1636-MMAE可通过靶抗原介导的内吞作用进入A431细胞, 然后释放游离MMAE, 从而发挥高特异性的杀伤作用。裸抗体hIMB1636对A431和NHDF细胞的IC₅₀均大于100 nmol·L^-1, 说明在该浓度范围内其对肿瘤细胞活性的影响不明显。同时, 本研究还比较了hIMB1636-MMAE与已上市靶向TROP2的ADC IMMU-132在A431细胞中的体外抗肿瘤作用。结果显示, hIMB1636-MMAE的拟合曲线与IMMU-132 (IC₅₀ = 5.45 ± 1.10 nmol·L^-1) 相近, 但IC₅₀更低, 表明hIMB1636-MMAE对A431细胞可能具有更好的体外抗增殖活性。

5　hIMB1636-MMAE诱导A431细胞周期阻滞并促进细胞凋亡

ADC的药效主要源于其携带的有效载荷。鉴于MMAE主要通过阻断微管蛋白聚合从而抑制有丝分裂发挥细胞毒作用, 本研究通过流式细胞术分析了hIMB1636-MMAE对A431细胞周期的影响。结果表明, hIMB1636-MMAE能浓度依赖性地将细胞周期阻滞于G2/M期(图5A)。与对照组相比, 用10 nmol·L^-1 hIMB1636-MMAE处理24 h后, G2期细胞比例显著增加, G1期细胞比例相应减少(图5C)。此外, Annexin V-FITC/PI双染实验表明, 经5、10和30 nmol·L^-1 hIMB1636-MMAE处理48 h后, A431细胞出现明显的凋亡(图5B), 凋亡率分别为38.51% ± 2.24%、47.96% ± 1.19%和54.23% ± 1.56%, 均显著高于对照组, 且呈现明显的剂量效应关系(图5D)。以上结果表明, hIMB1636-MMAE可通过引起G2/M期阻滞进而诱导A431细胞凋亡。

6　hIMB1636-MMAE在A431异种移植瘤模型中的抗肿瘤活性

为了评估hIMB1636-MMAE的体内抗肿瘤作用, 本研究构建了A431细胞的裸鼠异种移植瘤模型。经尾静脉注射10 mg·kg^-1 hIMB1636-MMAE (每4天一次, 共5次) 治疗后, 实验组小鼠的肿瘤体积较PBS对照组明显缩小(图6)。截至实验第30天, hIMB1636-MMAE对肿瘤生长抑制率达到了93.89%, 证明该ADC能有效抑制TROP2阳性皮肤癌移植瘤的生长。同时在整个治疗期间, 小鼠体重较对照组没有明显差别, 且未观察到其他明显不良反应, 说明hIMB1636-MMAE在荷瘤小鼠体内具有强烈的抗肿瘤活性。

讨论

收起

TROP2作为重要的肿瘤治疗靶点, 自2020年首个靶向TROP2的ADC药物sacituzumab govitecan (IMMU-132) 被FDA批准以来, 又相继出现德达博妥单抗(Dato-DXd)、sacituzumab tirumotecan (SKB264), 分别获得FDA和NMPA批准^{[21, 22]}, 主要用于三阴性乳腺癌和非小细胞肺癌的治疗。值得注意的是, 这些ADC均采用拓扑异构酶抑制剂作为有效载荷, 但随着拓扑异构酶抑制剂类药物在临床上的广泛应用, 肿瘤细胞通过过表达外排蛋白、增强药物代谢酶和DNA损伤修复能力等方式进化出多种复杂的耐药机制^[23], 可能会导致对该类ADC药物耐药。因此, 有必要研发具有新型载荷的抗TROP2 ADC药物, 其作用机制应不同于现有的拓扑异构酶抑制剂。MMAE为微管蛋白抑制剂类载荷, 其不易被转运蛋白泵出, 有助于维持细胞内药物浓度, 提高治疗指数^[24]。此外, 本实验室前期的研究结果显示, hIMB1636 (K_D = 0.295 nmol·L^-1) 与sacituzumab (K_D = 0.398 nmol·L^-1, IMMU-132和SKB264采用的抗体) 的亲和活性相近, 但hIMB1636在诱导抗体依赖性细胞毒性效应和直接抗肿瘤活性方面具有更显著的优势。同时, hIMB1636与sacituzumab有着不同的结合表位, 将其与MMAE偶联得到的ADC可能为克服现有治疗策略的耐药问题提供新思路^[25]。基于以上背景, 课题组在前期工作中制备了hIMB1636与MMAE的ADC, 本研究系统评估了hIMB1636-MMAE在皮肤癌A431细胞模型中的体外与体内抗肿瘤活性, 以验证其作为新一代TROP2靶向治疗药物的潜力。

通过Western blot检测, 本研究首先验证了TROP2在A431细胞中呈显著高表达, 而在正常人皮肤成纤维细胞NHDF中几乎不表达。抗体部分赋予ADC药物肿瘤靶向性, 因此通过流式细胞术检测了hIMB1636-MMAE对TROP2阳性细胞的特异性结合能力。结果显示, hIMB1636-MMAE能剂量依赖性地与A431细胞结合, 但不结合阴性细胞NHDF, 证明该ADC能选择性地结合TROP2阳性细胞, 为精准杀伤肿瘤细胞奠定基础。

抗体的内吞活性对ADC作用的发挥也至关重要。在这个过程中, ADC首先与靶抗原结合并被内吞运送到溶酶体。在溶酶体内的酸性环境中, ADC中的VC连接子被组织蛋白酶B识别并切割, 进而释放出毒性载荷, 引发细胞毒性反应。激光共聚焦实验证明了hIMB1636-MMAE不仅能与A431细胞膜上的TROP2抗原结合, 还能被细胞内吞并转运至溶酶体, 从而发挥杀伤作用。

随后, 在CCK-8实验中观察到经hIMB1636-MMAE处理48 h后, A431细胞的存活率呈浓度依赖性下降, 其IC₅₀为1.49 ± 0.22 nmol·L^-1, 优于同类已上市药物IMMU-132 (IC₅₀=5.45 ± 1.10 nmol·L^-1)。同时, 该ADC对阴性细胞NHDF未表现出明显的杀伤作用, 进一步证明其对TROP2阳性肿瘤细胞的选择性杀伤活性。此外, 本研究还通过流式细胞术对hIMB1636-MMAE的作用机制进行了初步探索, 发现其可将细胞周期阻滞于G2/M期, 并诱导肿瘤细胞凋亡。最后, 体内实验中hIMB1636-MMAE展现出优秀的抗肿瘤疗效, 给药组小鼠的瘤体积较对照组明显缩小, 且体重较对照组没有明显变化, 亦未发现其他不良反应。以上结果说明, hIMB1636-MMAE具有治疗TROP2阳性皮肤癌的潜能, 可作为该肿瘤治疗的潜在候选药物。

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

Gordon R. Skin cancer: An overview of epidemiology and risk factors [J]. Semin Oncol Nurs, 2013, 29: 160-169.

Linares MA, Zakaria A, Nizran P. Skin cancer [J]. Prim Care, 2015, 42: 645-659.

Wang M, Gao X, Zhang L. Recent global patterns in skin cancer incidence, mortality, and prevalence [J]. Chin Med J, 2025, 138: 185-192.

Corte-Real M, Veiga F, Paiva-Santos AC, et al. Improving skin cancer treatment by dual drug co-encapsulation into liposomal systems-an integrated approach towards anticancer synergism and targeted delivery [J]. Pharmaceutics, 2024, 16: 1200-1212.

Burns C, Kubicki S, Nguyen QB, et al. Advances in cutaneous squamous cell carcinoma management [J]. Cancers, 2022, 14: 3653-3666.

Chames P, Van Regenmortel M, Weiss E, et al. Therapeutic antibodies: Successes, limitations and hopes for the future [J]. Br J Pharmacol, 2009, 157: 220-233.

Sharma P, Joshi RV, Pritchard R, et al. Therapeutic antibodies in medicine [J]. Molecules, 2023, 28: 6438-6455.

Lou H, Cao X. Antibody variable region engineering for improving cancer immunotherapy [J]. Cancer Commun, 2022, 42: 804-827.

Shefet-Carasso L, Benhar I. Antibody-targeted drugs and drug resistance--challenges and solutions [J]. Drug Resist Updat, 2015, 18: 36-46.

Mckertish CM, Kayser V. Advances and limitations of antibody drug conjugates for cancer [J]. Biomedicines, 2021, 9: 872-884.

Lenárt S, Lenárt P, Šmarda J, et al. TROP2: Jack of all trades, master of none [J]. Cancers, 2020, 12: 3328-3342.

Hu Y, Zhu Y, Qi D, et al. TROP2-targeted therapy in breast cancer [J]. Biomark Res, 2024, 12: 82-94.

Xu C, Zhu M, Wang Q, et al. TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer [J]. J Nanobiotechnology, 2023, 21: 410-424.

Wu B, Yu C, Zhou B, et al. Overexpression of TROP2 promotes proliferation and invasion of ovarian cancer cells [J]. Exp Ther Med, 2017, 14: 1947-1952.

Shen M, Liu S, Stoyanova T. The role of TROP2 in prostate cancer: An oncogene, biomarker, and therapeutic target [J]. Am J Clin Exp Urol, 2021, 9: 73-87.

Kushiyama S, Yashiro M, Yamamoto Y, et al. Clinicopathologic significance of TROP2 and phospho-TROP2 in gastric cancer [J]. Mol Clin Oncol, 2021, 14: 105-112.

Foersch S, Schmitt M, Litmeyer AS, et al. TROP2 in colorectal carcinoma: Associations with histopathology, molecular phenotype, and patient prognosis [J]. J Pathol Clin Res, 2024, 10: 101-110.

Farag AGA, El-Rebey HS, El-Moneim Shoeib MA, et al. The role of TROP2 in BCC and cutaneous SCC: A clinical and immunohistochemical study [J]. Clin Cosmet Investig Dermatol, 2021, 14: 591-600.

Zhang B, Gao S, Li R, et al. Tissue mechanics and expression of TROP2 in oral squamous cell carcinoma with varying differentiation [J]. BMC Cancer, 2020, 20: 815-827.

Sun LP, Bai WQ, Zhou DD, et al. hIMB1636-MMAE, a novel TROP2-targeting antibody-drug conjugate exerting potent antitumor efficacy in pancreatic cancer [J]. J Med Chem, 2023, 66: 14700-14715.

Royce M, Shah M, Zhang L, et al. FDA approval summary: Datopotamab deruxtecan-dlnk for treatment of patients with unresectable or metastatic, HR-positive, HER2-negative breast cancer [J]. Clin Cancer Res, 2025, 31: 4405-4411.

Li N, Yang L, Zhao Z, et al. Antibody-drug conjugates in breast cancer: Current evidence and future directions [J]. Exp Hematol Oncol, 2025, 14: 41-53.

Sharma NK, Bahot A, Sekar G, et al. Understanding cancer's defense against topoisomerase-active drugs: A comprehensive review [J]. Cancers, 2024, 16: 680-695.

Bordeau BM, Nguyen TD, Polli JR, et al. Payload-binding Fab fragments increase the therapeutic index of MMAE antibody-drug conjugates [J]. Mol Cancer Ther, 2023, 22: 459-470.

Zhou DD, Sun LP, Yu Q, et al. Elucidating the development, characterization, and antitumor potential of a novel humanized antibody against TROP2 [J]. Int J Biol Macromol, 2023, 253: 127105-127116.

2026年第61卷第7期

PDF下载

237

103

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2025-1315

接收时间：2025-11-07
首发时间：2026-09-21
出版时间：2026-07-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2025-11-07
修回日期：2026-03-09

基金

作者信息

中国医学科学院北京协和医学院, 医药生物技术研究所, 北京 100050

通讯作者:

苗庆芳, Tel: 13691504102, E-mail: miaoqf@imb.pumc.edu.cn

周丹丹, Tel: 17810259269, E-mail: zhdd0080@163.com

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2025-1315

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT