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Article(id=1220655538594038754, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1220655523473571972, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2020-0325, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1584115200000, receivedDateStr=2020-03-14, revisedDate=1587657600000, revisedDateStr=2020-04-24, acceptedDate=null, acceptedDateStr=null, onlineDate=1768956559083, onlineDateStr=2026-01-21, pubDate=1597161600000, pubDateStr=2020-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768956559083, onlineIssueDateStr=2026-01-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768956559083, creator=13701087609, updateTime=1768956559083, updator=13701087609, issue=Issue{id=1220655523473571972, tenantId=1146029695717560320, journalId=1189982191388893191, year='2020', volume='55', issue='8', pageStart='1707', pageEnd='1982', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768956555479, creator=13701087609, updateTime=1768986579152, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1220781451944051235, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1220655523473571972, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1220781451944051236, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1220655523473571972, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1971, endPage=1977, ext={EN=ArticleExt(id=1220655539164463119, articleId=1220655538594038754, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Consideration of antibody drug conjugates development and regulation, columnId=1208489276405297283, journalTitle=Acta Pharmaceutica Sinica, columnName=New Drug Forum, runingTitle=null, highlight=null, articleAbstract=

Antibody drug conjugates (ADCs), as they combine the targetability of monoclonal antibody and cytotoxicity of small molecules, are a growing class of therapeutics for cancer. The key factor of ADCs development is the accurate selection of parameters including tumor target, monoclonal antibody, cytotoxic payload, and linkage strategy of antibody to payload. Here, we summarize the main elements in the structural design and the development of ADCs, as well as the regulatory consideration of product manufacturing and control, which would be helpful for the research and development of ADCs.

, correspAuthors=Yu BAI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2020 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=Zhong-bing ZHANG, Yang WANG, Yu BAI), CN=ArticleExt(id=1220655539592282176, articleId=1220655538594038754, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=抗体偶联药物研发及药学审评要点, columnId=1208489277814583462, journalTitle=药学学报, columnName=新药论坛, runingTitle=null, highlight=null, articleAbstract=

抗体偶联物（antibody drug conjugates，ADCs）兼具抗体的靶向性和小分子化合物的细胞毒性，目前已经成为抗肿瘤药物研发的热点之一。靶抗原、抗体、毒素、连接子或偶联方式的选择是影响ADCs药物开发成功的要素。本文介绍了ADCs药物在开发和结构设计方面需考虑的主要因素，以及在此类产品申报时药学技术审评的要点，希望能为研发单位开发ADCs药物提供参考。

, correspAuthors=白玉, authorNote=null, correspAuthorsNote=
*白玉, Tel:86-10-85243041, E-mail:
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Nat Rev Drug Discov, 2017, 16: 315-337., articleTitle=Strategies and challenges for the next generation of antibody-drug conjugates, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1220655539881689179, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, xref=null, ext=[AuthorCompanyExt(id=1220655539890077789, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, companyId=1220655539881689179, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China), AuthorCompanyExt(id=1220655539902660702, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, companyId=1220655539881689179, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=国家药品监督管理局药品审评中心, 北京 100022)])], figs=[ArticleFig(id=1220655542360523046, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
ADCs product Indication Approval date Target
antigen		 Antibody
conjugation		 Linker Payload
Mylotarg® (gemtuzumab ozogamicin) Relapsed AML 2001 (withdrawn in 2010 and reapproved in 2017) CD33 Human IgG4-
Lys		 Hydrazone Calicheamicin
Adcetris® (brentuximab
vedotin)		 Relapsed HL and
sALCL		 2011 CD30 Chimeric IgG1-Cys Dipeptide cleavable
(Val-Cit)		 MMAE
Kadcyla® (trastuzumab emtansine) HER2+ metastatic
breast cancer		 2013 HER2 Human IgG1-
Lys		 Thioether non-
cleavable		 Emtansine (DM1)
Besponsa® (inotuzumab ozogamicin) Relapsed or refractory CD22+B-ALL 2017 CD22 Human IgG4-
Lys		 Hydrazone Calicheamicin
Lumoxiti® (moxetumomab pasudotox) Relapsed or refractory HCL 2018 CD22 (VL+VH)-
disulfide bond		 Disulfide bond Immunotoxin (PE38)
Polivy® (polatuzumab
vedotin)		 Relapsed or refractory
DLBCL		 2019 CD79b Human IgG1-
Cys		 Dipeptide cleavable
(Val-Cit)		 MMAE
Enhertu® (fam-trastuzumab deruxtecan-nxki) HER2+ unresectable metastic breast cancer 2019 HER2 Human IgG1-
Cys		 Tetrapeptide cleavable (Gly-Gly-Phe-Gly) Exatecan
derivative
(Dxd)
Padcev® (enfortumab
vedotin)		 Locally advanced or
metastatic urothelial
cancer		 2019 Nectin-4 Human IgG1-
Cys		 Dipeptide cleavable
(Val-Cit)		 MMAE
), ArticleFig(id=1220655542448603441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, language=CN, label=Table 1, caption=

Approved antibody drug conjugates (ADCs) products by the Food and Drug Administration (FDA). AML: Acute myeloid leukemia; CD: Cluster of differentiation; IgG: Immunoglobin G; Lys: Lysine; HL: Hodgkin lymphoma; sALCL: Systemic anaplastic large cell lymphoma; Cys: Cysteine; Val-Cit: Valine-Citrulline; MMAE: Monomethyl auristatin E; HER2: Human epidermal growth factor receptor 2; DM1: N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)maytansine; B-ALL: B-cell precursor acute lymphoblastic leukemia; HCL: Hairy cell leukemia; VL + VH: Variable region of light chain + high chain; DLBCL: Diffuse large B-cell lymphoma; Gly: Glycine; Phe: Phenylalanine

, figureFileSmall=null, figureFileBig=null, tableContent=
ADCs product Indication Approval date Target
antigen		 Antibody
conjugation		 Linker Payload
Mylotarg® (gemtuzumab ozogamicin) Relapsed AML 2001 (withdrawn in 2010 and reapproved in 2017) CD33 Human IgG4-
Lys		 Hydrazone Calicheamicin
Adcetris® (brentuximab
vedotin)		 Relapsed HL and
sALCL		 2011 CD30 Chimeric IgG1-Cys Dipeptide cleavable
(Val-Cit)		 MMAE
Kadcyla® (trastuzumab emtansine) HER2+ metastatic
breast cancer		 2013 HER2 Human IgG1-
Lys		 Thioether non-
cleavable		 Emtansine (DM1)
Besponsa® (inotuzumab ozogamicin) Relapsed or refractory CD22+B-ALL 2017 CD22 Human IgG4-
Lys		 Hydrazone Calicheamicin
Lumoxiti® (moxetumomab pasudotox) Relapsed or refractory HCL 2018 CD22 (VL+VH)-
disulfide bond		 Disulfide bond Immunotoxin (PE38)
Polivy® (polatuzumab
vedotin)		 Relapsed or refractory
DLBCL		 2019 CD79b Human IgG1-
Cys		 Dipeptide cleavable
(Val-Cit)		 MMAE
Enhertu® (fam-trastuzumab deruxtecan-nxki) HER2+ unresectable metastic breast cancer 2019 HER2 Human IgG1-
Cys		 Tetrapeptide cleavable (Gly-Gly-Phe-Gly) Exatecan
derivative
(Dxd)
Padcev® (enfortumab
vedotin)		 Locally advanced or
metastatic urothelial
cancer		 2019 Nectin-4 Human IgG1-
Cys		 Dipeptide cleavable
(Val-Cit)		 MMAE
), ArticleFig(id=1220655542620569916, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Drug name Sponsor Indication Target
antigen		 Antibody
conjugation		 Linker Payload
Recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugates injection Shijiazhuang Pharmaceutical Group HER2+ advanced metastatic breast cancer HER2 Human IgG1-Gln Dipeptide cleavable (Val-Cit) MMAE
Recombinant humanized anti-HER2 monoclonal antibody maytansine conjugates for injection Bio-Thera Advanced solid tumors HER2 Human IgG1-Cys Thioether non-cleavable Batansine
Recombinant humanized anti-Trop2 monoclonal antibody maytansine conjugates for injection Bio-Thera Trop2+ advanced epithelial cancer Trop2 Human IgG1-Cys Thioether non-cleavable Batansine
Recombinant humanized anti-HER2 monoclonal antibody Tub114 conjugates for injection Hangzhou DAC Biotech HER2 overexpressed solid tumors HER2 Human IgG1-Cys Thioether non-cleavable Tub114
Recombinant humanized anti-HER2 monoclonal antibody-MMAF conjugates injection Shanghai Fosun Pharmaceutical HER2+ advanced solid tumors HER2 Human IgG1-Cys Isoprenoid MMAF
Recombinant humanized anti-HER2 monoclonal
antibody dolastatins DUO5 conjugates for injection		 Zova Biotherapeutics HER2+ advanced solid tumors HER2 Human IgG1-Lys Dipeptide cleavable (Val-Cit) Dolastatins (DUO5)
Recombinant chimeric anti-CD30 monoclonal antibody-MCC-DM1 conjugates for injection Shanghai Fudan-Zhangjiang Bio-Pharmaceutical CD30+ALCL, HL, and CTCL CD30 Chimeric IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-DM1 conjugates for injection Qilu Pharma HER2+solid tumors HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-MCC-DM1 conjugates for injection Shanghai Jiaolian Pharma HER2+locally advanced or metastatic breast cancer HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-DM1 conjugates for injection Hisun Pharma HER2 overexpressed metastatic breast
cancer		 HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-AS269 conjugates injection Zhejiang Medicine HER2+ malignant solid tumors HER2 Human IgG1-PAF p-Acetylphenylalanine MMAF
Recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugates for injection RemeGen HER2+breast cancer, gastric cancer,
ovarian cancer, and pulmonary cancer		 HER2 Human IgG1-Cys Dipeptide cleavable (Val-Cit) MMAE
RC88 for injection RemeGen MSLN+ malignant tumor MSLN Human IgG1-Cys Dipeptide cleavable (Val-Cit) MMAE
SHR-A1201 for injection Hengrui Medicine HER2+ metastatic breast cancer HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
SHR-A1403 for injection Hengrui Medicine Malignant tumor c-Met Human IgG2-Lys ATPPA MMAE
TRS005 for injection Teruisi Pharma Relapsed or refractory follicular lymphoma CD20 Chimeric IgG1-Lys Dipeptide cleavable (Val-Cit) MMAE
A166 for injection Kelun Pharma HER2+ advanced malignant solid tumor HER2 Human IgG1-Lys (Lys188) Dipeptide cleavable (Val-Cit) Dolastatins (DUO5)
MRG003 for injection Meiyake Biotech EGFR+ malignant solid tumor EGFR Human IgG1-Lys Dipeptide cleavable (Val-Cit) MMAE
GB251 for injection Genor Biopharma HER2+ metastatic breast cancer HER2 Human IgG1-Lys Dipeptide cleavable (Val-Cit) MMAE
), ArticleFig(id=1220655542742204748, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655538594038754, language=CN, label=Table 2, caption=

Approved investigational new drug application of ADCs products by National Medical Products Administration (NMPA)(https://db.yaozh.com/).Gln:Glutamine; Trop2:Trophoblast cell-surface antigen 2;MMAF:Monomethylauristatin F; MCC:4-(Nmaleimidomethyl)-cyclohexane-1-carboxylate; ALCL:Anaplastic large cell lymphoma; CTCL:Cutaneous T cell lymphoma; PAF:Platelet activating factor; MSLN:Magnetic solid lipid nanoparticles; c-Met:Tyrosine-protein kinase Met; EGFR:Epidermal growth factor receptor

, figureFileSmall=null, figureFileBig=null, tableContent=
Drug name Sponsor Indication Target
antigen		 Antibody
conjugation		 Linker Payload
Recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugates injection Shijiazhuang Pharmaceutical Group HER2+ advanced metastatic breast cancer HER2 Human IgG1-Gln Dipeptide cleavable (Val-Cit) MMAE
Recombinant humanized anti-HER2 monoclonal antibody maytansine conjugates for injection Bio-Thera Advanced solid tumors HER2 Human IgG1-Cys Thioether non-cleavable Batansine
Recombinant humanized anti-Trop2 monoclonal antibody maytansine conjugates for injection Bio-Thera Trop2+ advanced epithelial cancer Trop2 Human IgG1-Cys Thioether non-cleavable Batansine
Recombinant humanized anti-HER2 monoclonal antibody Tub114 conjugates for injection Hangzhou DAC Biotech HER2 overexpressed solid tumors HER2 Human IgG1-Cys Thioether non-cleavable Tub114
Recombinant humanized anti-HER2 monoclonal antibody-MMAF conjugates injection Shanghai Fosun Pharmaceutical HER2+ advanced solid tumors HER2 Human IgG1-Cys Isoprenoid MMAF
Recombinant humanized anti-HER2 monoclonal
antibody dolastatins DUO5 conjugates for injection		 Zova Biotherapeutics HER2+ advanced solid tumors HER2 Human IgG1-Lys Dipeptide cleavable (Val-Cit) Dolastatins (DUO5)
Recombinant chimeric anti-CD30 monoclonal antibody-MCC-DM1 conjugates for injection Shanghai Fudan-Zhangjiang Bio-Pharmaceutical CD30+ALCL, HL, and CTCL CD30 Chimeric IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-DM1 conjugates for injection Qilu Pharma HER2+solid tumors HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-MCC-DM1 conjugates for injection Shanghai Jiaolian Pharma HER2+locally advanced or metastatic breast cancer HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-DM1 conjugates for injection Hisun Pharma HER2 overexpressed metastatic breast
cancer		 HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
Recombinant humanized anti-HER2 monoclonal antibody-AS269 conjugates injection Zhejiang Medicine HER2+ malignant solid tumors HER2 Human IgG1-PAF p-Acetylphenylalanine MMAF
Recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugates for injection RemeGen HER2+breast cancer, gastric cancer,
ovarian cancer, and pulmonary cancer		 HER2 Human IgG1-Cys Dipeptide cleavable (Val-Cit) MMAE
RC88 for injection RemeGen MSLN+ malignant tumor MSLN Human IgG1-Cys Dipeptide cleavable (Val-Cit) MMAE
SHR-A1201 for injection Hengrui Medicine HER2+ metastatic breast cancer HER2 Human IgG1-Lys Thioether non-cleavable Emtansine (DM1)
SHR-A1403 for injection Hengrui Medicine Malignant tumor c-Met Human IgG2-Lys ATPPA MMAE
TRS005 for injection Teruisi Pharma Relapsed or refractory follicular lymphoma CD20 Chimeric IgG1-Lys Dipeptide cleavable (Val-Cit) MMAE
A166 for injection Kelun Pharma HER2+ advanced malignant solid tumor HER2 Human IgG1-Lys (Lys188) Dipeptide cleavable (Val-Cit) Dolastatins (DUO5)
MRG003 for injection Meiyake Biotech EGFR+ malignant solid tumor EGFR Human IgG1-Lys Dipeptide cleavable (Val-Cit) MMAE
GB251 for injection Genor Biopharma HER2+ metastatic breast cancer HER2 Human IgG1-Lys Dipeptide cleavable (Val-Cit) MMAE
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抗体偶联药物研发及药学审评要点
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张忠兵 , 王旸 , 白玉 *
药学学报 | 新药论坛 2020,55(8): 1971-1977
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药学学报 | 新药论坛 2020, 55(8): 1971-1977
抗体偶联药物研发及药学审评要点
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张忠兵, 王旸, 白玉*
作者信息
  • 国家药品监督管理局药品审评中心, 北京 100022

通讯作者:

*白玉, Tel:86-10-85243041, E-mail:
Consideration of antibody drug conjugates development and regulation
Zhong-bing ZHANG, Yang WANG, Yu BAI*
Affiliations
  • Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
出版时间: 2020-08-12 doi: 10.16438/j.0513-4870.2020-0325
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摘要
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抗体偶联物（antibody drug conjugates，ADCs）兼具抗体的靶向性和小分子化合物的细胞毒性，目前已经成为抗肿瘤药物研发的热点之一。靶抗原、抗体、毒素、连接子或偶联方式的选择是影响ADCs药物开发成功的要素。本文介绍了ADCs药物在开发和结构设计方面需考虑的主要因素，以及在此类产品申报时药学技术审评的要点，希望能为研发单位开发ADCs药物提供参考。

单克隆抗体  /  抗体偶联物  /  毒素  /  连接子  /  上市申请

Antibody drug conjugates (ADCs), as they combine the targetability of monoclonal antibody and cytotoxicity of small molecules, are a growing class of therapeutics for cancer. The key factor of ADCs development is the accurate selection of parameters including tumor target, monoclonal antibody, cytotoxic payload, and linkage strategy of antibody to payload. Here, we summarize the main elements in the structural design and the development of ADCs, as well as the regulatory consideration of product manufacturing and control, which would be helpful for the research and development of ADCs.

monoclonal antibody  /  antibody drug conjugate  /  cytotoxic payload  /  linker  /  marketing authorization application
张忠兵, 王旸, 白玉. 抗体偶联药物研发及药学审评要点. 药学学报, 2020 , 55 (8) : 1971 -1977 . DOI: 10.16438/j.0513-4870.2020-0325
Zhong-bing ZHANG, Yang WANG, Yu BAI. Consideration of antibody drug conjugates development and regulation[J]. Acta Pharmaceutica Sinica, 2020 , 55 (8) : 1971 -1977 . DOI: 10.16438/j.0513-4870.2020-0325
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单克隆抗体作为靶向药物在近30年来得到迅猛发展, 相关药物已经大量进入临床试验阶段并陆续上市[1]。相比于普通单抗药物仅靶向于细胞外或细胞表面抗原的局限, 由抗体和小分子细胞毒药物偶联组成的抗体偶联物(antibody drug conjugates, ADCs)则能进入肿瘤细胞内发挥靶向肿瘤杀伤作用, 降低了单抗药物和小分子药物的用药剂量, 极大提高了小分子细胞毒药物的治疗指数, 使某些毒性强的小分子化合物的成药成为可能。
相比于普通抗体及小分子药物, ADCs药物结合了化学小分子药物和抗体大分子药物的特征, 其化学结构、作用机制、生物活性和工艺与质量控制都具有特殊性。产品的开发从起始物料、工艺开发到终产品控制都需要化学和生物学等多学科参与, 其关键质量属性(critical quality attributes, CQA)和关键工艺参数(critical process parameter, CPP)的研究具有一定的复杂性, 而对ADCs类产品的认知也在不断提高和完善。
1 ADCs药物的结构特征
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ADCs类药物的结构一般由3部分组成: ①抗体(即裸抗), 一般为针对肿瘤细胞表面靶抗原设计的特异性单克隆抗体; ②高活性细胞毒素; ③连接子, 可使毒素和抗体以共价键方式稳定连接。由于抗体分子上存在大量的功能基团, 偶联反应可能在多个偶联位点进行, 这导致了ADCs药物实际上是由不同药物-抗体比(drug-antibody ratio, DAR)以及随机性偶联位点的偶联物共同组成的高度异质性的混合物。ADCs药物的异质性影响了药物的安全性和有效性。因此, 在ADCs药物的开发过程中, 需要对抗体制备、偶联化学反应(包括反应物、偶联条件和偶联位点)、游离药物、副产物和杂质以及后序纯化过程进行良好控制, 严格控制药物-抗体比和载药分布等关键质量属性, 以保证产品的均一性和质量稳定性。
2 ADC药物的申报现状
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鉴于ADCs药物的结构和工艺复杂性, 各国监管机构对ADCs药物的审批一直持相对谨慎的态度。ADCs概念的提出已近30年, 迄今为止仅有8个产品获美国食品药品管理局(Food and Drug Administration, FDA)批准上市(表 1)。但近年来, 随着单克隆抗体技术的发展, 以及新型毒素、连接子和肿瘤靶标的发现, ADCs药物已成为抗肿瘤药物研发的热点之一, 仅FDA在2019年就批准了3种ADCs药物上市(表 1)。根据Cortellis数据库统计, 截至2020年2月, 全球抗体偶联药物在研品种共231项。可选择的靶抗原包括细胞分化抗原分子(cluster of differentiation, CD, 如CD19、CD22、CD29、CD30、CD33、CD70和CD79)、表皮生长因子受体(epidermal growth factor receptor, EGFR)和HER2 (human EGFR 2)、前列腺特异性膜抗原(prostate specific membrane antigen, PSMA)、人滋养层细胞表面抗原2 (trophoblast cell-surface antigen 2, Trop2)和结合素4 (nectin-4)等。我国国家药品监督管理局(National Medical Products Administration, NMPA)于2020年1月批准了第1个ADCs药物上市, 即罗氏公司的Kadcyla® (恩美曲妥珠单抗, 中文商品名赫赛莱®)。目前国内企业获批进行临床试验的ADCs药物有20余种(表 2), 多数以HER2为靶标, 但在连接子或偶联方式上与已上市药物有差异。
3 ADCs药物研发和审评的主要考虑
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ADCs药物兼具抗体大分子的靶向性和小分子毒素的抗肿瘤活性, 其设计原理是基于小分子毒素的毒性强烈但并不适合直接给药, 而利用抗体与靶抗原结合的特性携带其进入肿瘤细胞从而发挥其细胞毒性的抗肿瘤作用。靶抗原、抗体、毒素、连接子或偶联方式的选择均是影响ADCs药物开发成功的关键。已成功上市的ADCs药物, 如罗氏公司的恩美曲妥珠单抗, 是通过双功能基团试剂[succinimidyl-4-(N-maleimidomethyl cyclohexane)-1-carboxylate, SMCC]作为连接子, 偶联抗HER2人源化单克隆抗体曲妥珠单抗与微管抑制剂美坦新[DM1, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)maytansine]而制成的单抗介导的细胞毒性药物。每分子恩美曲妥珠单抗是由1分子曲妥珠单抗通过SMCC平均连接3.5个DM1分子组成。恩美曲妥珠单抗可与HER2结合, 其亲和力与曲妥珠单抗类似, 与HER2结合后发生受体介导的内化并导致其在溶酶体中的降解, 使得DM1在细胞内释放并结合至微管蛋白, 进而破坏细胞内微管网络, 导致细胞周期停滞并引起细胞凋亡。
在ADCs产品相关的抗体、连接子、毒素制备以及偶联过程中, 细胞库及培养基成分的病毒风险控制、宿主细胞蛋白和DNA的残留以及小分子相关杂质的控制等因素均会影响产品安全性; 偶联位置、数目、批间一致性及工艺可控性等也可能会影响抗体的靶向性/亲和力和毒性药物的释放量/效应, 进而对产品的安全性和有效性造成影响。因此, 对ADCs药物的药学技术审评应关注其靶点选择的科学性、化学结构的复杂性以及申请单位在原材料、工艺和检测等方面对于ADCs复杂结构的维持能力和产品质量的控制水平。
3.1 肿瘤靶抗原
基于ADCs药物的作用原理, 所选择的靶抗原应在肿瘤细胞表面高表达, 并在正常细胞表面不表达或低表达。有研究发现[2], 肿瘤细胞表面靶抗原的表达水平仅需略高于正常细胞即可成功诱导ADCs药物活性, 而细胞表面抗原的数量可能对于ADCs药物的疗效更为重要。ADCs药物的抗肿瘤作用主要是通过与细胞表面靶抗原结合而使毒素药物内化并发挥细胞毒作用。因此, 所选靶抗原不一定是影响肿瘤细胞生长的分子[3, 4], 参与细胞分化过程的分子, 如CD30和CD70, 也可作为ADCs药物的靶抗原。
靶抗原的胞外结构域(extra-cellular domain, ECD)是ADCs中的抗体结合区域, 部分脱落的ECD进入体循环后可能会结合ADCs而影响ADCs药物向肿瘤细胞的传递[5]。另外, 靶抗原的异质性也会影响ADCs的疗效。已有文献证明[6-9]: ADCs的靶向作用更适合针对均质性表达的靶抗原; 而针对异质性抗原的靶向治疗易发生较多不良反应, 但可能更利于通过自由基或细胞毒性代谢物等分子杀伤附近的肿瘤细胞而发挥“旁观者”效应。
总之, ADCs药物可选择的靶抗原应具有如下特点, 包括相对高的表达水平, 有胞外结构域, 不容易从细胞表面脱落, 以及与抗体结合后应具有内吞能力等。
3.2 裸抗
ADCs药物中的抗体部分既作为毒素载体, 又承担靶向作用。一般来说, 所选抗体应具有高度特异性和亲和力、较低的免疫原性并可诱导细胞表面受体(靶抗原)介导的内吞作用。抗体高特异性可以避免与体内其他抗原分子发生交叉反应, 降低ADCs药物在到达肿瘤部位前的代谢清除, 并减少药物毒性反应。高亲和力抗体有利于携带毒素进入肿瘤细胞, 有研究认为[10], ADCs药物中的抗原–抗体亲和常数Kd一般需小于10 nmol·L-1。不同抗体与相同靶抗原结合后引起的内吞速率有所不同[5], 快速的内吞有利于降低药物脱靶风险, 可提高药物有效性和安全性[11]。
虽然抗体活性也可通过细胞因子的信号调节或免疫效应功能如抗体依赖细胞介导的细胞毒作用(antibody-dependent cell-mediated cytotoxicity, ADCC)、抗体依赖的细胞吞噬作用(antibody-dependent cellular phagocytosis, ADCP)和补体依赖的细胞毒性(complement dependent cytotoxicity, CDC)等实现, 但由于ADCs药物中的毒素分子作用强大, 抗体Fc区(the fragment crystallizable region)功能相关的肿瘤杀伤作用通常被掩盖, 使得ADCs的治疗作用主要体现于其携带的毒素分子的抗肿瘤活性。抗体的药代动力学性质对于ADCs药物设计也很重要, 通常ADCs在血浆中的半衰期比裸抗短, 可被快速清除, 这也有利于提高药物的安全性[12]。
3.3 毒素
ADCs药物中的毒素分子可以来源于植物、动物或微生物, 可以是化学小分子或肽类, 如果是肽类分子在人体内应具有比较低的免疫原性。据报道, 体内肿瘤细胞对抗体的摄取约占每克药剂量的0.003%~0.08%[13, 14], 而且多数肿瘤细胞表面抗原的低表达和较弱的内吞活性会导致递送至肿瘤细胞内部的ADCs少之又少。因此, 抗体携带的毒素分子必须具有极高的细胞毒性, 其毒性一般应高于常见化疗药物毒性的10倍以上, 这样即使仅能递送最少的毒素也能杀死绝大部分的肿瘤细胞。研究认为, 选择的毒素分子对KB细胞作用24 h的半数抑制浓度(the half maximal inhibitory concentration, IC50)至少应低于10 nmol·L-1浓度才适合开发为ADCs[13, 14]。在目前上市或正在开发的ADCs药物中, 常用的毒素分子为DNA合成抑制剂或细胞有丝分裂抑制剂, 如微管蛋白抑制剂澳瑞他汀类(monomethyl auristatin E, MMAE)对不同肿瘤细胞的IC50值为10~500 pmol·L-1[15]。
毒素分子一般应具有较好的化学和物理稳定性, 生产和储存条件不应过于苛刻, 能够选用恰当方法控制偶联反应和储存过程中可能产生的杂质。毒素化合物一般具有优良的水溶性, 适宜的水溶性便于毒素分子与抗体在水溶液中发生偶联反应, 而脂溶性过高的反应体系不利于抗体等蛋白分子的稳定。另外, 偶联产物上带有较强的脂溶性分子也可能会导致抗体的生物学性质改变, 在偶联或储存过程中发生聚集反应[16], 但ADCs药物进入肿瘤细胞后形成的游离小分子化合物上携带的较多疏水基团则有利于其在血液循环中的清除并能提高药物的安全性[17]。如果初始毒素分子的性质并不合适在ADCs中使用, 也可以对其进行化学修饰, 使之具有合适的物理化学性质并容易发生偶联反应。
综合以上, 细胞毒素一般应该具有高细胞毒性、低免疫原性、生产及储存过程中的稳定性, 并且其在体循环中应比较耐受并较容易发生偶联反应。
3.4 连接方法或连接子
ADCs药物中的连接子或裸抗–毒素的连接方式对平衡ADCs药物的有效性及毒性起着重要作用。连接子或连接方式决定了抗体的连接位点、DAR、偶联药物分布和连接的稳定性。ADCs药物中常采用链间二硫键和抗体表面暴露的赖氨酸作为连接位点, 也可使用糖基化结构中的羟基作为连接位点[18]。任何偶联位点都会不可避免地造成ADCs药物的异质性。据统计, 抗体分子的轻、重链上约有40个赖氨酸残基可作为偶联位点, 每个抗体分子中可偶联0~8个毒素分子, 由此造成的ADCs分子约有100万个; 抗体分子中的4个链间二硫键还原后可产生8个半胱氨酸巯基偶联位点, 每个抗体分子中可偶联0~8个毒素分子, 由此产生的ADCs分子约有100个以上[19]。由于ADCs药物并非单一分子组成, 较难预测所有成分的有效性、安全性和稳定性, 因此在ADCs药物设计和开发过程中应尽量降低产品的异质性。采用非天然氨基酸突变或利用空间位阻效应阻断其他偶联位点, 使连接子-毒素与抗体特定氨基酸发生定点偶联, 可大大降低ADCs产品的异质性, 目前已有产品进入临床开发阶段。
ADCs作为一种靶向给药系统在应用于体内时必须克服多种阻碍, 包括体循环中各种酶的降解、细胞表面抗原的结合、内吞作用和毒素释放, 最终毒素在细胞内发挥抗肿瘤作用。不稳固的连接方式容易造成毒素提前释放而增大药品毒性。理想的连接方式是使ADCs在体循环中保持完整, 并能够在靶细胞内部发生裂解以使毒素释放, 这就要考虑使体循环中的裂解因子(如蛋白酶、还原剂等)水平明显低于肿瘤细胞内。有的ADCs药物使用不可断裂的连接子如硫醚连接物(maleimidomethyl cyclohexane-1-carboxylate, MCC或maleimidocaproyl, MC), 这种连接方式较为稳固, 可延长ADCs进入健康细胞的作用时间而增加药物在某些特定组织中如造血系统中的毒副反应[20]。连接子的不同可能造成ADCs代谢产物的不同, 会一定程度影响ADCs的某些性能参数, 如IC50和最大耐受剂量(maximal tolerable dose, MTD)等。另外, 为了患者的安全, 应该采用合适方法对未结合的毒素和残留有机溶剂的含量进行控制。
3.5 ADCs药物的药学审评要点
考虑到ADCs药物结构上一般是由抗体大分子和化学小分子组成, 其药学评价一般涉及生物和化学2个团队协作完成。如FDA一般由Office of Biotechnology Products (OBP)和Office of New Drug Quality Assessment (ONDQA)共同负责该类产品的药学技术审评。我国监管部门对于ADCs药物的技术审评也有类似安排, 有从业者认为ADCs药物较传统裸抗具有更高的异质性, 是单抗药物中药学评价内容最多、难度最大的品种[21]。ADCs药物审评主要围绕“结构设计”、“原材料”、“生产工艺”和“质量研究”等方面展开。
结构方面, 应关注ADCs药物结构中抗体、毒素、连接子或偶联方式以及靶抗原的选择依据。建议申请人对所选择的抗体、毒素、连接子的特性及可能的风险进行深入调研分析, 可以引用文献或已获批品种进行佐证。
生产原材料方面, 研发单位应基于风险评估原则对ADCs生产中使用到的宿主细胞、培养基、试剂等物料进行控制。ADCs中的裸抗可以是创新型抗体, 也可以是生物类似药, 应有清晰的目的基因来源和背景资料, 裸抗生产用细胞库的检定和稳定性符合中国药典和国际人用药品注册技术协调会(International Conference on Harmonization, ICH) Q5A等指导原则要求, 且培养基与添加剂等成分应无遗传性海绵状脑病(transmissible spongiform encephalopathig, TSE)或牛海绵状脑病(bovino spongiform encephalopathy, BSE)风险。小分子毒素和连接子作为ADCs药物的关键原材料, 可参考小分子化学新药的相关要求, 提供详细的起始物料、合成工艺、结构确证和质量控制信息(包括工艺涉及到的特殊有机溶剂及毒性数据), 如为发酵来源的产品还应提供菌株、培养基及工艺信息。由于不可偶联杂质可在与裸抗偶联过程中除去, 因此应重点关注具有偶联能力的杂质、基因毒性杂质和有机溶剂残留, 具体可参照ICH Q3A或《中国药典》相关规定。申报资料中的常见问题主要包括毒素和连接子的合成物料或中间体的质量控制过于简单, 重要原材料中杂质含量较高或外购中间体缺少工艺和质控标准, 以及结构中含有手性中心但缺少立体异构体的控制等。
生产工艺方面, ADCs的3个不同组分(单克隆抗体、连接子和毒素)应根据GMP (good manufacturing practice)要求进行开发和制造, 工艺涉及发酵、纯化、合成、偶联、超滤等步骤。工艺开发中应明确产品的CQA和CPP, 通过对CQA的分析, 设置关键工艺参数控制范围, 并建立中间体验收标准, 以保证工艺稳健性和产品质量一致性。对病毒灭活、清除以及有重要安全性风险相关的杂质的去除, 应按照ICH Q5A和Q11等指导原则要求进行充分的工艺验证和风险评估。考虑到ADCs产品重要的异质性问题, 建议偶联工艺重点关注单抗二硫键打开比例、毒素偶联位点和结合数量的控制、杂质的偶联情况等。如为定点偶联应关注其定点反应原理、可能的非定点偶联发生概率及其他副反应情况。偶联反应后的分离纯化工艺方面应关注还原试剂、偶联试剂和偶联杂质及不可偶联杂质的去除验证和残留控制。部分工艺仅采用单一的分离方法如超滤法, 则应对生产过程中可能引入或产生的杂质, 尤其是大分子杂质进行全面评估以确定纯化效果。制剂方面, 由于ADCs制剂剂量规格明显低于常见单抗药物, 且分子中携带了疏水性毒素分子, 其蛋白不稳定性风险较高, 因此应密切关注制剂中蛋白的聚集和颗粒形成, 以及输液袋等容器对药物的吸附, 开展规范的制剂稳定性和包材相容性研究。原液和制剂生产地点不一致的, 应进行原液的运输稳定性研究。
质量研究方面, 对裸抗中间体的质量控制可参考ICH Q6B等相关指导原则要求进行全面的结构及特性分析、活性测定和质量标准研究。例如, 按照生物类似药标准研发的产品应与原研药进行质量对比研究; 按照创新性抗体标准研发的产品应关注其与已上市同靶点抗体的比较, 包括与靶抗原的结合位点和结合力等因素的比较。对于裸抗的关注重点包括宿主细胞蛋白、残留DNA和protein A等工艺杂质, 多聚体、片段、脱酰胺和氧化等产品相关杂质的控制, 以及批次间的质量一致性等。对于连接子和毒素等中间体应参考化药相关要求进行结构确证和质量研究, 重点是杂质谱及限度控制。多肽类化合物的质控标准可参考国家药品审评中心发布的相关技术指导原则[22]。原材料或中间体中如存在手性中心, 应采取合适方法进行光学异构体限度的控制。鉴于毒素-连接子仅作为ADCs中间体存在, FDA相关审评报告中一般对于合成的毒素-连接子中部分小分子杂质的控制限度适当放宽, 而在ADCs终产品中进行控制。对于ADCs色谱图中超过0.1%的杂质应进行定性研究, 重要毒性杂质的控制限度应符合ICH Q3A相关要求或有毒理学数据支持。由于偶联毒素分子后可能会造成裸抗的物理、化学及生物学性质发生改变, 因此ADCs应与裸抗进行全面质量比对研究, 并说明偶联修饰后的抗体结构与功能改变是否符合预期, 如偶联工艺是否对抗体功能抗原决定簇互补区(complementarity-determining region, CDR)造成影响和不同载量ADCs的结合活性比较情况等。ADCs原液与制剂质量标准控制项目中, 在裸抗质量标准基础上应体现对平均载药量(或载药分布)、偶联位点和相关杂质(游离药物、残留有机溶剂和未偶联裸抗等)的控制。
可比性研究方面, ADCs药物在开发过程中多涉及原材料或中间体供应商、处方工艺、规模、场地、质量标准的变更, 多数变更需要进行可比性研究。可比性研究应基于风险评估原则并参照ICH Q5E等要求进行, 关注变更前后关键质量属性的变化。对于裸抗需注意过程控制参数变化、中间体以及产物的质量检测, 包括各种变异体、宿主蛋白和残留DNA、抗原亲和力等质量属性的合理性范围; 对于小分子化合物应重点关注杂质谱的变化、残留溶剂等影响药物安全性的潜在因素; 对于偶联物应关注DAR、载药分布等重要指标, 以及储存过程中分子大小变异体、电荷异构体、游离药物和生物活性的变化。鼓励申请人就临床过程中发生的重大变更及时和监管机构进行沟通。
4 结语
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ADCs药物自上市以来, 被认为是对抗肿瘤的特洛伊木马, 可以“欺骗性”被肿瘤细胞表面抗原识别并进入细胞内部, 释放毒素分子发挥肿瘤杀伤作用。ADCs药物开发的4个要素(肿瘤靶抗原、抗体、毒素和连接子)的选择对药物的有效性和安全性有重要影响, 是决定药物最终开发成功的关键。ADCs结构包括了大分子的复杂性和小分子的单一性, 工艺涉及到重组DNA技术、化学合成及偶联等多学科技术, 质量控制涵盖了大分子的源头和过程控制以及小分子的杂质控制策略。考虑到ADCs药物的复杂性和特殊性, 我国监管部门和制药企业的一些技术专家已达成部分共识可供研发单位参考[23]。目前药品监管部门对ADCs药物的技术审评一般由跨学科团队协作完成, 同时鼓励申请人和监管机构在产品开发阶段保持密切沟通。
随着强效毒素分子发现、定点偶联、生物偶联以及纳米抗体、双特异性抗体等技术的发展, 对于新型ADCs药物的开发热情不断高涨, 这也给相关技术审评带来挑战[24]。ADCs的药学审评应充分考虑其创新性和复杂性, 临床阶段重点关注影响临床安全性的因素, 以满足未可及的临床需求为主要导向; 上市阶段更应侧重产品的工艺稳健性和质量一致性, 上市阶段产品的质量应以不低于支持其上市的临床样品质量为最低要求, 鼓励申请人在产品上市后密切关注相关产品的国内外安全性数据, 不断提高其工艺和质量控制水平。随着我国鼓励创新和药品审评审批制度改革等政策的持续推进, 相信在制药企业和监管部门的共同努力下, 会有更多的优质ADCs药物获批上市, 使我国人民的医疗水平不断提高。
致谢 本文撰写过程中得到了国家药品监督管理局药品审评中心魏开坤老师的悉心指导和帮助, 在此深表感谢。
作者贡献:张忠兵负责论文组织和撰写; 王旸负责小分子偶联物部分的撰写和审核; 白玉负责全文的审核。
利益冲突:本文全体作者在此声明, 本文不涉及任何利益冲突。
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2020年第55卷第8期
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doi: 10.16438/j.0513-4870.2020-0325
  • 接收时间：2020-03-14
  • 首发时间：2026-01-21
  • 出版时间：2020-08-12
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  • 收稿日期：2020-03-14
  • 修回日期：2020-04-24
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    国家药品监督管理局药品审评中心, 北京 100022

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*白玉, Tel:86-10-85243041, E-mail:
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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
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