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Article(id=1200860509818966132, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-1324, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1700755200000, receivedDateStr=2023-11-24, revisedDate=1712764800000, revisedDateStr=2024-04-11, acceptedDate=null, acceptedDateStr=null, onlineDate=1764237056449, onlineDateStr=2025-11-27, pubDate=1715443200000, pubDateStr=2024-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764237056449, onlineIssueDateStr=2025-11-27, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764237056449, creator=13701087609, updateTime=1764237056449, updator=13701087609, issue=Issue{id=1200860506031518620, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='5', pageStart='1101', pageEnd='1508', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764237055547, creator=13701087609, updateTime=1764241222263, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200877982563824311, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200877982563824312, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1210, endPage=1217, ext={EN=ArticleExt(id=1200860510783656068, articleId=1200860509818966132, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress on nanobody-drug conjugate, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Antibody-drug conjugate (ADC) has become an effective method for treating various diseases, especially cancer, due to its clear target and good selectivity in clinical practice. However, the monoclonal antibodies in traditional ADC have poor tissue permeability, high modification costs, pose risks such as immunogenicity and immunotoxicity. The nanobody (Nb) which is extracted from the blood of camel animals, is the smallest antibody fragment known to have complete antigen binding ability. It has advantages such as strong tissue permeability, strong specificity, low immunogenicity, and high stability, and can replace traditional monoclonal antibodies to participate in the construction of nanobody-drug conjugate (NDC). This article reviews and discusses the advantages of Nb structure, the construction and application of NDC in the hope of providing ideas for the research and development of NDC.

, correspAuthors=Yu-lin LIU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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=Xue-yan ZHANG, Bai-song ZHOU, Yu-lin LIU), CN=ArticleExt(id=1200860511882563786, articleId=1200860509818966132, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=纳米抗体偶联药物的研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

抗体偶联药物(antibody-drug conjugate, ADC) 因其具有靶点清晰、特异性强等优点已成为临床上治疗多种疾病尤其是癌症的有效手段。但传统ADC中的单克隆抗体组织渗透能力差, 存在免疫原性和免疫毒性等风险, 且改造成本高。由驼科动物血液中提取的纳米抗体(nanobody, Nb) 是目前已知具有完整抗原结合能力的最小抗体片段, 具有组织渗透能力强、免疫原性低、特异性强、稳定性高等优势, 可以代替传统单克隆抗体参与构建纳米抗体偶联药物(nanobody-drug conjugate, NDC)。本文从纳米抗体结构优势、NDC的构建、纳米抗体偶联物的应用三个方面进行综述与讨论, 以期为NDC的研究与发展提供思路。

, correspAuthors=刘玉林, authorNote=null, correspAuthorsNote=
*刘玉林, Tel: 17743444656, E-mail:
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Xianyang: Northwest A & F University, 2021., articleTitle=null, refAbstract=null)], funds=[Fund(id=1201106655116223378, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, awardId=20210204092YY, language=CN, fundingSource=吉林省科技发展计划基金项目(20210204092YY), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1201106647738442259, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, xref=null, ext=[AuthorCompanyExt(id=1201106647746830868, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, companyId=1201106647738442259, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Changchun Institute of Biological Products Co., Ltd., Changchun 130012, China), AuthorCompanyExt(id=1201106647759413783, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, companyId=1201106647738442259, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=长春生物制品研究所有限责任公司, 吉林 长春 130012)])], figs=[ArticleFig(id=1201106652050186950, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, language=EN, label=null, caption=null, figureFileSmall=wnCdbnS6aRGbmedU0FauqA==, figureFileBig=QGOgJyBRUfd8aLsF1lSHDA==, tableContent=null), ArticleFig(id=1201106652188598995, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, language=CN, label=Figure 1, caption= Structural characteristics of Nb (Green: FR area; Red: CDR1; Yellow: CDR2; Blue: CDR3). A: Nb <i>β</i>-sandwich structure; B: The CDR3 of the nanoantibody exhibits a finger-shaped structure that penetrates deeply <i>β</i>2 adrenergic receptor active pockets and stabilize their active conformation (PDB ID: 3P0G). 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CharacteristicADCNDC
FeatureMonoclonal antibodyNb
Specificity+++++++
Immunogenicity+++++
Solubility++++++
Tissue penetration+++++
Drug delivery+++++
Stability+++++
Production costsHighLow
Technology roadmapMatureLimited
Listed productsMultiple listed productsNone listed product
), ArticleFig(id=1201106652771607318, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, language=CN, label=Table 1, caption=

Comparison of ADC and NDC. ADC: Antibody-drug conjugate; NDC: Nanobody-drug conjugate; Nb: Nanobody; +: Weak; ++: Medium; +++: Second strong; ++++: Strong

, figureFileSmall=null, figureFileBig=null, tableContent=
CharacteristicADCNDC
FeatureMonoclonal antibodyNb
Specificity+++++++
Immunogenicity+++++
Solubility++++++
Tissue penetration+++++
Drug delivery+++++
Stability+++++
Production costsHighLow
Technology roadmapMatureLimited
Listed productsMultiple listed productsNone listed product
), ArticleFig(id=1201106654000538402, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
NameApplication areaStudy phaseTargeted receptor
Nb-PS conjugatesPDTPreclinicalTumor cell
f [131I]SGMIB-2Rs15dCancer treatmentPreclinicalHER2
Pt-NGC, Pt-NGCACancer treatmentPreclinicalHER2
ENb-TRAILReshaping TIMEPreclinicalTumor cell
IL 2-anti-PD-L1 VHHReshaping TIMEPreclinicalPD-L1
IFNγ-anti-PD-L1 VHHCancer treatmentPreclinicalPD-L1
VGRNb-PECancer treatment, reshaping TIMEPreclinicalTumor vasculature
[68Ga]Ga-THP-APN 09RIIRecruitmentSolid tumor
PD-L2-Nb probeRIIRecruitmentSolid tumor
CLDN18.2-Nb probeRIIRecruitmentSolid tumor
), ArticleFig(id=1201106654176699189, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, language=CN, label=Table 2, caption=

Examples of research progress on NDC. PDT: Photodynamic therapy; HER2: Human epidermal growth factor receptor 2; TIME: Tumor immune microenvironment; RII: Radioimmunoimaging; IL: Interleukin; IFN: Interferon

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NameApplication areaStudy phaseTargeted receptor
Nb-PS conjugatesPDTPreclinicalTumor cell
f [131I]SGMIB-2Rs15dCancer treatmentPreclinicalHER2
Pt-NGC, Pt-NGCACancer treatmentPreclinicalHER2
ENb-TRAILReshaping TIMEPreclinicalTumor cell
IL 2-anti-PD-L1 VHHReshaping TIMEPreclinicalPD-L1
IFNγ-anti-PD-L1 VHHCancer treatmentPreclinicalPD-L1
VGRNb-PECancer treatment, reshaping TIMEPreclinicalTumor vasculature
[68Ga]Ga-THP-APN 09RIIRecruitmentSolid tumor
PD-L2-Nb probeRIIRecruitmentSolid tumor
CLDN18.2-Nb probeRIIRecruitmentSolid tumor
), ArticleFig(id=1201106654357054287, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860509818966132, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
ClinicalTrials.gov IDApplication areaLinkerDrug
NCT05436093RIIRadiolabel18F-FDG
NCT05156515RIIRadiolabelNuclide 68Ga
NCT05803746RIIRadiolabel18F-FDG
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Clinical typical examples of NDC

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ClinicalTrials.gov IDApplication areaLinkerDrug
NCT05436093RIIRadiolabel18F-FDG
NCT05156515RIIRadiolabelNuclide 68Ga
NCT05803746RIIRadiolabel18F-FDG
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纳米抗体偶联药物的研究进展
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张雪嫣 , 周柏松 , 刘玉林 *
药学学报 | 综述 2024,59(5): 1210-1217
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药学学报 | 综述 2024, 59(5): 1210-1217
纳米抗体偶联药物的研究进展
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张雪嫣, 周柏松, 刘玉林*
作者信息
  • 长春生物制品研究所有限责任公司, 吉林 长春 130012

通讯作者:

*刘玉林, Tel: 17743444656, E-mail:
Research progress on nanobody-drug conjugate
Xue-yan ZHANG, Bai-song ZHOU, Yu-lin LIU*
Affiliations
  • Changchun Institute of Biological Products Co., Ltd., Changchun 130012, China
出版时间: 2024-05-12 doi: 10.16438/j.0513-4870.2023-1324
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摘要
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抗体偶联药物(antibody-drug conjugate, ADC) 因其具有靶点清晰、特异性强等优点已成为临床上治疗多种疾病尤其是癌症的有效手段。但传统ADC中的单克隆抗体组织渗透能力差, 存在免疫原性和免疫毒性等风险, 且改造成本高。由驼科动物血液中提取的纳米抗体(nanobody, Nb) 是目前已知具有完整抗原结合能力的最小抗体片段, 具有组织渗透能力强、免疫原性低、特异性强、稳定性高等优势, 可以代替传统单克隆抗体参与构建纳米抗体偶联药物(nanobody-drug conjugate, NDC)。本文从纳米抗体结构优势、NDC的构建、纳米抗体偶联物的应用三个方面进行综述与讨论, 以期为NDC的研究与发展提供思路。

纳米抗体  /  抗体偶联药物  /  纳米抗体偶联药物

Antibody-drug conjugate (ADC) has become an effective method for treating various diseases, especially cancer, due to its clear target and good selectivity in clinical practice. However, the monoclonal antibodies in traditional ADC have poor tissue permeability, high modification costs, pose risks such as immunogenicity and immunotoxicity. The nanobody (Nb) which is extracted from the blood of camel animals, is the smallest antibody fragment known to have complete antigen binding ability. It has advantages such as strong tissue permeability, strong specificity, low immunogenicity, and high stability, and can replace traditional monoclonal antibodies to participate in the construction of nanobody-drug conjugate (NDC). This article reviews and discusses the advantages of Nb structure, the construction and application of NDC in the hope of providing ideas for the research and development of NDC.

nanobody  /  antibody-drug conjugate  /  nanobody-drug conjugate
张雪嫣, 周柏松, 刘玉林. 纳米抗体偶联药物的研究进展. 药学学报, 2024 , 59 (5) : 1210 -1217 . DOI: 10.16438/j.0513-4870.2023-1324
Xue-yan ZHANG, Bai-song ZHOU, Yu-lin LIU. Research progress on nanobody-drug conjugate[J]. Acta Pharmaceutica Sinica, 2024 , 59 (5) : 1210 -1217 . DOI: 10.16438/j.0513-4870.2023-1324
正文
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21世纪初, 随着首个抗体药物偶联物(antibody-drug conjugate, ADC) (商品名Mylotarg, Pfizer研发) 问世并被FDA批准用于治疗急性粒细胞白血病[1], ADC靶向治疗便成为了肿瘤研究领域的热点。但抗体分子作为生物大分子, 其本身存在一般生物大分子的毒性风险, 如抗体依赖性细胞介导细胞毒性(antibody dependentcell mediatedcytotoxicity, ADCC)、补体依赖性细胞毒性(complement dependent cytotoxicity, CDC)、肾基底膜免疫复合物沉积等。这些毒性风险影响了ADC的稳定性, 参与构建的抗体免疫原性越强, ADC的体内稳定性越弱[2]。同时, 在ADC药物中, 抗体分子最重要的作用是靶向作用, 如果抗体选择性较差, 则会造成细胞毒药物投递到正常细胞中, 造成靶向毒性。所以构建ADC药物的理想抗体应兼具特异性和安全性。
近几十年, 纳米抗体(nanobody, Nb) 逐渐进入了人们的视野。1989年比利时科学家首次在骆驼血液中发现纳米抗体[3, 4], 其是一种分子质量只有15 kDa, 在羊驼外周血液中存在的天然缺失轻链的抗体, 该抗体只包含一个重链可变区(VHH) 和两个常规的CH2与CH3区, VHH是已知的可结合目标抗原的最小单位[5]。纳米抗体具有溶解性好, 不易聚集, 耐高温、酸、碱等致变性条件的特点, 适合于原核表达和各种真核表达系统, 在保留了抗体特异性的同时兼具小分子药物的特点, 避免了生物大分子毒性的缺陷; 2007年由Ablynx研发的首个纳米抗体进入临床试验[6]; 国内, 康宁杰瑞制药于2016年申报KN-035产品(PD-L1靶点, 单链抗体FC融合) 临床试验, 并在2021年在中国获批上市(全球首个皮下注射的纳米抗体药物)。利用纳米抗体取代传统抗体, 建立纳米抗体-药物偶联体系、研制纳米抗体偶联药物(nanobody-drug conjugate, NDC) 成为研究的热点。与ADC相比, NDC具有免疫原性弱、组织穿透能力强、稳定性高、生产成本低等优势。表 1对比了ADC与NDC的特点。
1 纳米抗体的结构特点
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纳米抗体的二级结构是由9条p折叠片段及连接的loop区通过一对二硫键形成的典型的β-夹心结构(图 1A), 其抗原结合区由3个互补性决定区(complementarity determining region, CDR) 组成, CDR区被4个相对保守的框架区(framework regions, FR) 包围[7]。特殊的结构特点增加了NDC对靶细胞的渗透能力, 易于穿透组织和血脑屏障[8], 减小药物的损失, 降低服药剂量, 减小毒副反应。在传统抗体中, 抗原结合区域由VH与VL的6个CDR区组合而成[9], 由于纳米抗体缺失VL, 其抗原结合区仅由3个CDR区组成, 在空间上可呈突出的指状结构[10]。如图 1B所示, 纳米抗体可以利用指状结构, 识别一些常规抗体无法接近的抗原表位, 从而改变其活性[11]。这个特点使NDC比ADC具有更强的特异性。
纳米抗体表面有数个疏水氨基酸残基被亲水氨基酸残基替换, 从而改变了其表面形状, 降低了聚集性, 使其具有更好的水溶性、亲水性[10]。此外, 纳米抗体常在CDR3上形成另一对二硫键, 增强了CDR区的刚性, 使得纳米抗体的抗逆性和稳定性显著增强[12]。因此, 纳米抗体具有稳定性好, 可用于正电子发射型计算机断层显像(positron emission computed tomography, PET) 成像[13]; 免疫原性低[14]等优势。有些纳米抗体可以抵抗消化酶的降解; 或是耐受盐酸胍、尿素等变性剂; 或是经过高温处理而不变性[15, 16]。这些特性使NDC具有更好的环境耐受性, 抗逆性与稳定性大大增强, 并且具有耐受消化酶的特点, 一定程度上缓解了传统抗体偶联药物无法口服给药或口服给药困难的问题。
2 纳米抗体偶联药物的构建
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NDC的发展主要取决于其各个参数的优化, 在理想的情况下, 抗体应能特异性结合到目标蛋白或细胞上而不与其他细胞或蛋白结合。NDC的连接方法决定了药物负载的化学计量和均匀性, 同时在药动学、活性及耐受性中扮演重要角色[17]。纳米抗体以连接子与小分子药物相连, 共同构成一个完整的NDC。
2.1 纳米抗体的筛选
设计NDC首先需要筛选出合适的纳米抗体, 作为载体负载偶联药物特异性地与靶细胞或靶蛋白结合。
蛋白展示平台构建纳米抗体文库, 从中筛选出目的抗体基因后进行重组表达是现在常用的方法。现有的蛋白展示平台有噬菌体展示、核糖体展示、大肠杆菌展示、酵母菌展示、哺乳动物细胞展示和反转录病毒展示等[7]。这些不同的蛋白展示平台在一定程度上既有相似性和共通性, 又各有其优缺点和应用领域[18]。
噬菌体展示技术是一种经典的表达技术, 该技术是在1990年建立和发展起来的, 是诸多蛋白展示平台中开发最早、技术最成熟、操作简单, 并且是目前使用最广泛的展示平台[19]。它是将外源抗体片段与噬菌体的衣壳蛋白融合, 将其展示在噬菌体表面, 筛选特异性抗原的抗体, 通过原核表达可以大规模生产抗体[20], 为抗体的大量、快速生产提供了技术手段[21]。常用的M13噬菌体(丝状噬菌体) 结构如图 2所示, 含有5种结构蛋白, 其中pⅢ蛋白和pⅧ蛋白可用于外源蛋白展示, 构建了pⅢ和pⅧ展示系统[22], pⅢ蛋白参与对宿主的识别和侵染, 可在N端的柔性区插入并展示一些较大的多肽和蛋白质[23]。主流纳米抗体文库一般选用M13噬菌体的pⅢ系统作为展示平台[24]。
利用噬菌体展示技术筛选相应的纳米抗体是非常高效和快速的方法, 免疫的方案可以缩短至6周以内[25]。为了提高转化效率, 噬菌粒载体pCOM3和pHEN被成功制得, 并与辅助噬菌体联用于制备单价纳米抗体展示文库[26]。构建的纳米抗体文库的大小及多样性是获得高亲和力纳米抗体的前提, 此外, 新鲜血液的采集和mRNA及cDNA制备的质量是构建高质量文库的关键[27]。
除了噬菌体展示技术外, 核糖体或mRNA展示技术、酵母或细菌表面展示技术和酵母双杂交筛选技术等[28]也成功应用到抗体生产中。核糖体展示技术利用功能性蛋白质的相互作用, 将mRNA与其转录翻译后正确折叠的蛋白质共同连接在核糖体上, 形成“mRNA-核糖体-蛋白质”三元复合物, 实现基因型与表型的偶联。核糖体展示技术具有全程在体外操作、多样性好的优势。已广泛应用于小分子抗体的筛选和进化[29]。在酵母和细菌系统中, 每一轮反转录聚合酶链式反应(reverse transcription-PCR, RT-PCR) 后, 可能会引入序列的微小突变, 这样有利于筛选结合力更强的抗体[30]。与其他筛选方法相比, 利用细菌或酵母系统形成的展示技术建库简单、库容量较大, 筛选简便, 也是较为理想的筛选技术。
2.2 纳米抗体的表达纯化
纳米抗体的表达量依赖受体细胞的选择, 大肠杆菌[31]、毕氏酵母或HEK293细胞都是目前最常用的蛋白表达系统, 由于其优良的表达能力, 它们广泛应用于重组蛋白尤其是药用重组蛋白的表达生产中[32]。
相较毕氏酵母和HEK293细胞, 大肠杆菌作为基因工程受体菌具有许多优点: ①培养条件简单、培养周期短; ②易于高密度发酵; ③重组蛋白质表达水平极高; ④极低培养成本等[33]。因此, 大肠杆菌成为纳米抗体表达纯化最常用的菌种。
2.3 连接子技术的选择
连接子是连接抗体与细胞毒药物的桥梁。NDC有多种连接形式, 纳米抗体与细胞毒性药物之间可通过转肽酶SrtA、点击化学、马来酰亚胺与巯基反应等方式偶联[34]。根据连接子性质差异可大致分为两类: 可裂解连接子和不可裂解连接子, 二者在传统ADC药物的第2、3代均有应用[35], 通常使用化学共价键如二硫键、肽键、硫醚键等实现抗体和毒性小分子药物的连接[36], 这类连接子属于可裂解连接子。另一种连接子其偶联的负载的释放并不依赖于血浆和某些胞质腔室性质的不同[37], 这类连接子被认为是不可裂解的连接子, 不可裂解连接子所链接的抗体在靶细胞的溶酶体内水解后仍与药物共价连接[38, 39]。理想的连接物在外周血液循环中要足够稳定, 避免因细胞毒分子释放而产生毒性。
2.3.1 可裂解连接子
可裂解连接子分为3种类型: ①酸依赖性腙键(代表性药物如Mylotarg); ②氧化还原依赖的二硫键; ③可酶切肽键[35]。腙类连接子和二硫化物连接子在设计上利用了血浆与一些胞质腔室之间性质上的差异[37]。促进腙连接子释放药物的胞内条件是内涵体和溶酶体的酸性环境[40], 而二硫化物连接子因其含有高浓度的巯基(如谷胱甘肽) 将在细胞质中被还原[39, 41-43]。与之相比, 利用基于肽的连接子技术可以更好地控制药物的释放[37]。由于血液中存在内源性抑制剂, 且血液pH高于溶酶体内pH, 溶酶体蛋白水解酶在血液中的活性极低[44], 因此预计肽键具有良好的血清稳定性。根据临床前体内研究发现, 肽连接子具有更高的循环内稳定性, 且靶细胞内可实现药物的快速酶释放[45]。2021年, Fan等[46]开发了一种四价双互补位的表皮生长因子受体(epidermal growth factor receptor, EGFR) 特异性NDC, 该NDC能够串联表达纳米抗体7D12和9G8, 细胞毒性药物monomethyl auristatin E (MMAE) 与7D12上的半胱氨酸偶联, 如此构建的NDC由于拥有多个结合界面, 可克服临床上出现的EGFR耐药性。2022年, Bao等[34]利用一个八氨基酸肽链GGG-VC-PAB作为连接子, 成功获得偶联细胞毒性药物MMAE的NDC: JVZ-0072-VC-PAB-MMAE, 结果表明, 该NDC具备特异性杀伤前列腺特异性膜抗原(prostate-specific membrane antigen, PSMA) 阳性肿瘤细胞的能力。
2.3.2 不可裂解连接子
由不可裂解连接子(如硫醚键的代表性药物Kadcyla) 参与的ADC细胞毒性药物的释放发生在进入溶酶体腔室之后, 通过胞内蛋白水解将抗体降解到氨基酸水平[39], 这一过程释放出了药物衍生物, 这种衍生物由细胞毒性药物、连接子和与连接子共价连接的氨基酸残基所组成。只有当释放出的药物代谢产物能够作为细胞毒性药物的活性组分发挥作用时, 方可认为不可裂解的连接子已被成功利用[38, 43, 47]。
不可裂解的连接子优势在于血液环境中更加稳定, 仅在溶酶体中切割释放细胞毒素, 安全性明显更好, 然而不可切割连接子通常会残留在细胞毒素上, 影响其杀伤活性及细胞穿透性, 因而对周围的异质性肿瘤细胞杀伤作用有限, 不能充分发挥旁观者效应[35]。
传统的ADC是将药物偶联在抗体的赖氨酸残基或二硫键还原而产生的半胱氨酸残基上, 这种连接方式不仅会导致药物抗体偶联比(即每个抗体分子上偶联的药物数目, DAR) 不均一及连接位点不一致等问题, 而且通过打开的链间二硫键偶联会破坏抗体的完整性[48-52]。这不仅制约了NDC的研发和生产, 还降低了NDC的疗效甚至产生未知的毒副反应。
近年来, 有研究者采用基因工程技术对抗体进行改造, 从而实现抗体与小分子药物的定点偶联, 所得到的偶联物不仅具有均一的偶联比还表现出极好的体内药动学性质, 大大提高了疗效[53]。纳米抗体体内半衰期短, 传统连接物不能达到目的, 因此将纳米抗体进行改造以延长半衰期、加强药效的方法正逐渐成为研究NDC的新思路。
3 应用
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3.1 纳米抗体的应用
纳米抗体由于其结构特点, 在疾病诊断和治疗等各方面的应用中发挥了独一无二的优势: ①在组织中溶解度高[54], 适合于分子影像诊断实体肿瘤[55]; ②可以克服血脑屏障(blood brain barrier, BBB), 为治疗脑部疾病提供解决方法[56]; ③抗逆性强[57], 可以实现口服给药、检测与鉴别较难检出的靶点及外来病原物或毒素[58, 59]; ④易于进行化学修饰[60], 实现肿瘤细胞疗法上的应用; ⑤具有良好的肿瘤特异性, 可作为给药载体[61, 62]; ⑥易于定点偶联且可以通过原核表达系统大量制备, 可用于蛋白质纯化配体, 降低吸附剂成本[63]。
纳米抗体可以作为蛋白药物, 比利时Ablynx公司的卡普赛珠单抗(caplacizumab) 是全球第一个上市的纳米抗体药物, 已被美国食品药品监督管理局(FDA) 列入标准治疗方案中[64, 65]。中国康宁杰瑞公司开发的程序性细胞死亡配体-1 (programmed cell death 1 ligand, PD-L1) 纳米抗体KN035可用于治疗胆道癌, 已完成Ⅲ期临床, 并于2020年1月被FDA授予孤儿药资格[66, 67]。
3.2 纳米抗体偶联药物的应用
在肿瘤治疗方面, 由于ADC可以特异性地向肿瘤部位输送强效的化疗药物的特点[55], 已经有至少9种ADC已被批准用于癌症治疗[68], 超过100种ADC正在进行临床试验, 更多的ADC也正处于临床前研发阶段[69]。但由于ADC单克隆抗体分子尺寸较大, 难以从血管壁渗出和进入实体肿瘤的特点, 以纳米抗体代替单克隆抗体, 构建NDC药物, 为靶向癌症治疗中药物偶联提供了新的解决方案, 如表 2列举的一些NDC研究进展实例。
2016年, Fang等[70]通过将细胞毒性药物DM1偶联到靶向小鼠Ⅲ类主要组织相容性复合体抗原(the mouse major histocompatibility complex class Ⅲ, MHC-Ⅲ) 的纳米抗体(VHH7) 上, 首次提出NDC的概念。通过sortase酶催化将甘氨酸修饰的美登素(mertansine, DM1) 与C端含有LPETGG-His6标签的VHH7连接, 以位点特异性偶联的方式得到了偶联物VHH7-DM1, 研究发现VHH7-DM1在动物水平上有效地抑制了肿瘤的生长和转移, 且没有明显的全身毒性。Stenton等[71]通过可剪切的双功能连接剂将抗HER2纳米抗体(2Rb17c) 与聚乙二醇化的多柔比星前药结合, 构建了一个NDC体系。该体系选择性地对HER2阳性的肿瘤细胞具有较高的毒性, 产生了较好的治疗效果。铀类抗肿瘤药物由于存在非特异性的靶向作用, 在给药时会产生严重的不良反应。Huang等[72]构建了一种基于铂的肿瘤靶向治疗的NDC。利用纳米抗体的优点, 实现了具有不同功能的蛋白质结构域的融合。双价的抗EGFR纳米抗体7D12-9G8可以特异性结合EGFR受体, 并在融合蛋白C端引入C3-tag (Cys-Cys-Cys) 进行位点特异性的铂药偶联, 将铂类药物特异性地传递到EGFR阳性的肿瘤细胞中, 选择性诱导细胞凋亡; 钆结合蛋白ProCA32实现肿瘤MRI成像功能; 抗血清白蛋白纳米抗体Albl用来延长NDC在体内的保留时间, 进一步增强了药效。该NDC的应用效果在细胞和动物模型上都得到了验证。这是关于多功能NDC的首次报道, 不同功能的融合体现了纳米抗体在靶向给药应用中的优势, 弥补了传统ADC的不足, 为后续NDC的研究方向提供了新的可能。
除了靶向递送化疗药物外, 纳米抗体还可与光敏剂(photosensitizer, PS) 连接以增强PDT对肿瘤的特异性。Heukers等[73]将光敏剂IRDye700DX与双价抗EGFR纳米抗体(7D12-9G8) 偶联。基于细胞水平的检测结果表明, 该NDC可特异性诱导EGFR阳性细胞的光毒性, 并在药物低至纳摩尔浓度的条件下光照杀死肿瘤细胞。体内实验也表明, 该NDC可选择性诱导小鼠肿瘤模型上的肿瘤细胞死亡。Beltrán Hernández等[74]在研究中发现, 由于7D12-PS的PDT作用导致肿瘤细胞坏死, 而死亡细胞的损伤相关分子模式可导致抗肿瘤免疫。7D12-PS也会引起EGFR阳性细胞树突状细胞的成熟和CD4+ T细胞的活化, 表明纳米抗体-光敏剂模式的NDC不仅可以对原发肿瘤造成损伤, 还可诱导机体免疫反应来对抗肿瘤转移和防止肿瘤复发。
除上述两种NDC, 纳米抗体还可与放射性核素偶联用以靶向放射性核素治疗(targeted radionuclide therapy, TRNT), 其是将细胞毒性放射性核素输送到癌细胞, 同时将健康组织暴露在最低程度上。2017年, D'Huyvetter等[75]报道了一种131I标记的抗HER2纳米抗体作为HER2过表达癌症治疗的治疗工具。小鼠模型中生物分布测定表明, 131I-Nb在肿瘤中具有特异性积累和良好的滞留效应, 能够显著延长小鼠的生存期, 而且毒副反应较低。Pruszynski等[76]通过p-SCN-Bn-DOTA连接225Ac和2Rsl5d构建了HER2靶向的TRNT, 可定位于HER2过表达的SKOV-3肿瘤细胞, 并在接触周围健康组织最少的情况下提供较高的细胞致死能力。除此之外, 纳米抗体与放射性核素偶联可用于实体肿瘤的RII, 3种用于免疫成像的NDC药物已进入临床阶段, 它们的偶联方法均为与放射性核素连接, 携带药物分别为氟代脱氧葡萄糖(fludeoxyglucose, 18F-FDG)、核素68Ga、18F-FDG (表 3)。
这些结果表明, 纳米抗体与放射性核素连接的NDC既可以有效用于靶向TRNT, 也可以形成探针, 用于肿瘤免疫成像, 为NDC的应用提供更多可能。
除了在肿瘤治疗与成像方面的应用, 在其他疾病治疗上, NDC同样是研究的热点。Zhao等[77]设计并开发了一种基于刚性共轭聚合物的多价NDC, 用以对阿尔茨海默症高效多靶点的治疗和干预, 拓宽了NDC的应用领域, 为其他疾病治疗和药物研究提供更多可能性。
4 总结与展望
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NDC兼具ADC药物的高特异性和强效作用, 又具备纳米抗体自身的小分子、易于修饰、免疫原性小等优势, 是未来重组蛋白药物的新趋势。
NDC在许多方面得以应用: ①与细胞毒性药物偶联治疗癌症; ②与放射性小分子偶联用于成像; ③重塑肿瘤免疫微环境; ④延长小分子药物半衰期等。
基于纳米抗体的结构优势, NDC较传统抗体偶联物具有更小的空间结构、更强的靶细胞特异性和靶细胞渗透能力, 穿透组织与血脑屏障的能力明显增加, 能够更好地达到给药治疗的目的、减弱毒副反应。NDC还具有更强的环境耐受度, 无论是储存运输条件、给药途径方面都有更多选择。这些特点配合经典的纳米抗体筛选技术(如噬菌体展示技术), 高效的表达技术(如原核表达技术), 搭配合适的连接子, 获得的NDC具有均一的偶联比、更好的体内药动学性质、疗效有所提高、半衰期得以延长等优势。
但NDC在成药方面依然存在劣势, 纳米抗体半衰期较短, 以纳米抗体为基础的NDC虽然具有组织穿透性好的优势, 但在体内很快会被清除代谢。目前已有策略用以延长NDC半衰期, 如聚乙二醇法、多纳米抗体串联、融合白蛋白和融合Fc结构域[78]等。除此之外, 由于NDC在连接子与偶联方式上具有多种选择, 因此需要进行大量预实验, 使NDC的构建更加繁琐复杂。但同样由于连接子的多种选择, 使NDC具有更多可能性。
尽管纳米抗体在疾病治疗方面已经取得了一些成果, 在重组蛋白药物研究中也已经逐步成为不可忽视的部分, 由于ADC药物具有免疫原性过高, 分子质量较大, 对人体造成较为强烈的不良反应等缺点, 未来以纳米抗体和新兴连接子为基础的NDC将具有巨大的发展前景。
作者贡献: 张雪嫣负责资料收集、文章撰写和文章修改; 周柏松负责稿件审阅; 刘玉林参与了稿件审阅。
利益冲突: 本文所有作者声明不存在利益冲突关系。
基金
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  • 吉林省科技发展计划基金项目(20210204092YY)
文献
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doi: 10.16438/j.0513-4870.2023-1324
  • 接收时间：2023-11-24
  • 首发时间：2025-11-27
  • 出版时间：2024-05-12
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  • 收稿日期：2023-11-24
  • 修回日期：2024-04-11
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    长春生物制品研究所有限责任公司, 吉林 长春 130012

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2种不同金属材料的力学参数
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species		 占总种数比例
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total species (%)		 属
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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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