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Article(id=1218263400690405759, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263392100467355, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2017-0973, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1506528000000, receivedDateStr=2017-09-28, revisedDate=1510588800000, revisedDateStr=2017-11-14, acceptedDate=null, acceptedDateStr=null, onlineDate=1768386228964, onlineDateStr=2026-01-14, pubDate=1513267200000, pubDateStr=2017-12-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768386228964, onlineIssueDateStr=2026-01-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768386228964, creator=13701087609, updateTime=1768386228964, updator=13701087609, issue=Issue{id=1218263392100467355, tenantId=1146029695717560320, journalId=1189982191388893191, year='2017', volume='52', issue='12', pageStart='1777', pageEnd='1974', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768386226916, creator=13701087609, updateTime=1768386745881, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218265568860357555, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263392100467355, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218265568860357556, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263392100467355, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1811, endPage=1819, ext={EN=ArticleExt(id=1218263401613152676, articleId=1218263400690405759, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research and development of innovative antibody-based drugs, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=REVIEWS, runingTitle=null, highlight=null, articleAbstract=

With the development of antibody manufacturing technology and improvement in new drug research and development (R&D) capabilities in domestic industry, more and more innovative antibody-based drugs were registered at the Investigational New Drug (IND). This type of drugs could be divided into three categories:new sequence antibodies (biobetter or new target antibodies), bispecific antibodies (or antibody cocktails), and antibody drug conjugates. Comparing with biosimilar antibodies, the innovative antibodies R&D was characterized by some significant features including "innovation", "clinical phase-appropriate" and "progressing". The minimum requirements of Chemical, Manufacturing and Control (CMC) content for innovative antibodies were obviously different from biosimilar antibodies. Here, the recent progress of antibody engineering and IND date of innovative antibodies in domestic are summarized. The general regulatory requirement and special considerations for representative innovative antibodies were proposed. Some common problems concerning innovative antibodies R&D are discussed.

, correspAuthors=Jian-hui LUO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright © 2017 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=Bo-ning LIU, Jian-hui LUO), CN=ArticleExt(id=1218263402116469191, articleId=1218263400690405759, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=关于创新型抗体药物药学评价的思考, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

近年来，随着我国生物制药自主创新能力的提高，越来越多的创新型抗体药物申请注册临床试验。按照其技术特点，可分为全新序列抗体（改良型抗体或新靶点抗体）、双特异性抗体（或复方抗体）、抗体偶联物等三类。与生物类似药不同，创新型抗体的开发具有"创试性"、"阶段性"和"渐进性"等显著特点。与之相适应，其药学评价内容与技术要求也区别于生物类似药。本文总结了近年来国内外创新型抗体的发展趋势与申报现状，对代表品种的技术特点进行分析。并结合新药审评实践，着重就创新型抗体药学评价的关注点、一般考虑与评价要点展开探讨，以期促进此类药物由研发顺利转入早期临床试验阶段。

, correspAuthors=罗建辉, authorNote=null, correspAuthorsNote=
* 罗建辉, Tel:86-10-68586655, E-mail:
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Category Type Platform technology or mutation site Structure feature or clinical advantage
Variable region pH (Calcium)-dependent SMART-Ig (Chugai) Be delivered less frequently or at lower
engineering antigen binding doses
Bispecific antibodies BiTE®, Diabody®, DART®, TandAbs® A fusion protein of VH and VL without Fc
Triomab®, Knobs-into-holes®, CrossMab®, DVD-Ig®, Promote bispecificity by heterodimer
Duobody®; Common light chain, F-Star®, Two-in-One Formation
Single-domain antibody Nanobody® (Ablynx) Smaller size and more stability
Constant region Mutation sites Alemtuzumab (S239D/I332E, S239D/I332E/A330L) Enhancing ADCC activity in vivo
engineering Xmab5574(S239D/I332E), S298A/E333A/K334A
F243L/R292P/Y300L/V305I/P396L
Atezolizumab (N297A), L234A/L235A, D265A Inhibiting ADCC activity in vivo
S267E/H268F/S324T, G236A/I332E, K326W/ E333A Enhancing CDC activity in vivo
M252Y/S254T/T256E (MedImmune), M428L/N434S Extend the half-life time of antibody
IgG4 (S228P) Provent IgG4 Fab-arm exchange in vivo
Glycosylation engineering GlycoMab® (Glycart); Potelligent® (BioWa) Increased binding affinity of CD16 and ADCC
ADCs Random conjugation Lysine amide coupling; Cysteine coupling, Pt(Ⅱ)-linker High potency and cancer cell specificity
re-bridges
Site-specific chemical THIOMAB®; Non-natural amino acid incorporation;
conjugation Enzymatic conjugation; N-Glycan engineering
Probody drug conjugates Probody® (Cytomx) Be activated in the disease microenviroment
), ArticleFig(id=1218968468754453257, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263400690405759, language=CN, label=Table 1, caption=

The latest technology progress of antibody engineering[6, 7, 19-23]

, figureFileSmall=null, figureFileBig=null, tableContent=
Category Type Platform technology or mutation site Structure feature or clinical advantage
Variable region pH (Calcium)-dependent SMART-Ig (Chugai) Be delivered less frequently or at lower
engineering antigen binding doses
Bispecific antibodies BiTE®, Diabody®, DART®, TandAbs® A fusion protein of VH and VL without Fc
Triomab®, Knobs-into-holes®, CrossMab®, DVD-Ig®, Promote bispecificity by heterodimer
Duobody®; Common light chain, F-Star®, Two-in-One Formation
Single-domain antibody Nanobody® (Ablynx) Smaller size and more stability
Constant region Mutation sites Alemtuzumab (S239D/I332E, S239D/I332E/A330L) Enhancing ADCC activity in vivo
engineering Xmab5574(S239D/I332E), S298A/E333A/K334A
F243L/R292P/Y300L/V305I/P396L
Atezolizumab (N297A), L234A/L235A, D265A Inhibiting ADCC activity in vivo
S267E/H268F/S324T, G236A/I332E, K326W/ E333A Enhancing CDC activity in vivo
M252Y/S254T/T256E (MedImmune), M428L/N434S Extend the half-life time of antibody
IgG4 (S228P) Provent IgG4 Fab-arm exchange in vivo
Glycosylation engineering GlycoMab® (Glycart); Potelligent® (BioWa) Increased binding affinity of CD16 and ADCC
ADCs Random conjugation Lysine amide coupling; Cysteine coupling, Pt(Ⅱ)-linker High potency and cancer cell specificity
re-bridges
Site-specific chemical THIOMAB®; Non-natural amino acid incorporation;
conjugation Enzymatic conjugation; N-Glycan engineering
Probody drug conjugates Probody® (Cytomx) Be activated in the disease microenviroment
), ArticleFig(id=1218968468918031127, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263400690405759, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Category Drug candidate Sponsor
Anti-PD-1 antibody JS001 Taizhou Junshi Biosciences Co., Ltd
Camrelizumab (SHR-1210) Shanghai Hengrui Pharmaceutical Co., Ltd
IBI308 Innovent Biologics, Inc.
BGB-A317 BeiGene
Genolimzumab GenorBiopharma
Anti-PD-1 antibody Bio-Thera Solution., Ltd
AK103 AkesoBiopharma
LZM009 LivzonMabpharm Inc.
HLX10 Shanghai Henlius Biotech, Inc.
GLS-010 (WBP3055) Harbin Gloria Pharmaceuticals Co. Ltd
Anti-PD-L1 antibody KN035 Alpharmab Co. Ltd
CS001 (WBP3155) Cstone Pharmaceutical Co. Ltd
SHR-1316 Jiangsu Hengrui Pharmaceutical Co., Ltd
KL-A167 Kelun Pharmaceutical Co., Ltd
STI-A1014 Zhaoke Pharmaceutical Co., Ltd
TQB2450 Chia Tai Tianqing Pharmaceutical Group Co., Ltd
Anti-PCSK9 antibody JS-002 Shanghai Junshi Biosciences Co., Ltd
IBI306 Innovent Biologics, Inc.
AK102 Kangrong Dongfang Pharmaceutical Co., Ltd
Anti-GLP-1antibody GMA-102 Hangzhou Gmaxbiopharm Biomedical Engineering Co., Ltd
Bispecific antibodies IBI302 Innovent Biologics, Inc.
M701 (EpCAM×CD3) Wuhan YZY Biopharm
M701 (HER2×CD3) Wuhan YZY Biopharm
KN026 Alpharmab Co. Ltd
Antibodies Cocktail MIL77 Academy of Military Medical Sciences
SYN023 Synermore Biologics
ADCs Iodine [131I] Tumor Necrosis therapy monoclonal antiobdy Shanghai Medipharm Biotech Pharmaceutical
Iodine [131I] Metuximab Chengdu Huasun Biological
SHR-A1201 Jiangsu Hengrui Pharmaceutical Co., Ltd
BAT8001 Bio-Thera Solution., Ltd
anti-her2 antibody-DM1 Qilu Pharmaceutical Co., Ltd
anti-her2 antibody-DM1 3S guojian Pharmaceutical Co., Ltd
anti-her2 antibody-DM1 Zhejiang Hisun Pharmaceutical Co., Ltd
MRG003 Shanghai Miracogen Inc.
RC48-ADC Rangchang Pharmaceuticals, Ltd
ARX788 HER2 ADC Ambrx.Inc and Zhejiang Medical Co., Ltd
SHR-A1403 Jiangsu Hengrui Pharmaceutical Co., Ltd
TRS005 Zhejiang Teruisi Pharmaceutical Inc.
), ArticleFig(id=1218968469064831778, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263400690405759, language=CN, label=Table 2, caption=

The list of recent innovative antibodies IND submission by domestic sponsors. Data sources: http://www.cde.org.cn/; http://www.chinadrugtrials.org.cn; htpp://www.db.yaozhi.com

, figureFileSmall=null, figureFileBig=null, tableContent=
Category Drug candidate Sponsor
Anti-PD-1 antibody JS001 Taizhou Junshi Biosciences Co., Ltd
Camrelizumab (SHR-1210) Shanghai Hengrui Pharmaceutical Co., Ltd
IBI308 Innovent Biologics, Inc.
BGB-A317 BeiGene
Genolimzumab GenorBiopharma
Anti-PD-1 antibody Bio-Thera Solution., Ltd
AK103 AkesoBiopharma
LZM009 LivzonMabpharm Inc.
HLX10 Shanghai Henlius Biotech, Inc.
GLS-010 (WBP3055) Harbin Gloria Pharmaceuticals Co. Ltd
Anti-PD-L1 antibody KN035 Alpharmab Co. Ltd
CS001 (WBP3155) Cstone Pharmaceutical Co. Ltd
SHR-1316 Jiangsu Hengrui Pharmaceutical Co., Ltd
KL-A167 Kelun Pharmaceutical Co., Ltd
STI-A1014 Zhaoke Pharmaceutical Co., Ltd
TQB2450 Chia Tai Tianqing Pharmaceutical Group Co., Ltd
Anti-PCSK9 antibody JS-002 Shanghai Junshi Biosciences Co., Ltd
IBI306 Innovent Biologics, Inc.
AK102 Kangrong Dongfang Pharmaceutical Co., Ltd
Anti-GLP-1antibody GMA-102 Hangzhou Gmaxbiopharm Biomedical Engineering Co., Ltd
Bispecific antibodies IBI302 Innovent Biologics, Inc.
M701 (EpCAM×CD3) Wuhan YZY Biopharm
M701 (HER2×CD3) Wuhan YZY Biopharm
KN026 Alpharmab Co. Ltd
Antibodies Cocktail MIL77 Academy of Military Medical Sciences
SYN023 Synermore Biologics
ADCs Iodine [131I] Tumor Necrosis therapy monoclonal antiobdy Shanghai Medipharm Biotech Pharmaceutical
Iodine [131I] Metuximab Chengdu Huasun Biological
SHR-A1201 Jiangsu Hengrui Pharmaceutical Co., Ltd
BAT8001 Bio-Thera Solution., Ltd
anti-her2 antibody-DM1 Qilu Pharmaceutical Co., Ltd
anti-her2 antibody-DM1 3S guojian Pharmaceutical Co., Ltd
anti-her2 antibody-DM1 Zhejiang Hisun Pharmaceutical Co., Ltd
MRG003 Shanghai Miracogen Inc.
RC48-ADC Rangchang Pharmaceuticals, Ltd
ARX788 HER2 ADC Ambrx.Inc and Zhejiang Medical Co., Ltd
SHR-A1403 Jiangsu Hengrui Pharmaceutical Co., Ltd
TRS005 Zhejiang Teruisi Pharmaceutical Inc.
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关于创新型抗体药物药学评价的思考
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刘伯宁 , 罗建辉 *
药学学报 | 综述 2017,52(12): 1811-1819
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药学学报 | 综述 2017, 52(12): 1811-1819
关于创新型抗体药物药学评价的思考
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刘伯宁, 罗建辉*
作者信息
  • 国家食品药品监督管理总局药品审评中心, 北京 100038

通讯作者:

* 罗建辉, Tel:86-10-68586655, E-mail:
Research and development of innovative antibody-based drugs
Bo-ning LIU, Jian-hui LUO*
Affiliations
  • Center for Drug Evaluation, China Food and Drug Administration, Beijing 100038, China
出版时间: 2017-12-15 doi: 10.16438/j.0513-4870.2017-0973
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摘要
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近年来，随着我国生物制药自主创新能力的提高，越来越多的创新型抗体药物申请注册临床试验。按照其技术特点，可分为全新序列抗体（改良型抗体或新靶点抗体）、双特异性抗体（或复方抗体）、抗体偶联物等三类。与生物类似药不同，创新型抗体的开发具有"创试性"、"阶段性"和"渐进性"等显著特点。与之相适应，其药学评价内容与技术要求也区别于生物类似药。本文总结了近年来国内外创新型抗体的发展趋势与申报现状，对代表品种的技术特点进行分析。并结合新药审评实践，着重就创新型抗体药学评价的关注点、一般考虑与评价要点展开探讨，以期促进此类药物由研发顺利转入早期临床试验阶段。

创新型抗体  /  抗体工程  /  抗体药物偶联物  /  双特异性抗体  /  程序化细胞死亡受体1

With the development of antibody manufacturing technology and improvement in new drug research and development (R&D) capabilities in domestic industry, more and more innovative antibody-based drugs were registered at the Investigational New Drug (IND). This type of drugs could be divided into three categories:new sequence antibodies (biobetter or new target antibodies), bispecific antibodies (or antibody cocktails), and antibody drug conjugates. Comparing with biosimilar antibodies, the innovative antibodies R&D was characterized by some significant features including "innovation", "clinical phase-appropriate" and "progressing". The minimum requirements of Chemical, Manufacturing and Control (CMC) content for innovative antibodies were obviously different from biosimilar antibodies. Here, the recent progress of antibody engineering and IND date of innovative antibodies in domestic are summarized. The general regulatory requirement and special considerations for representative innovative antibodies were proposed. Some common problems concerning innovative antibodies R&D are discussed.

innovative antibodies  /  antibody engineering  /  antibody-drug conjugates  /  bispecific antibodies  /  programmed cell death 1 receptor
刘伯宁, 罗建辉. 关于创新型抗体药物药学评价的思考. 药学学报, 2017 , 52 (12) : 1811 -1819 . DOI: 10.16438/j.0513-4870.2017-0973
Bo-ning LIU, Jian-hui LUO. Research and development of innovative antibody-based drugs[J]. Acta Pharmaceutica Sinica, 2017 , 52 (12) : 1811 -1819 . DOI: 10.16438/j.0513-4870.2017-0973
正文
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长期以来, 我国的生物制药产业以跟踪、仿制国外已上市品种为主, 注册申报的单抗药物多为国外已上市品种的生物类似药[1]。近年来, 随着国内企业在“抗体药物制备关键技术”上的突破[2]以及自主创新能力的提高, 我国抗体药物的研发与注册已经由“生物类似药”开始向“创新药”转变。截止2017年8月, 国内已有至少40余种创新型抗体药物注册临床试验。上述品种按照其技术特点可分为:已有靶点的改良抗体(bio-better)、全新靶点抗体药物(new target anybodies)、双特异性抗体(bispecific antibodies)、复方抗体(antibodies cocktail)、抗体偶联药物(antibody-drug conjugates, ADCs)、纳米抗体(nanobody)等。
由于创新型抗体药物的靶点、结构特征与作用机制, 有别于已上市抗体或传统生物类似药, 工业界与监管界对此类品种的科学认知积累有限, 其安全性、有效性需要全面的临床前研究和临床试验研究。因此对于创新型抗体药物的药学研究, 工业界通常结合临床试验进展“分阶段”开展(clinical phase-appropriate), 产品上市前普遍存在多次生产工艺变更[3, 4]。可以说, 创新型抗体药物的研发规律具备“创试性”(临床研究存在较大失败风险)、“阶段性” (药学研究分阶段展开)和“渐进性”(临床期间普遍存在工艺变更)等显著特征。上述特点也决定了此类品种药学评价的一般考虑与特殊要求区别于生物类似药。近年, 由于工业界与监管方对于创新风险评价经常存在分歧, 加之缺乏有效的沟通交流机制, 造成目前此类品种“审评周期长, 发补率高”等情况。本文回顾了近年来创新型抗体药物研发趋势与申报现状, 并结合代表品种的技术特点, 就创新型抗体药学评价一般考虑与特殊要求展开讨论, 以期促进药物研发顺利转入临床试验。
1 抗体工程技术研究进展与创新型抗体申报现状
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1.1 国际上“抗体工程技术”研究进展
早期的单克隆抗体来自免疫小鼠的鼠源单抗, 为降低抗体药物的免疫原性, 需要进行嵌合抗体、人源化抗体等改造。近年来, 随着体外展示(噬菌体、酵母菌、核糖体等)、人源化小鼠、单个B细胞等技术的发展, 目前全人序列基因工程单克隆抗体已经成为抗体药物的主流[5]; 在此基础上, 利用“抗体工程技术”(anti-body engineering)对可变区、恒定区的改构可进一步提高抗体分子的成药性, 最终催生出多种类型的创新型抗体药物进入临床[6, 7]。
在抗体可变区改构方面, 依赖pH[8]或钙离子[9]结合的“清道夫” (sweeping antibody)在溶酶体内可实现抗原-抗体复合物的解离。由于此类抗体经FcRn转运胞外后可多次中和靶标, 临床上可显著减少给药剂量或延长给药间隔; 通过构建靶向T细胞和肿瘤细胞的双特异性抗体BiTE (bispecific T cell engager)或DARTs (dual-affinity re-targeting protein), 可直接连接并诱导效应细胞(T细胞)杀伤靶细胞(肿瘤细胞); 通过构建靶向转铁蛋白受体(transferrin receptor)或胰岛素受体的双功能抗体, 可以促使抗体药物借助转运机制穿过血脑屏障或进行肠道给药[10]。
在抗体恒定区改构方面, 通过对受体结合位点的氨基酸突变, 来改变抗体的恒定区(Fc)效应功能、延长半衰期, 或提高结构稳定性。如:抗C5单抗eculizumab (Soliris®)采用IgG2/4型恒定区来消除效应功能[11]; 抗CD52单抗alemtuzumab (Lemtrada®)通过恒定区改构(S239D/I332E, S239D/I332E/A330L)提高ADCC (antibody-dependent cell-mediated cyto-toxicity)效应; 抗PD-L1 (programmed death-ligand 1)单抗atezolizuamb (Tecentriq®)通过突变糖基化位点(N297A)消去Fc效应功能; 抗CTLA-4 (cytotoxic T lymphocyte-associated protein 4)融合蛋白belatacept (Nujolix®)和abatacept (Orencia®)通过对铰链区多处氨基酸突变, 消除ADCC与CDC效应[6, 7]; 抗PD-1 (programmed cell death 1 receptor)单抗nivolumab通过恒定区改构(S228P)避免IgG4恒定区形成半抗体[12]; 抗金葡菌抗体MEDI4893通过恒定区改构(M252Y/S254T/T256E), 提高FcRn亲和力以延长体内半衰期[13]。
近年来研究发现, 抗体的糖型分布(去岩藻糖、半乳糖、唾液酸、非人糖基化修饰等)可显著影响其临床生物活性与免疫原性, 应作为抗体药物的“关键质量属性”进行研究和控制[14, 15]。如:抗CD20单抗obinutuzumab (Gazyva®)和抗CCR4单抗mogamu-lizumab (Poteligeo®)经宿主细胞改造后降低或消除岩藻糖修饰, 临床上提高抗体的ADCC效应[16]。
为提高抗体的生物活性, 可在传统裸抗的基础上偶联小分子药物构建抗体药物偶联物(ADCs)。裸抗与小分子药物的连接方式, 早期多使用不稳定连接子(腙键、二硫键等), 目前应用较多的稳定连接子(蛋白酶缬氨酸-瓜氨酸连接肽、硫醚键等); 使用较多的小分子药物有ImmunoGen公司的美登素系列(DM1、DM4等)和Seattle Genetics公司的海兔毒素系列(MMAE、MMAF)等。传统的随机偶联或半定点偶联造成了ADCs药物的高度“异质性”。未来通过糖基化修饰和氨基酸突变或非天然氨基酸引入进行“定点偶联”将是ADCs药物发展方向[17, 18]。
1.2 国内外创新型抗体药物研发现状
截止2017年5月, 世界范围内进入临床研究阶段的候选抗体药物有719种。这其中除了传统裸抗外(493种), 还包括抗体片段(13种)、抗体药物偶联物(87种)、双特异性抗体(61种)、Fc融合蛋白(37种)、放射性偶联抗体(17种)、免疫细胞因子(11种)等[5, 7]。在我国, 目前受理申报临床的创新型抗体药物总数已经超过40个, 按照其技术特点可分为:全新序列抗体(改良型抗体或新靶点抗体)、双特异性抗体(或复方抗体)、抗体偶联物等三类(表 1)[6, 7, 19-23]。如:降低临床不良反应的抗EGFR (epidermal growth factor receptor)单抗[24]、增强ADCC效应的抗HER2单抗、抗PD-L1单域抗体KN-035[25]、抗埃博拉病毒复方抗体MIL77[26]、国内首个抗PD-1单抗JS-001[27]、国内上市品种抗VEGFR1/2-Fc融合蛋白Conbercept[28]等(表 2)。
值得一提的是, 其中多个自主研发的创新型抗体药物已经在欧美同期注册或开展临床。如:抗PD-1抗体BGB-A317、抗c-MET抗体偶联药物SHR-A1403、抗PD-L1抗体SHR-1316、抗PD-L1单域抗体KN-035、抗EGFR改良抗体HLX07、抗MET单抗emibetuzumab等[29]。这也标志我国抗体药物的创新能力提升, 已经获得国际监管界的认可, 中国制药公司开始参与全球生物制药创新的进程[30]。
1.3 创新型抗体药物研究的一般规律与评价逻辑
与生物类似药不同, 创新型抗体药物的分子结构、作用机制和临床效果有待临床试验的研究, 研发过程中仍存在着较大的失败风险。如:抗CD28单抗TGN1412在Ⅰ期临床中引起严重的“细胞因子风暴”, 因安全性终止临床实验; 礼来公司治疗阿尔兹海默症抗体solanezumab, Ⅲ期临床试验未达到主要终点宣告失败; 辉瑞公司抗PCSK9 (proprotein convertase subtilisin/kexin type 9)抗体bococizumab中止Ⅲ期临床试验; 西雅图遗传公司终止抗体偶联药物SGN-CD33A的临床试验等[31]。因此, 对于创新型抗体药物的开发, 药学研究通常在保证临床基本安全性的前提下可分阶段、有步骤地展开, 产品上市前通过工艺变更逐步提高生产效率。
长期以来, 我国的生物制药申报以“生物类似药”为主, 药物评价关注于候选药与原研药之间质量比对研究的“相似性”, 药效毒理比较研究的“桥接性”、临床试验的“非劣性”和临床价值的“可接受性”。因此, 抗体生物类似药在申请IND前应基本确定生产工艺, 并进行充分的结构确证与质量研究[1]。而创新型抗体药物研发进程具有“创试性” (临床试验存在较大的失败风险)、“阶段性” (药学研究可分阶段展开)和“渐进性” (临床期间通常发生工艺变更)的特征, 其评价关注点应区别于传统生物类似药, 药学研究内容可按照临床试验进展分阶段进行要求, 重点关注于影响临床用药“基本安全性”的药学问题。
2 创新型抗体药物药学研究的一般原则与审评要点
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笔者认为, 参照创新型化药审评实践[4]与国外同类品种技术要求[32, 33], 对于创新型抗体药物的药学研究与评价的一般原则如下:在保证临床用药“基本安全性”的前提下, 基于科学与风险的评估(science-and risk-based approach), 药学研究应按照早期临床试验、关键性临床试验和申请上市等不同时间节点分阶段进行要求。对于创新型抗体药学研究的审评要点, 除了满足一般重组单抗药物的基本要求外, 还应结合其分子结构、作用机制的“新”特点进行特殊要求。下文拟结合国内外创新型抗体代表品种的药学评价实践, 对上述观点进一步阐述。
2.1 全新序列抗体药物(改良单抗或新靶点单抗)
自2013年肿瘤免疫疗法位列年度“科学十大突破”首位后, 以PD-1/L1为代表的免疫检查点蛋白已经成为抗肿瘤抗体开发的新靶点。目前国际上已经有两个抗PD-1单抗(nivolumab、pembrolizumab)和3个抗PD-L1单抗(atezolizumab、avelumab和durvalumab)上市。目前早期的抗PD-1/L1单抗多使用无效应功能的IgG4 (S228P)或IgG1 (N297A)恒定区。后期开发的抗PD-L1抗体出于作用机制的考虑采用具备效应功能的IgG1亚型[12, 34]。在国内, 也有至少10个抗PD-1/L1单抗注册临床。
对于此类新靶点抗体药物, 由于其氨基酸序列为自主筛选优化, 药学资料应说明基因序列来源, 并详述分子构建过程(如:免疫原、免疫方法、人源化过程等)。并且, 应通过免疫学、生物学活性研究说明可变区结合表位是否与已有上市抗体发生重叠。若恒定区存在改构, 还应说明突变位点选择依据、改构方法, 并进行功能验证。上述信息不仅可为后期临床试验的设计和评价提供必要信息, 也从药学角度及早规避了候选药物开发风险。如:目前已经证实多个抗PD-1/L1单抗的抗原结合表位并未重叠、亲和力也不尽相同, 这为其分析临床差异提供了线索[35]。而最早进入临床研究的抗PD-1单抗CT-011进展缓慢, 已经证实是其结合靶点和作用机制不仅依赖于设计靶标(PD-1), 还可能与结合Delta-like 1有关[36]。
利用“抗体工程技术”对已上市抗体进行“分子改构”是开发“改良药” (biobetter)的惯用策略。如:抗SP2/0细胞生产的EGFR西妥系单抗由于可变区存在非人糖基化, 临床上容易产生免疫原性。可通过改变表达系统[37, 38]、去除可变区糖基化位点[24]或优化亲和力降低毒副作用[39]。抗CD20抗体obinuuzumab通过减少恒定区岩藻糖修饰提高了与FcγR的亲和力, 增强抗体的ADCC效应功能[40]。
对于此类“改良”型抗体药物, 由于其设计依据在于通过分子改构, 克服原型蛋白临床局限性。因此, 其药学评价应重点关注其“分子改构”的目的、方法与效果。上游构建方面应结合立题依据, 在详述分子改构的原因、突变位点的选择依据。质量研究中应结合原型抗体进行比较研究, 从结构确证、免疫学活性、生物活性等方面验证分子改构符合预期。如果缺乏与原型抗体(或已上市抗体)的质量比较数据, 或证实上述改构不具有功能学意义, 是不支持其作为“创新药”生物制品进入临床试验的。
2.2 双特异性抗体或复方抗体
双特异性抗体改变了传统单抗的双价、单靶点的结构特点, 通过靶向多个抗原或同一抗原不同表位, 实现阻断或激活多个信号通路。目前, 工业界已报道构建双特异性抗体的形式多达40多种。这其中最具代表性的技术是, 基因泰克公司的“杵-臼”结构(knobs-into-holes, crossover)以及安进公司的T细胞激活剂(BiTE)技术等[22]。目前, 我国自主开发多个双特异性抗体绝大多数也是沿用此类国外成熟技术(表 2)。
与传统抗体相比, 双特异性抗体改变了既往单抗“双价、单靶标”的结合模式。因此, 此类创新抗体的质量研究应重点对多个活性区域的结构与功能进行研究, 如:肽图中应说明结合不同靶标的轻、重链氨基酸序列及complementarity-determining region特征肽段; 功能学研究应说明不同靶标的结合能力和生物活性。此外, 还应关注双特异性抗体区别于天然抗体的独特性质。如: BiTE型抗体由于不含恒定区、体内半衰期较短和T细胞激活功能的临床使用剂量小(μg级), 临床使用过程中需使用特殊溶解方式和给药装置[41]。
复方抗体是多个单克隆抗体的混合物, 可识别病毒颗粒的不同表位, 提高临床上的保护效力。如:抗埃博拉病毒复方抗体MIL77由单抗MIL77-1 (c2G4可变区)、MIL77-2 (c4G7可变区)和MIL77-3 (c13G6可变区)复方组成[26]。抗狂犬病复方抗体CL184由CR57单抗和CR4098单抗等比混合而成[42]
由于复方抗体的有效成分为多种单抗, 其药学资料应包括提供不同抗体的原材料、生产工艺、质量研究, 以及复方制剂的混合方式。质量研究中应结合不同抗体结合表位、生物活性, 说明复方组成的立题依据。对于制剂灌装前进行混合的复方抗体, 应关注半成品混合工艺的控制; 对于单独包装、临用混合的复方抗体, 应关注混合配伍后的临床使用稳定性。
2.3 抗体药物偶联物
ADCs由裸抗、小分子和连接子组成, 生产工艺包括单抗生产、化学偶联和下游纯化, 结构特征较传统裸抗更具“异质性”。因此, ADCs是单抗药物中药学评价内容最多、难度最大的品种。目前, 国内有近10个ADCs药物申报临床, 多数为在已注册单抗(或生物类似药)基础上进行“二次开发”。偶联方式多选择传统的赖氨酸随机偶联、巯基半定点偶联, 也有采用氨基酸突变定点偶联[43]的方式。对于ADC药物的药学评价, 一般采用与化药专业“联合审评”的模式, 围绕“原材料”、“生产工艺”和“质量研究”等3个方面展开[21, 44, 45]。
生产原材料方面, 裸抗分子可参照同类品种(全新序列抗体或生物类似药)进行评价。小分子毒素、连接子作为ADC药物的关键原材料, 应提供详细的起始物料、合成工艺、结构确证、质量控制等信息, 应重点关注影响产品安全性的小分子化药杂质(可偶联、不可偶联)和有机溶剂残留。建议申请人对于含量较高的杂质(> 0.1%)应进行结构鉴定或安全性评估, 有机溶剂残留应符合按照ICH Q3A或2015版《中国药典》相关规定。
生产工艺方面, 应结合产品质量属性(平均载药量、聚体等)对化学偶联相关工序进行优化, 通过设置工艺参数控制范围和建立中间体验收标准, 保证工艺稳健性和产品质量一致性。偶联后纯化工艺一般采用凝胶过滤、切向流过滤或超滤技术等去除小分子杂质和有机溶剂。应结合工艺相关杂质的去除效果或残留量, 对纯化工艺关键参数(过滤体积等)验证。
质量研究方面, 由于化学修饰会造成裸抗分子的等电点、纯度、生物活性等改变, ADCs应与裸抗进行全面质量比对研究, 说明偶联修饰后的抗体结构与功能改变是否符合预期。ADCs原液与制剂质量标准应体现对平均载药量(或载药分布、偶联位点)[46]、相关杂质(游离药物、残留有机溶剂、未偶联裸抗等)含量的限度要求。稳定性研究中若样品生物活性显著提高, 可能提示由于连接子稳定性造成游离小分子药物含量超标。
3 关于创新型抗体药物药学评价中的焦点问题
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由于工业界和监管界对于创新型抗体的研发经验、审评认知均在积累过程中。申请人往往因缺乏可供参考的生产工艺与“原研药”, 致使其药学研究不充分; 审评员也可能惯用“生物类似药”审评原则和标准进行要求。双方对于药学研究中的一些“焦点问题”存在着明显的认识分歧, 如:创新药的临床风险认识、IND阶段药学研究的必要内容、临床期间工艺变更、优先审评与沟通交流政策等。上述问题也是造成此类品种药学审评中发补率高, 甚至多轮发补的主要原因。
3.1 药学研究的风险控制与阶段性要求
创新药的药学研究主要是为了满足不同阶段临床试验需要, IND阶段药学研究应首先能控制临床用药的“基本安全性”[47]。目前, 一般认为, 对于创新药可能引起临床安全性的主要风险包括:产品未知或不纯组分、化学结构含有或潜在毒性成分、稳定性差、杂质未充分确定等[48]。这其中涉及单抗产品的主要风险为, 细胞库未充分检定、动物源性成分生物安全性风险、生产工艺不稳定造成生物活性改变等[29]。因此, 药学研究若存在上述(不限于)影响临床用药安全性的重大缺陷, 申请人必须在开展临床试验前予以解决。
按照国内外通行的技术指导原则[32, 33, 48], 创新型抗体药物申报临床试验前, 一般应完成可支持开展临床试验的主细胞库建立与检定; 细胞遗传稳定性试验应支持中试生产规模工艺。生产工艺与规模具备初步的稳健性, 并可满足临床试验用药需求, 完成影响临床安全性的产品杂质去除研究; 初步建立质量标准, 生物活性可暂时使用免疫学方法, 产品相关杂质含量应结合毒理研究和临床最大剂量进行评估, 相关项目限度要求可预留收紧空间; 具备支持临床试验用药的初步稳定性研究结果。
申请产品上市前(或临床试验期间)应完成:建立符合商业化生产要求的工作细胞库并完成全面检定; 确定拟上市产品的工艺、规模与地点并完成验证, 如:层析介质使用寿命、整个纯化工艺对于逆转录病毒的去除效果[49]; 质量研究应对相关物质(或杂质)进行分离、鉴定与测活, 质量标准宜采用能够模拟临床作用机制的细胞测活法, 含量、纯度、活性等重要指标不低于已上市同类产品; 长期稳定性数据支持拟定保存条件和有效期。
3.2 临床期间的工艺变更
随着创新型单抗临床试验的进展, 其生产工艺通常会进一步优化。主要的工艺变更包括:重新构建工程细胞株、优化培养基组分, 改变发酵设备与规模、采用新型纯化方法或介质、调整制剂处方与规格等。如:抗PD-1抗体nivolumab非临床和早期临床试验采用了A工艺; 关键性临床期间经工艺、场地变更后采用B工艺; 上市申请前为提高下游工艺稳健性采用C工艺[50]。
因此, 建议申请人在药学资料中采用列表的方式, 明确临床前、不同临床试验所用样品的批次、生产规模与工艺信息。重大工艺变更的时间节点应结合临床试验进行统筹安排, 关键性验证临床实验前, 建议明确生产工艺、规模、地点, 以确保商业化产品与临床试验样品质量保持一致。临床期间的工艺变更按照ICHQ5E及国内相关指导原则, 经风险评估后进行充分的可比性研究。
3.3 优先审评与沟通交流
长期以来国内创新药物审评时间长一直是备受业内诟病。这其中既有因审评能力不足导致过度担忧的原因, 也有对创新药缺乏有效沟通、滚动提交资料的体制原因。美国FDA为促进创新药物的研发, 对于治疗重大疾病(或临床未满足的需求)候选药物采用“快速通道” (fast track)、“突破疗法”(breakthrough therapy)、“加速批准”(accelerated approval)和“优先审评”(priority review)等途径加快审评。如:抗2015年PD-1单抗Keytruda®、Opdivo®, 均是在治疗非小细胞肺癌上获得“突破性疗法”资格[51]。我国已经出台了有关“特殊审评 & 特别审评”或“优先审评”的相关政策, 建议申请人充分利用现有审评通路, 通过多渠道沟通交流、动态补充资料等来提高药物研究与评价的效率。
沟通交流可弥补书面资料的不足, 是实现药品科学评价的重要保障措施。近年来, 药审中心也先后出台了“沟通交流会议”、“一般技术问题咨询”相关规定。药学研究中的共性问题, 建议申请人就采用“一般性技术问题咨询”书面沟通。对于涉及具体品种重大决策的药学问题, 建议在新药研发的重要节点(pre-IND、end-of-phase 2、pre-NDA)申请“沟通交流会议”, 会后形成的会议纪要可作为药物研发、审评和审批的重要依据。需要特别指出的是, 由于沟通交流中讨论的内容和时间有限, 未来政策法规、技术要求存在变化的可能, 因此申请人不能将“沟通交流”定位于“预审评”[52], 应着眼于与监管方就新药研发规律和评价考虑开展探讨。既不能因为审评的问题制约临床试验的进程, 更不能因为研发的缺陷影响到受试者的临床试验基本安全。
4 结语
收起
目前, 我国已经超过40个创新型抗体药物申请临床试验, 且多个品种同期在欧美申报进入临床, 国内单抗药物未来申报趋势正由“生物类似药”向“全球新”转变。相比于工业界日新月异的技术发展, 基于既往国情制定的指导原则与技术要求已经显现滞后。过去几年创新型抗体药物的“审评周期长、发补次数多”, 因此, 对于创新药的审评能力与技术要求一直存在担忧, 如:审评与审批是否会成为制约新药开发的限速步骤[53]、国内外IND阶段的药学研究内容与要求尚不统一[29]等。随着我国药品审评审批改革的深入, 未来药品注册法规与相关技术要求将会持续更新[54], 结合国情并与国际接轨; 对于创新型抗体的药学评价, 也将充分考虑其作为“创新药”的研发规律与技术特点, 在保证临床安全性的前提下分阶段、适时进行要求, 重点关注影响临床安全性的重大药学问题; 同时, 未来出台指导原则、申报资料技术要求等文件将进一步实现对创新药研发“事前指导”。相信在工业界创新驱动与监管界风险管控的互动推进下, 未来将有更多的创新型抗体药物会及早进入临床试验, 造福病患。
基金
收起
  • 国家科技重大专项“重大新药创制”课题资助项目(2015ZX09501008)
文献
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2017年第52卷第12期
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doi: 10.16438/j.0513-4870.2017-0973
  • 接收时间：2017-09-28
  • 首发时间：2026-01-14
  • 出版时间：2017-12-15
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  • 收稿日期：2017-09-28
  • 修回日期：2017-11-14
基金
国家科技重大专项“重大新药创制”课题资助项目(2015ZX09501008)
作者信息
    国家食品药品监督管理总局药品审评中心, 北京 100038

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species		 占总种数比例
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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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