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Article(id=1220655292103185224, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1220655289922143078, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2019-1064, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1577289600000, receivedDateStr=2019-12-26, revisedDate=1583337600000, revisedDateStr=2020-03-05, acceptedDate=null, acceptedDateStr=null, onlineDate=1768956500316, onlineDateStr=2026-01-21, pubDate=1591891200000, pubDateStr=2020-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768956500316, onlineIssueDateStr=2026-01-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768956500316, creator=13701087609, updateTime=1768956500316, updator=13701087609, issue=Issue{id=1220655289922143078, tenantId=1146029695717560320, journalId=1189982191388893191, year='2020', volume='55', issue='6', pageStart='1073', pageEnd='1356', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768956499796, creator=13701087609, updateTime=1768957205309, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1220658249112671213, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1220655289922143078, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1220658249112671214, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1220655289922143078, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1345, endPage=1350, ext={EN=ArticleExt(id=1220655292631667535, articleId=1220655292103185224, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Impact of glycosylation on monoclonal antibody structure, function and related CMC regulatory considerations, columnId=1208489276405297283, journalTitle=Acta Pharmaceutica Sinica, columnName=New Drug Forum, runingTitle=null, highlight=null, articleAbstract=

Fc region of a monoclonal antibody usually contains two N-glycosylation, which have a profound influence on its structure and function. Here, we review the relationship between various glycoforms and their impact on structure and function of monoclonal antibodies, along with the technologies for glycosylation analysis. In addition, some related Chemistry, Manufacturing and Controls (CMC) regulatory considerations are also discussed, such as specification improvement, biosimilarity assessment as well as comparability of pre- and post-process changes in glycosylation.

, 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=Gang-ling XU, Wei WEI, Jian-hui LUO, Yu BAI), CN=ArticleExt(id=1220655293315339112, articleId=1220655292103185224, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=单抗药物N-糖基化修饰对结构功能影响及相关药学问题考量, columnId=1208489277814583462, journalTitle=药学学报, columnName=新药论坛, runingTitle=null, highlight=null, articleAbstract=

单克隆抗体Fc段上通常存在两个N-糖修饰，对单抗的结构和功能具有重要影响。本文对各种糖型与单抗结构和功能的关系以及糖基化分析研究方法进行综述，并讨论了糖型在质量标准建立和提高、工艺变更前后糖型可比性评价和单抗生物类似药糖型的相似性评价中的药学考量。

, correspAuthors=白玉, authorNote=null, correspAuthorsNote=
*白玉, Tel:86-10-85243041, E-mail:
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articleId=1220655292103185224, language=CN, orderNo=4, keyword=质量标准), Keyword(id=1220655295676731404, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292103185224, language=CN, orderNo=5, keyword=工艺变更), Keyword(id=1220655295769006098, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292103185224, language=CN, orderNo=6, keyword=生物类似药)], refs=[Reference(id=1220655296280711222, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1220655292103185224, doi=null, pmid=null, pmcid=null, year=2012, volume=7, issue=null, pageStart=1401, pageEnd=1413, url=http://d.old.wanfangdata.com.cn/NSTLQK/NSTL_QKJJ0227951696/, language=null, rfNumber=[1], rfOrder=0, authorNames=Jefferis R, journalName=Expert Opin Biol Ther, refType=null, unstructuredReference= Jefferis R . 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单抗药物N-糖基化修饰对结构功能影响及相关药学问题考量
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徐刚领 , 韦薇 , 罗建辉 , 白玉 *
药学学报 | 新药论坛 2020,55(6): 1345-1350
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药学学报 | 新药论坛 2020, 55(6): 1345-1350
单抗药物N-糖基化修饰对结构功能影响及相关药学问题考量
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徐刚领, 韦薇, 罗建辉, 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:
Impact of glycosylation on monoclonal antibody structure, function and related CMC regulatory considerations
Gang-ling XU, Wei WEI, Jian-hui LUO, Yu BAI*
Affiliations
  • Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
出版时间: 2020-06-12 doi: 10.16438/j.0513-4870.2019-1064
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摘要
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单克隆抗体Fc段上通常存在两个N-糖修饰，对单抗的结构和功能具有重要影响。本文对各种糖型与单抗结构和功能的关系以及糖基化分析研究方法进行综述，并讨论了糖型在质量标准建立和提高、工艺变更前后糖型可比性评价和单抗生物类似药糖型的相似性评价中的药学考量。

抗体药物  /  糖基化修饰  /  药学评价  /  质量标准  /  工艺变更  /  生物类似药

Fc region of a monoclonal antibody usually contains two N-glycosylation, which have a profound influence on its structure and function. Here, we review the relationship between various glycoforms and their impact on structure and function of monoclonal antibodies, along with the technologies for glycosylation analysis. In addition, some related Chemistry, Manufacturing and Controls (CMC) regulatory considerations are also discussed, such as specification improvement, biosimilarity assessment as well as comparability of pre- and post-process changes in glycosylation.

antibody drug  /  glycosylation  /  chemistry, manufacturing and controls review  /  specification  /  manufacturing process change  /  biosimilar
徐刚领, 韦薇, 罗建辉, 白玉. 单抗药物N-糖基化修饰对结构功能影响及相关药学问题考量. 药学学报, 2020 , 55 (6) : 1345 -1350 . DOI: 10.16438/j.0513-4870.2019-1064
Gang-ling XU, Wei WEI, Jian-hui LUO, Yu BAI. Impact of glycosylation on monoclonal antibody structure, function and related CMC regulatory considerations[J]. Acta Pharmaceutica Sinica, 2020 , 55 (6) : 1345 -1350 . DOI: 10.16438/j.0513-4870.2019-1064
正文
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免疫球蛋白为一种血清糖蛋白, 目前发现在人体中有IgM、IgA、IgD、IgG和IgE五个类型, 其中IgG由两个Fab段和一个Fc段构成, Fab可特异性结合识别的抗原, 而Fc则可以与不同的Fc受体或补体结合介导其效应子功能如抗体依赖的细胞介导的细胞毒性作用(antibody-dependent cell-mediated cytotoxicity, ADCC)、抗体依赖的细胞介导的细胞吞噬作用(antibody-dependent cellular phagocytosis, ADCP)或补体依赖的细胞毒性(complement dependent cytotoxicity, CDC)效应的发挥, 另外IgG在体内较长的半衰期则是通过其与内皮细胞上FcRn结合实现的。血清IgG的N-糖基化位于Fc片段的CH2区的共有序列(Asn297-X-Ser/Thr, X是除脯氨酸的任意氨基酸残基), 通过酰胺键与抗体共价结合, 其中30%在Fab也具有一个N-糖基化位点[1]。血清抗体的糖基化为复杂的双天线糖型, 并且可能具有分支N-乙酰葡糖胺结构。绝大部分单抗由CHO、SP2/0和NS0细胞表达, 并且大多只在重链Fc上的约297位具有N-糖基化位点(西妥昔除外), 且不包含分支N-乙酰葡糖胺结构。本文综述了糖型对单抗的结构影响、与ADCC、CDC效应的发挥以及半衰期和免疫原性的影响, 并讨论了在质量标准制定和提高、工艺变更前后糖型的可比性研究、生物类似药糖型相似性评价等需要予以关注和考虑的内容。
1 N-糖结构以及和功能的关系
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1.1 N-糖的结构
经典的单抗通常由两条重链和两条轻链组成, 一般在两条重链的297位或邻近的谷氨酰胺残基上具有N-糖修饰, 通过酰胺键与N-糖的非还原端N-乙酰葡萄糖胺(GlcNAc)连接。两个N-乙酰葡萄糖胺和3个甘露糖(Man)组成N-糖的核心五糖结构, 其还原端若再加和两个N-乙酰葡萄糖胺则为G0; G0基础上非还原端加和一个半乳糖(Gal)则为G1, G1有两种异构体, 分别为α-1, 6臂和α-1, 3-臂, 若加和两个半乳糖则为G2;若加和核心岩藻糖(Fuc)则分别为G0F、G1F、G2F。半乳糖非还原端还可加和唾液酸(Sia)或者半乳糖, 其中唾液酸可分为乙酰神经氨酸(N-acetylneuraminic acid, Neu5Ac)和羟乙酰神经氨酸(N-glycolylneuraminic acid, Neu5Gc)两种, 半乳糖则通过α-1, 3键连接, 此末端半乳糖简称为α半乳糖(α-gal)[2]。N-糖的复杂型结构如图 1所示。此外还有高甘露糖型和杂合型结构。
1.2 N-糖的结构可维持单抗的构象并影响Fc效应子功能
IgG-Fc晶体结构显示寡糖被包裹在两个CH2结构域内, 糖型结构和Fc结构域存在多个疏水性相互作用, 研究表明G0糖型与单抗Fc Cγ2结构域共有52个相互作用, 核心岩藻糖具有7个相互作用, α1-6臂上的半乳糖具有27个相互作用, 值得注意的是α1-3臂上糖并不与单抗表面接触, 而是深入两条重链Fc上所组成的空间内[3]。两条糖链α1-3臂上的甘露糖之间存在相互作用, 对维持单抗的构象十分重要。若无糖链存在, Fc的CH2结构域会稍微扩大, 导致在分子排阻色谱中其洗脱时间表现稍提前, 在热加速实验中表现为更敏感且容易聚集[4], 并且其ADCC和CDC效应消失[5], 对蛋白酶敏感性增强而不稳定[6]。罗氏公司的Atezolizumab单抗将重链297位天冬酰胺替换为丙氨酸, 使其极少与FcγR结合, 从而在人体内预期浓度下不产生Fc效应子功能[7]。
治疗用单抗一般都存在一定比例的非糖基化重链, 理论上其以半糖基化抗体形式存在, 即一条链糖基化另一条链则无糖基化。有文献[8]报道半糖基化抗体可以使其ADCC及CDC功能明显减弱, 提示对非糖基化重链比例的控制具有一定的意义。
1.3 N-糖结构与ADCC、ADCP的关系
Fc上N-糖可含有通过α1-6岩藻糖转移酶转移至核心N-乙酰葡糖胺上的核心岩藻糖[9], 而核心岩藻糖的缺失可使单抗Fc与FcγRⅢa结合力明显增强, 进而导致其ADCC效应明显增强[10], 所以在工程细胞中敲除α1-6岩藻糖转移酶可获得无核心岩藻糖单抗[11], Yamane-Ohnuki等[12]将CHO细胞的FUT基因敲除, 发明了生产无核心岩藻糖单抗的POTELLIGENT®技术, 目前国内企业研发的单抗MBS301[13]等产品即是采用此技术生产, 已有应用此技术生产的单抗mogamulizumab-kpkc (Anti-CCR4)获得FDA批准上市。另外分支N-乙酰葡萄糖胺的存在可阻碍核心岩藻糖的生成, 若在工程细胞中过表达β1-4-N-乙酰葡萄糖胺转移酶增加分支N-乙酰葡萄糖胺的合成, 也可使所表达单抗的ADCC效应增强[14], 其代表性技术为罗氏公司的Glycart-Roche技术, 已成功上市的Obinutuzumab (Anti-CD20)即为应用此技术所生产的单抗产品[7]。高甘露糖型N-糖可增强单抗的ADCC功能, 其机制可能也是由于高甘露糖型N-糖型缺少核心岩藻糖所致[15]。Fc上N-糖末端的唾液酸可减弱单抗的ADCC效应, 其机制可能是高唾液酸化可使单抗Fc与FcγRⅢa的结合力减弱, 另外高唾液酸化的N-糖可能变构铰链区, 使单抗的Fab从双价变成单价结合影响膜抗原[16]。
目前糖型对ADCP功能发挥的影响研究较少, 但有文献[17]报道FcγRⅡa是作为发挥ADCP效应的主要受体, 去除核心岩藻糖和末端半乳糖会增强ADCP效应, 含有末端Neu5Gc的糖型也会增强ADCP效应。
1.4 N-糖结构与CDC的关系
Fc上N-糖末端可能包含0、1或2个末端Gal残基(G0、G1或G2), 末端Gal含量通过增加抗体和C1q的结合力增加CDC效应, 但不影响抗体和FcγRIIIa的结合, 所以对ADCC活性没有影响。例如去除利妥昔单抗末端半乳糖可使其CDC效应减少一半[18], 所以有文献[19]强调了监测单抗Fc上N-糖末端半乳糖水平的重要性, 同时Gramer等[20]通过流加培养方式对GS-CHO进行发酵, 通过调节尿嘧啶、氯化锰和半乳糖的浓度, 可使单抗的半乳糖末端水平明显升高。另外Fc上含高甘露糖型N-糖单抗的CDC效应也减弱, 其机制可能为高甘露糖型N-糖其末端不含半乳糖[15]。但是目前只有利妥昔Fc上N-糖末端半乳糖水平与CDC关系的报道, 二者的关联关系是否在其他单抗上有所体现, 需要进一步实验验证。另外有研究表明Fc上具有高唾液酸N-糖的单抗其CDC活性降低, 这可能与唾液酸减弱C1q和Fc的结合有关[21]。
1.5 N-糖结构与单抗药物代谢的关系
抗体的长循环半衰期在很大程度上归因于它们与新生儿Fc受体(FcRn)结合, 血管内皮细胞、巨噬细胞等所表达的FcRn可以结合循环中的IgG, 经内体循环后可重新释放于血液, 从而保护单抗不被降解。FcRn和IgG的CH2/CH3结构域表面发生相互作用, 与糖型无关。和特异性的糖型有关介导蛋白结合和清除的受体包括无唾液酸糖蛋白受体(asialoglycoprotein receptor, ASGPR)和高甘露糖受体。
ASGPR可结合糖蛋白的末端半乳糖和N-乙酰葡萄糖胺[22], 可通过内吞作用介导糖蛋白的降解而降低糖蛋白的半衰期, 例如红细胞生成素(erythropoietin, EPO)等糖蛋白高唾液酸化后可避免其半乳糖暴露从而延长其半衰期。但是Fc上不同的糖基化类型并不能影响单抗的半衰期[23], 可能是由于N-糖位于单抗CH2结构域内部, 由于空间位阻并不能和ASGPR结合。近来也有文献报道高唾液酸修饰的糖型可能通过影响抗体空间构象而延长半衰期[24]。
甘露糖受体可结合糖蛋白末端的甘露糖[25], 同ASGPR相似, 可通过内吞作用介导糖蛋白的降解而降低糖蛋白的半衰期。有文献[26, 27]证明含高甘露糖型N-糖单抗的半衰期明显缩短, 但是同时有文献[28]证明高甘露糖型N-糖由于被血清中的甘露糖酶降解, 所表现的高甘露糖型单抗较少并不是单抗半衰期的缩短, 高甘露糖型可能并不会影响单抗的半衰期。虽然文献中有矛盾的表述, 但是主流观点仍然是高甘露糖型可缩短单抗的半衰期, 所以应注意对单抗高甘露糖型比例的控制。
1.6 N-糖结构与免疫原性的关系
许多因素会影响抗体的免疫原性, 包括蛋白序列变异体、变性失活、聚体、糖基化等。由于人类在进化过程中合成α-gal的基因缺失[29], 合成Neu5Gc的基因突变[30], 人体内存在抗α-gal和抗Neu5Gc的抗体, 抗α-gal的IgE抗体[31]和抗Neu5Gc抗体所介导的免疫反应均有报道。鼠源性细胞所表达的糖蛋白含有两种非人源单糖, 即α-半乳糖(α-gal, galactose-α-1, 3-galactose)和羟乙酰神经氨酸(Neu5Gc)[32], 其中中国仓鼠卵巢(CHO)细胞所表达的单抗只含有无法检测到或痕量水平α-gal[33]和Neu5Gc[34], 而鼠骨髓瘤细胞系(包括SP2/0和NS0细胞)所表达的单抗通常含有相对较高水平的α-gal和Neu5Gc[35, 36]。
由于目前上市的单抗有一定比例为SP2/0或NS0细胞所表达, 所以其表达的α-gal和Neu5Gc可能引起的不良反应值得注意。西妥昔单抗由SP2/0细胞表达, 除在Fc上有N-糖基化位点外, 在其Fab上也含N-糖, 其Fab上N-糖末端的α-gal可引起强烈的过敏反应[31], Neu5Gc也可引起免疫不良反应, 可使西妥昔的半衰期缩短。但是除西妥昔外, 其他绝大多数单抗只有Fc上含N-糖基化位点, 有文献证明单抗Fc上N-糖末端的α-gal并不能和人体内预存的抗α-gal的IgE抗体结合, 提示其α-gal并不能引起免疫不良反应[35]; 另外有研究表明, 只有部分Fc上含两个及以上的Neu5Gc的单抗才能和抗Neu5Gc抗体结合, 提示单抗Fc上的Neu5Gc只有微弱的免疫原性[37]。
1.7 高唾液酸型糖和抗炎作用之间的关系
由人血分离的天然抗体制备而成的静注人免疫球蛋白(intravenous immunoglobulin, IVIG)中可起到抗炎作用的成分主要是其中含有高唾液酸的组分[38], Anthony等[39]进一步证明其主要发挥作用的组分为具有高唾液酸化N-糖的Fc, 若用唾液酸酶去除IVIG的唾液酸, IVIG则完全失去抗炎作用。高唾液酸化使Fc结构变得更为紧密, 使其与FcγR的结合力变弱, 与一种免疫负调节的受体DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, DC-SIGN)结合力则变强, 从而起到抗炎作用, 上调免疫细胞表面抑制型FcγRIIb受体的表达从而起到抗炎作用[40]。这为单抗药物代替静注人免疫球蛋白的抗炎作用打开了大门, 但是值得注意的是, IVIG的Fc N-糖末端的唾液酸为α2-6连接, 也只有α2-6连接的末端唾液酸才能起到抗炎作用, 而CHO细胞表达单抗所含的唾液酸则为α2-3连接, SP2/0和NS0细胞表达单抗所含唾液酸则为α2-6连接。Hamilton等[41]发明了GlycoFi技术, 敲除酵母的4种酵母特异性糖合成相关基因, 并敲入14种异源性糖合成相关基因, 使酵母合成了具有Fc N-糖末端高唾液酸化的抗体。随着技术的进步, Fc上N-糖高唾液酸化的重组单抗可能会代替静注人免疫球蛋白的抗炎治疗作用。
2 N-糖的分析研究
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国内外的相关指导原则中均要求在产品特性分析中对糖型进行全面的分析, 目前蛋白质N-糖基化修饰可以在4个不同水平进行研究:第一种是通过质谱手段在完整糖蛋白水平或者蛋白亚基水平进行分析, 完整蛋白水平分析可获得蛋白分子量信息以及不同糖型的相对含量; 还原后的重链进行分析, 能获得更为准确的糖型以及其他如赖氨酸缺失、氧化等翻译后修饰的信息; 第二种是在糖肽水平进行分析, 可以获得糖基化修饰位点信息, 通常在蛋白含有多个糖基化位点时通常采用此方法; 第三种是将糖蛋白通过酶切或者化学法处理分析游离寡糖, 由于在碱性条件下进行肼解或经典的β消除反应特异性不强, 一般采用特异性酶切(如EndoH、PNGase F和PNGase A等)的方式将N-寡糖从蛋白上释放出来, 将游离N-糖进行荧光标记(2-AB、2-AA、APTS、叔胺-NHS氨基甲酸酯等), 再通过液相色谱或者毛细管电泳分析检测; 第四种为单糖分析, 使用外切糖苷酶阵列特异性地切断单糖之间糖苷键, 该方法可获得单糖的连接顺序和连接位置的信息, 但相对复杂较少应用。
3 糖型相关问题的考虑
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3.1 糖型质量标准建立和提高
质量研究是逐步递进的过程, 贯穿于产品的整个生命周期, 在产品研发早期应对可能具有Fc效应子功能的抗体(如针对膜抗原的IgG1单抗)糖型予以关注, 通过细胞来源筛选、细胞株的改造、培养过程中工艺参数的优化以及特定成分添减的控制等达到预期目的; 即使对尚未发现具有Fc效应子功能的抗体, 糖型的监控也可作为对工艺一致性和稳健性评价的参考性指标[42]。
随着临床研究的不断深入, 对其作用机制的认识也在逐渐清晰全面、不断深入, 如针对HER2靶点单克隆抗体药物, 早期认为主要通过Fab端结合HER2抑制信号通路阻断肿瘤细胞的生长, 所以在其质量标准中活性检测只包括了体外细胞增殖抑制活性, 但近年来研究表明ADCC机制在Her2单抗的抗肿瘤效应中也发挥了重要的作用。又如针对CD20靶点单克隆抗体药物, 研究表明B细胞溶解的可能机制包括CDC和ADCC效应, 而在目前质量标准中生物学活性的检项中仅对CDC活性进行分析。针对此类可能涉及多种作用机制而目前质量标准中只纳入某一活性检项且未对糖型进行控制的已上市品种, 鉴于糖型对ADCC、CDC效应有重要影响, 建议考虑将糖型纳入质量标准或增加相应生物学活性检测项目。
另外对于一些新靶点, 如抗CTLA-4单抗长期以来认为主要是通过阻断抑制性的CTLA-4/B7信号通路, 从而促进T细胞的激活而发挥抗肿瘤作用, 而近来研究表明抗CTLA-4抗体发挥治疗肿瘤功效的主要分子机制是通过巨噬细胞介导的ADCC和ADCP效应清除肿瘤局部的Treg细胞, 与当前流行的在癌症免疫治疗中针对CTLA-4分子的免疫检查点的理论假说[43, 44]相比较, 又取得了新的认知, 所以对该类产品质量控制中也应考虑增加对糖型的控制或增加相应的生物学活性评价方法。
对于理论上无ADCC和CDC作用或很弱的IgG4类抗体, 其作用机制依赖于抗体的Fab端的结合能力, 所以不同企业对于糖型的控制策略有所不同, 如目前国内已批准上市的5个抗PD-1抗体品种, 有2个品种的质量标准中纳入了糖型控制, 另外3个品种暂未纳入, 但是药学方面建议作为内控指标持续监控收集糖型数据, 以便为如有必要时纳入质量标准时或上市后变更可比性研究提供支持。
3.2 生产工艺变更前后糖型可比性评价
生物制品通常会在整个生命周期中发生生产工艺变更, 需按照ICH Q5E和NMPA发布的《已上市生物制品药学变更研究技术指导原则》等相关指导原则评估工艺变更前后的可比性[45], 而培养工艺参数(如培养基、发酵规模等)的变更、培养基改换、组分加入时机调整、发酵规模放大等可能会导致糖型发生变化, 其作为理化特性的一项关键指标, 也需要证实其变更前后的可比性。在进行糖型的可比性研究时, 通常选取变更前工艺具有代表性的多个批次的检测结果建立可比性接受标准(一般严于质量标准), 对变更后至少3批样品进行分析, 首先要确认变更前后糖型种类是否一致以及非糖基化重链的修饰比例变化, 对于不同糖型含量的可比性, 可采用统计学手段并结合历史数据进行分析, 目前运用的统计学方法包括EAC、平均值±nSD (考虑工艺和方法的变异性)等, 申请人需说明其合理性, 同时需关注统计学的差异是否会带来临床意义的差异。但是需要关注的是糖型可比性分析也应遵循基于作用机制的认知、生产检验数据积累与临床使用结果之间的关联性认识等, 采取“case-by-case”的原则, 对于具体品种需重点分析对可能会影响产品质量的糖型。
3.3 抗体类生物类似药糖型相似性评价
糖基化是生物体内最为重要的蛋白质翻译后修饰形式之一, 在抗体类药物的生物学功能、半衰期和免疫原性中发挥着重要作用。糖基化的比对分析也是抗体生物类似药与原研药质量相似性评估的重要内容之一。抗体类生物类似药与原研药N-糖基化比对研究至少应包括4个方面:糖基化位点(LC-MS)、非糖基化重链(还原CE-SDS)含量、N-糖类别(LC-MS)和N-糖相对含量(UPLC、HPLC或CE等)。
目前国际上领先的抗体类生物类似药研发公司通常会选取多批(通常大于十批甚至几十批)原研药进行分析建立相似性范围, 在进行糖型相似性评价时首先要确认糖基化位点、分析糖型类别是否具有差异, 再对糖型的含量进行相似性评价, 重点关注和生物学功能、半衰期和免疫原性有关的糖型含量(如上文所述高甘露糖型、末端半乳糖型、非岩藻糖型、末端唾液酸)。若糖型分析存在一定差异, 可通过和FcγR、C1q的结合能力以及ADCC、ADCP、CDC活性进一步说明是否有差异, 若仍有差异还需综合分析原研药和生物类似药的糖型的差异是否在PK、安全性、有效性和免疫原性等方面具有临床意义。
前几年在国内研发申报的抗体类生物类似药的高潮期和追逐期, 对研发期间变更引入风险的重要性认识不够, 加上临床患者又亟需, 因此, 在申报临床阶段时工艺规模较小或工艺参数研究不充分, 在临床试验期间进行了工艺优化、工艺规模的放大、场地转移等变更, 极易发生与糖基化修饰相关的质量属性漂移, 由此可能导致商业化规模样品和临床前试验用样品、早期临床样品糖型和其他质量属性存在差异, 这对上市后产品质量的控制、风险防范及基于整体证据的相似性评价带来了挑战, 所以提请研发者对于研发各阶段, 例如临床试验前、临床试验期间、注册上市申请及上市后变更的设计考虑不同于创新单抗类制品, 尽早在申报临床前开展充分的比较研究, 在申报临床阶段采用拟商业化的生产工艺和生产规模, 尽可能避免在临床试验期间及上市后早期阶段的匆忙变更, 若必须变更, 申请人需要开展更多的衔接性比较研究, 例如非临床批次、关键临床批次和商业化生产批次之间的可比性, 以及与原研药的相似性。
另外在相似性评价中还需关注原研药糖型分布的“偏移”, Sandoz公司对效期在2007~2011年利妥昔单抗进行糖型分析, 发现效期在2010年5月至2011年期间的产品G0糖型含量约增加3倍, 导致ADCC效应增强; 依那西普效期在2009年底至2011年的G2F糖型含量前由2009年底前的50%降至30%[46]; Samsung Bioepis发现赫赛汀有效期至2018年10月(欧盟来源)和2018年08月(美国来源)的批次开始, 观察到非岩藻糖型和高甘露糖型比例的增加[47]。建议申请人关注, 收集更多、时间跨度更大的批次, 全面了解原研药的质量属性范围, 建立严谨、基于充分数据支持的相似性评价标准。
4 结语
收起
单抗复杂的翻译后修饰可使其具有1×108以上的变异体, 其中糖基化修饰的异质性对其结构和功能具有至关重要的作用。核心岩藻糖的缺失(包括高甘露糖型所伴随核心岩藻糖缺失)和分支N-乙酰葡萄糖胺的存在与单抗的ADCC效应正相关, N-糖的唾液酸修饰则与其呈负相关; 末端半乳糖水平与单抗的CDC效应正相关; 高甘露糖型可使单抗的半衰期缩短; 单抗Fc上的N-糖末端异源性单糖α-gal尚未见报道对人的免疫原性, Neu5Gc的免疫原性则较低; Fc上N-糖高唾液酸的抗体具有抗炎作用。这些不同N-糖类型对抗体功能的影响对指导单抗生产工艺以及质量控制具有重要实践意义, 同时在产品质量标准建立和提高、单抗生物类似药糖型的相似性评价和工艺变更前后糖型可比性评价中应予以关注。
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2020年第55卷第6期
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doi: 10.16438/j.0513-4870.2019-1064
  • 接收时间：2019-12-26
  • 首发时间：2026-01-21
  • 出版时间：2020-06-12
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  • 收稿日期：2019-12-26
  • 修回日期：2020-03-05
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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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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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