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Article(id=1240710436623012012, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.10.03, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1683734400000, receivedDateStr=2023-05-11, revisedDate=null, revisedDateStr=null, acceptedDate=1718208000000, acceptedDateStr=2024-06-13, onlineDate=1773738019376, onlineDateStr=2026-03-17, pubDate=1729785600000, pubDateStr=2024-10-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773738019376, onlineIssueDateStr=2026-03-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773738019376, creator=13701087609, updateTime=1773738019376, updator=13701087609, issue=Issue{id=1240710432898478399, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='10', pageStart='721', pageEnd='800', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773738018488, creator=13701087609, updateTime=1773738214158, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240711253669237259, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240711253669237260, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1240710432898478399, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=736, endPage=742, ext={EN=ArticleExt(id=1240710437617062066, articleId=1240710436623012012, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Research progress on immunogenicity of PEGylated drugs, columnId=1207314219599499390, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

The use of polyethylene glycol (PEG) modified drugs or nano-carriers is a widely accepted method that can effectively improve therapeutic effects of drugs in vivo. However, PEGylated drugs are usually immunogenic in vivo and can trigger the secretion of anti-PEG immunoglobulin IgG and IgM, leading to a significant increase in blood clearance efficiency of drugs and the occurrence of hypersensitivity reactions. The physicochemical properties of PEG molecules,drugs, or drug carriers will affect the secretion of anti-PEG antibodies, and the PEG modification density and administration frequency will also affect the immunogenicity of PEGylated drugs. Optimizing the causes and influencing factors is an effective method to improve the immunogenicity of PEGylated drugs in vivo. PEG alternative biomaterial is a new direction of drug research and development.

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利用聚乙二醇（PEG）修饰药物或纳米药物载体是目前被广泛接受的可有效提高药物体内治疗效果的方法，但PEG化药物多具有体内免疫原性。PEG化药物通过胸腺依赖或非胸腺依赖途径引发抗PEG免疫球蛋白IgG和IgM的分泌，导致药物在血液中的清除效率显著增高并引发超敏反应。PEG分子、药物或药物载体的理化特性会影响抗PEG抗体的分泌，PEG化修饰密度、给药频率等也会影响PEG化药物的免疫原性。优化PEG化药物免疫原性的产生原因及影响因素是改善其体内免疫原性的有效方法，PEG可替代生物材料是药物研发的新方向。

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唐海玲
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潘永红，女，副主任医师，硕士，主要从事妇科肿瘤及盆底专业的研究，E-mail:

唐海玲，女，助理研究员，博士，主要从事肿瘤综合治疗和新型给药载体系统的研究，E-mail:

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潘永红，女，副主任医师，硕士，主要从事妇科肿瘤及盆底专业的研究，E-mail:

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药物名称适应证临床试验阶段NCT编号
ADI-PEG20（PEG20000偶联精氨酸脱氨酶）肝癌Ⅲ期NCT01287585
Uricase-PEG20（PEG20000偶联尿素酶）高尿酸血症Ⅰ期NCT01038947
［18F］fluoro-PEG-folate（18F标记的PEG偶联叶酸）卵巢上皮癌诊断Ⅰ期NCT05215496
PEG3350外周神经损伤Ⅰ期NCT02359825
PEG5000偶联尿酸氧化酶高尿酸血症Ⅰ期NCT05226013
cRGDY-PEG-Cy5.5标记的纳米粒头颈部黑色素瘤Ⅰ期NCT02106598
PEG-rhG-CSF（PEG20000偶联的重组人粒细胞集落刺激因子）复发或转移性鼻咽癌Ⅰ期NCT05222009
PEG-rhGH（PEG40000偶联重组人生长激素）特发性矮小症Ⅱ期NCT03255694
PEG重组人凝血因子Ⅷ Fc融合蛋白严重血友病AⅢ期NCT01775618
PEG偶联干扰素α慢性乙型肝炎Ⅱ期NCT05734807
), ArticleFig(id=1240719593304543774, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1240710436623012012, language=CN, label=表1, caption=

目前处于临床试验Ⅰ~Ⅲ期的聚乙二醇（PEG）化药物

, figureFileSmall=null, figureFileBig=null, tableContent=
药物名称适应证临床试验阶段NCT编号
ADI-PEG20（PEG20000偶联精氨酸脱氨酶）肝癌Ⅲ期NCT01287585
Uricase-PEG20（PEG20000偶联尿素酶）高尿酸血症Ⅰ期NCT01038947
［18F］fluoro-PEG-folate（18F标记的PEG偶联叶酸）卵巢上皮癌诊断Ⅰ期NCT05215496
PEG3350外周神经损伤Ⅰ期NCT02359825
PEG5000偶联尿酸氧化酶高尿酸血症Ⅰ期NCT05226013
cRGDY-PEG-Cy5.5标记的纳米粒头颈部黑色素瘤Ⅰ期NCT02106598
PEG-rhG-CSF（PEG20000偶联的重组人粒细胞集落刺激因子）复发或转移性鼻咽癌Ⅰ期NCT05222009
PEG-rhGH（PEG40000偶联重组人生长激素）特发性矮小症Ⅱ期NCT03255694
PEG重组人凝血因子Ⅷ Fc融合蛋白严重血友病AⅢ期NCT01775618
PEG偶联干扰素α慢性乙型肝炎Ⅱ期NCT05734807
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聚乙二醇化药物免疫原性的研究进展
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潘永红 1 , 张玉凤 1 , 唐海玲 2
中国新药与临床杂志 | 综述 2024,43(10): 736-742
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中国新药与临床杂志 | 综述 2024, 43(10): 736-742
聚乙二醇化药物免疫原性的研究进展
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潘永红1 , 张玉凤1, 唐海玲2
作者信息
  • 1.青岛市即墨区人民医院，山东 青岛　266228
  • 2.广西中医药大学，广西 南宁　530200

    • 潘永红，女，副主任医师，硕士，主要从事妇科肿瘤及盆底专业的研究，E-mail:

    唐海玲，女，助理研究员，博士，主要从事肿瘤综合治疗和新型给药载体系统的研究，E-mail:

通讯作者:

唐海玲
Research progress on immunogenicity of PEGylated drugs
Yong-hong PAN1 , Yu-feng ZHANG1, Hai-ling TANG2
Affiliations
  • 1.The People’s Hospital of Jimo. Qingdao, Qingdao SHANDONG 266228, China
  • 2.Guangxi University of Chinese Medicine,Nanning GUANGXI 530200, China
出版时间: 2024-10-25 doi: 10.14109/j.cnki.xyylc.2024.10.03
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摘要
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利用聚乙二醇（PEG）修饰药物或纳米药物载体是目前被广泛接受的可有效提高药物体内治疗效果的方法，但PEG化药物多具有体内免疫原性。PEG化药物通过胸腺依赖或非胸腺依赖途径引发抗PEG免疫球蛋白IgG和IgM的分泌，导致药物在血液中的清除效率显著增高并引发超敏反应。PEG分子、药物或药物载体的理化特性会影响抗PEG抗体的分泌，PEG化修饰密度、给药频率等也会影响PEG化药物的免疫原性。优化PEG化药物免疫原性的产生原因及影响因素是改善其体内免疫原性的有效方法，PEG可替代生物材料是药物研发的新方向。

聚乙二醇  /  免疫原性  /  生物药学  /  纳米药物  /  PEG化药物  /  抗PEG抗体

The use of polyethylene glycol (PEG) modified drugs or nano-carriers is a widely accepted method that can effectively improve therapeutic effects of drugs in vivo. However, PEGylated drugs are usually immunogenic in vivo and can trigger the secretion of anti-PEG immunoglobulin IgG and IgM, leading to a significant increase in blood clearance efficiency of drugs and the occurrence of hypersensitivity reactions. The physicochemical properties of PEG molecules,drugs, or drug carriers will affect the secretion of anti-PEG antibodies, and the PEG modification density and administration frequency will also affect the immunogenicity of PEGylated drugs. Optimizing the causes and influencing factors is an effective method to improve the immunogenicity of PEGylated drugs in vivo. PEG alternative biomaterial is a new direction of drug research and development.

polyethylene glycol  /  immunogenicity  /  biopharmaceutics  /  nanomedicine  /  PEGylated drugs  /  anti-PEG antibodies
潘永红, 张玉凤, 唐海玲. 聚乙二醇化药物免疫原性的研究进展. 中国新药与临床杂志, 2024 , 43 (10) : 736 -742 . DOI: 10.14109/j.cnki.xyylc.2024.10.03
Yong-hong PAN, Yu-feng ZHANG, Hai-ling TANG. Research progress on immunogenicity of PEGylated drugs[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (10) : 736 -742 . DOI: 10.14109/j.cnki.xyylc.2024.10.03
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聚乙二醇（polyethylene glycol，PEG）是一类具有良好生物相容性的合成聚合物分子，已在医药领域得到了广泛的应用，例如作为容积性泻剂的PEG-4000[1]、修复受伤神经和细胞膜的促融剂PEG3350[2]等。PEG与纳米生物药物以共价键或非共价键连接，可以增加药物分子的水溶性和水合动力学粒径，从而减少药物分子自身间的聚集，以及与血液中蛋白和单核吞噬系统细胞的结合[3]。这些PEG化纳米生物药物，既包括了抗体、酶和核酸药物，也包括了装载药物的递送载体系统如脂质体、胶束、树枝状高聚物、聚合物纳米粒子、固体脂质纳米粒等[4]。对于药物递送载体，PEG通常是修饰在载体的表面，增加药物制剂在体内外的稳定性，减少在血液循环过程中的单核巨噬系统清除率，提高体内的循环时间和药物治疗效果[5]。
目前已有较多PEG化药物进入临床试验阶段，见表1。与精氨酸脱氨酶、叶酸等相连接的PEG分子量一般在2 000~40 000范围内。经PEG修饰的纳米生物药物可以通过PEG遮掩具有免疫原性的抗原表位，从而降低药物的免疫原性。但是，随着越来越多的不同PEG修饰的纳米药物制剂进入临床试验，研究人员发现在动物模型和患者体内都会产生抗PEG的免疫球蛋白IgM和IgG抗体[6]。抗PEG抗体可能会显著降低药物的治疗效果，并引起严重的免疫副作用[7]。抗PEG抗体还会针对性地加速PEG化药物的血液清除（accelerate blood clearance，ABC效应），引发超敏反应[8]，患者可能发生过敏性休克，甚至死亡。因此，对PEG的免疫原性及其诱导的ABC效应和超敏反应的免疫机制进行研究，将有助于更深入地了解和认识PEG化纳米生物药物临床应用的安全性和有效性。
PEG化药物的化学结构特点
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1　共价连接键
PEG类分子是一类高度灵活的线性或树枝状的亲水性聚合物分子，分子量在400~40 000之间，两端可以与不同的官能基团连接。其中一个末端基团可与生物大分子或药物递送载体材料中的游离羧基（-COOH）、氨基（-NH2）、巯基（-SH）等通过共价键结合的方式实现PEG表面修饰。二硬脂酰磷脂酰乙醇胺（DSPE）-PEGs是制备靶向脂质体，对脂质体进行蛋白、多肽、核酸适体等配体表面修饰的关键功能性辅料[9]。以DSPE-PEGs为例，对PEG分子修饰药物或载体材料时使用的功能性官能基团进行罗列，见图1。PEG分子一端的-COOH与二磷脂酰胺的-NH2通过缩合反应形成酰胺键（-NH-CO-），另一端的末端基团可选择功能性官能基团，如琥珀酰胺基、马来酰胺基等，实现与带巯基、羧基、氨基等官能基团的多肽、蛋白、核酸适体的共价键连接。也可以利用生物素修饰PEG聚合物分子，再与相应的亲和素通过非共价键作用实现相应抗体的PEG修饰。
2　结构特点的分子动力学模拟
经PEG修饰的药物可以利用PEG长链在空间上遮掩包封的药物，避免药物与血流中的血浆蛋白结合，从而延长药物在体内的循环时间。第一个PEG化的蛋白药物是AdagenⓇ，PEG5000修饰的腺苷脱氨酶，于1990年被美国食品和药物管理局（FDA）批准应用于临床[10]。尽管PEG化药物在医药领域得到了成功的应用，但是关于PEG链长的尺寸、构象及PEG与药物的结合密度对药物递送效率的影响还未能从分子水平上得到很好的解释[11]。最早进行PEG化药物开发的研究者通过将PEG修饰在重组蛋白上，降低了重组蛋白的免疫原性，同时延长了其体内的循环时间和活性效果，并认为亲水性聚合物分子修饰的蛋白表面是不易被免疫系统识别的[12]。HOFFMAN等[13]深入研究了PEG修饰表面阻碍血液中蛋白吸附的机制，认为PEG化的表面与血液中的蛋白吸附是受PEG结合水驱动的。利用差示热扫描可以观察到PEG的水合峰，当PEG分子量小于500时，PEG的水合峰会消失。一般一个乙二醇的结构单元可以吸附2~3个水分子。当与PEG结合的水分子出现解吸附时，熵增和自由能的下降会促使蛋白吸附的增加。PEG分子量的增加可导致自发折叠形成自由的卷曲结构，将结合的水分子包封在卷曲结构中，可以有效地阻碍纤维蛋白的吸附，产生熵排斥效应。
1995年，利用全原子和马提尼粗粒化模拟PEG的力场被开发，但是直到2000年，能被分子模拟的主要还是短链PEG（分子量<2 000）。近20年来，随着计算机运算能力的显著提升，新的模拟方法学的开发使得复杂的PEG支链蛋白药物能够越来越多的被模拟。这些分子动力学模拟可以从分子水平解释PEG化对药物分子或者转运体的结构和表面属性的影响，从而对PEG化药物的PEG链长、结构和药物表面的修饰密度进行优化[14]。MANJULA等[15]对PEG化血红蛋白的全原子模拟，展示了在蛋白表面的PEG链具有折叠结构而不是伸展的构象，这就减弱了血红蛋白和其他生物聚合物间的相互作用。YANG等[16]对PEG化胰岛素进行了水环境的模拟，结果显示PEG链不仅可以与胰岛素残基相互作用，也能与水中的氢键相互作用，从而增加PEG化胰岛素的粒径，提高了胰岛素在水溶液中的稳定性。KHAMENEH等[17]对PEG化人生长激素及其受体进行分子动力学的对接分析，结果显示PEG的随机卷曲结构可降低人生长激素和受体间的亲和力。有研究者对非键合的马提尼粗粒度PEG力场的参数进行了重新设置，可预测PEG在单个氨基酸上的局部密度，模拟PEG与血浆蛋白如牛血清白蛋白、人血清白蛋白、人血清转铁蛋白的相互作用[18, 19]。
脂质体是由磷脂膜组成的封闭囊泡，为了提高包封药物的体内循环时间，常对脂质体表面进行PEG化修饰，是临床应用的典型PEG化纳米药物。PEG链长和浓度的增加，可有效地避免脂质体与血流中的血浆蛋白结合，使包封的药物更加稳定。Alexander–de Gennes理论可用于解释脂质体表面PEG聚合物分子链在蘑菇状（mushroom）和刷状（bush）构象之间的转变机制。低密度PEG存在于脂质体表面时，PEG链向水环境伸展成为独立的链，导致了蘑菇状构象的形成；当高密度PEG存在于脂质体表面时，PEG链间因为拥挤，导致了PEG的刷状交互作用结构的形成。SZLEIFER等[20]通过自由能计算，发现优化PEG表面密度较优化PEG链长更能抵抗蛋白的吸附。PEG结合密度的增加可以抑制小蛋白的吸附，增加PEG厚度可以抑制大蛋白的吸附。PAL等[21]对PEG化脂质双层进行了全原子模拟和自由能计算，结果表明PEG和双层的脂质头基有很强的相互作用。MAGARKAR等[22]利用马提尼粗粒化模拟发现，PEG化脂质可以促使脂质双层构象向胶束相转变。
脂质和PEG化脂质的混合物在不同的摩尔比例下会影响自组装脂质体和胶束形成。对PEG链的粗粒化模拟，捕获刷状和蘑菇状的构象转变过程，展示了分子模拟和Alexander–de Gennes理论很好的一致性。对比分析不同PEG分子量和表面修饰密度对脂质体膜表面蛋白吸附的影响，发现PEG刷状结构相比蘑菇状结构更能抑制蛋白的吸附[23]。这些通过分子动力学模拟对PEG链长、结构和结合密度的优化，为理性设计PEG化药物输送系统提供了有利工具。
PEG化药物免疫原性产生的原因和机制
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1　胸腺依赖性抗原反应
PEG化蛋白和多肽类药物可通过经典的T细胞依赖路径引发抗PEG抗体响应。当B细胞受体（B cell receptors，BCRs）与PEG骨架特异性结合时，B细胞被激活分化为浆母细胞，分泌抗PEG的IgM抗体。而如果要分泌抗PEG的IgG抗体，则B细胞需要接受来自CD4+ T细胞的信号，这种CD4+ T细胞被称为次级淋巴器官中的滤泡辅助T细胞（TFH细胞）。TFH细胞的CD40L与B细胞的CD40相互作用可以诱导胞苷脱氨酶的表达[24]。B细胞通过内吞大量的PEG偶联物，在膜表面产生多肽的主要组织相容性复合体（major histocompatibility complex，MHC），使B细胞更容易与TFH细胞发生相互作用。B细胞通过分泌抗PEG抗体来识别PEG偶联物的PEG结构，TFH细胞可以识别PEG偶联物的非人源治疗蛋白产生免疫应答。这是胸腺依赖的抗PEG抗体产生的原因和机制。
2　非胸腺依赖性抗原反应
在动物模型中，体内的B细胞和T细胞因为将PEG化人源蛋白作为外源蛋白，产生了免疫应答。非蛋白类的抗原都可被划分为非胸腺依赖性抗原，可以诱导体内抗体响应，包括分泌IgM、IgG、IgA抗体。这些非蛋白类抗原包括核酸、空白脂质体、纳米粒、包封细胞毒药物的脂质体、核酸纳米粒等。与多肽MHC Ⅱ抗原不同，非胸腺依赖型Ⅱ型抗原（thymus-independent type 2 antigens, TI-2抗原）具有多价性，可以与B细胞表面的BCRs交联。单链PEG聚合链存在多个可与抗体结合的表型位点，因此可以被作为TI-2抗原。边缘B细胞主要承担了对TI-2抗原的抗体响应。交互作用的BCRs提供了初始信号，固有免疫细胞还可利用Toll样受体（toll-like receptors, TLR）提供额外的激活信号，其中就包括重要的B细胞信号激活因子肿瘤坏死因子家族[25]。对于非T细胞依赖性抗原，小鼠边缘B细胞主要产生IgM、IgG2b、IgG3、IgA抗体，人边缘B细胞主要产生IgM、IgG1、 IgG2和IgA2抗体。PEG化药物引起体内抗PEG抗体产生的潜在能力与PEG化药物的物理属性密切相关。
PEG化药物的体内ABC效应
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随着聚合物分子PEG在化妆品领域和食品领域的广泛使用，许多正常健康个体血液中可检测到抗PEG抗体。一项研究分析了2 404名汉族健康受试者的血液样品，采用人源化抗PEG的IgM和IgG单克隆抗体作为参照标准，观察健康受试者体内抗PEG抗体的表达。发现其中有634名受试者的血液中含抗PEG的IgM抗体，601名受试者的血液中含抗PEG的IgG抗体，199名受试者血液中同时含有抗PEG的IgM和IgG抗体，抗PEG抗体的整体响应率为43.1%；女性受试者体内同时表达抗PEG的IgM和IgG抗体的概率要高于男性；所有抗PEG抗体阳性受试者体内抗PEG的IgM抗体的浓度范围为0.2~57 μg·mL-1，抗PEG的IgG抗体的浓度范围为0.3~238 μg ·mL-1[26]。
动物模型和患者体内的抗PEG抗体会引起PEG化药物的快速清除和药效的降低，即ABC效应[27]。注射空白的脂质体可以诱导体内抗PEG抗体的产生，当重复注射PEG化脂质体时，就会产生ABC效应。人体内抗PEG的IgM和IgG抗体会引起PEG化多柔比星脂质体体内明显的ABC效应，导致药物在肿瘤组织聚集减少、抗肿瘤活性降低[28]。但是，一些同样PEG化的胶束或白蛋白纳米粒注入体内后，却很少观察到ABC效应。这也引起了研究者对ABC效应影响因素及其机制的深入研究，包括PEG化纳米粒和蛋白的不同空间结构与抗PEG抗体的结合差异，PEG化药物粒径对抗PEG抗体清除的影响，抗PEG的IgM抗体对PEG不同特异性和表型的亲和力，亲水性PEG链和疏水性共嵌段结构与抗PEG抗体的界面结合属性等。抗PEG抗体的摩尔浓度直接影响ABC效应[29]。单个PEG化药物结合的抗PEG抗体的数目越多，就越容易在体内被清除。因此，PEG化药物的体内ABC效应，与给药剂量、给药频率是密切相关的。
PEG化药物免疫原性的影响因素
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1　结构特性的影响
PEG化药物的免疫原性与PEG分子、药物、药物载体系统的理化特性密切相关。RICHTER等[30]分析了不同分子量PEG（3 000~6 000 000）和PEG修饰的蛋白肌内注射后动物体内的抗PEG抗体的表达水平。结果表明即使辅以佛氏佐剂，游离的低分子量的PEG分子不具有或只体现极微弱的免疫原性；血清中抗PEG抗体对高分子量（4 000~6 000 000）、高浓度（> 63 μg·mL-1）PEG分子的免疫反应最为强烈。SAIFER等[31]对比了不同PEG分子结构与抗PEG抗体的亲和力特性，发现末端官能基团分别是羟基和甲氧基的PEG体现了不同的免疫原性，带疏水头基的甲氧基PEG蛋白药物会引起更强的免疫反应；产生的抗PEG抗体体现出不同的结合特异性，骨架特异性抗PEG抗体的结合亲和力主要取决于骨架的长度，甲氧基特异性抗PEG抗体的亲和力大小取决于末端官能团的疏水性。
因诱导免疫机制的差别，动物模型中或人体内产生的抗PEG抗体具有多样性特点。如前所述，抗PEG抗体对PEG的骨架或末端基团具有不同的结合特点，PEG骨架结构与抗PEG抗体的结合亲和力相对低，且结合的抗体数量受PEG长度的限制。一般PEG2000可以结合8~15个IgG分子。不同PEG末端基团中，与抗PEG抗体结合亲和力的强弱顺序为羟基<氨基<甲氧基<丁氧基<异丁氧基[31]。
PEG纳米药物内核的亲疏水性同样也是影响抗PEG抗体产生的重要因素。例如，具有疏水性内核的PEG纳米药物可以诱导抗PEG的IgM免疫响应。但是尚无完全特异性的抗PEG单克隆或多克隆抗体，表现出对PEG的末端基团、中间连接键或骨架结构具有绝对的特异性[32]。
对于PEG化蛋白药物而言，蛋白自身的免疫原性以协同的方式促使PEG特异性抗体IgG的分泌，依赖于T细胞免疫途径，在体内产生很强的免疫原性，最终可能影响药物的临床应用[33]。
2　表面修饰密度的影响
抗PEG抗体的分泌除了受PEG聚合物分子、PEG偶联药物或药物载体的理化属性影响外，蛋白和载体系统表面PEG化修饰的密度是诱导免疫原性的另一个关键因素。PEG化蛋白可以被多个PEG分子覆盖，PEG药物载体系统与PEG的连接也可以存在多个结合位点。以PEG修饰的脂质体药物为例，PEG分子在脂质体表面不同的空间结构构象由脂质体表面的PEG修饰密度决定。通常PEG2000脂质分子的摩尔百分比小于4 mol%时，在脂质体表面呈蘑菇状构象结构，厚度约为3~4 nm。当PEG2000脂质分子的摩尔百分比达到9~10 mol%时，PEG在脂质体的表面就会形成刷状结构，厚度增加至4~10 nm连续的PEG层，此时的PEG链之间会存在相互作用，影响PEG化药物的体内免疫原性。
早在19世纪70年代，已开展了关于蛋白表面PEG化程度对PEG化药物免疫原性影响的研究。研究观察了固定界面膜表面PEG修饰密度对PEG水化层纤维蛋白吸附能力的影响，结果显示当膜表面连接的PEG［HO-（CH2-CH2-O）6-H］达到50~60 mol%时，PEG水化层对溶液蛋白的排斥效应显著提高，进而降低蛋白的表面吸附[13]。但PEG化药物体内的免疫原性依然不容易预测。LI等[34]发现3 mol%和9 mol%PEG修饰的脂质体静脉注射后，可以诱导相同程度的抗PEG IgM的分泌。研究结果也显示9 mol% PEG修饰的脂质体再次注射后，较3 mol% PEG修饰的脂质体，有更快的体内清除率。
有研究对新冠疫苗Comirnaty® （一种PEG修饰的脂质纳米粒）注射到体内后，血液中抗PEG的IgG、IgM、IgE的表达水平进行了定量分析[34]。接受mRNA脂质纳米粒（lipid nanoparticles, LNP）的78名受试者，注射3周后，体内IgG表达水平明显高于IgM，IgE未检出。与低密度PEG（0.3 mol% DSPE-PEG 2000）表面修饰的脂质纳米粒相比，含1.5 mol% PEG的Comirnaty®与抗PEG抗体的亲和力明显减弱，因为Comirnaty®使用的ALC 0159是由C14肉豆蔻酰构成的PEG脂质，相比较C18硬脂酰DSPE-PEG2000更容易从脂膜上脱落。抗PEG抗体的分泌与LNP中的PEG表面修饰密度呈明显的浓度依赖性[9]。
3　其他影响因素
除了PEG表面修饰密度，PEG的链长也会影响抗PEG抗体的产生。PEG30000修饰的白蛋白（BSA）和PEG20000修饰的卵清蛋白（OVA），与PEG2000修饰的BSA和PEG5000修饰的OVA相比，可以诱导更高的体内抗PEG IgM响应。对于PEG修饰的纳米粒，如果脂质体和腺病毒上的PEG链长相对较短（分子量<2 000），PEG链的刷状伸展并不能增加免疫原性。通过优化不同的化学共价连接键，可以提高PEG化药物的水溶性[35]。POPPENBORG等[36]的研究显示，PEG和天冬酰胺酶选择酰胺或琥珀酰胺键作为共价连接键，诱导产生抗PEG抗体的程度相当，并且可以同时检测到抗PEG抗体和抗琥珀酰胺抗体。此外，给药途径、给药频率以及患者的免疫状态也都会影响体内抗PEG抗体的产生[37, 38]。
小结
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改善PEG化药物的免疫原性需要对PEG化药物的空间结构特性、连接键属性、治疗疾病的生理病理特点、PEG免疫原性机制等有深入全面的了解。寻找PEG可替代的生物材料也是有效避免PEG化药物体内免疫原性的新方向。
基金
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  • 广西中医药大学校级博士课题科研启动基金(2019BS010)
  • 广西高校中青年教师科研基础能力提升项目(2020KY0747)
  • 广西中医药大学自然科学研究面上项目(2020MS002)
文献
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2024年第43卷第10期
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文章信息
doi: 10.14109/j.cnki.xyylc.2024.10.03
  • 接收时间：2023-05-11
  • 首发时间：2026-03-17
  • 出版时间：2024-10-25
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  • 收稿日期：2023-05-11
  • 录用日期：2024-06-13
基金
广西中医药大学校级博士课题科研启动基金(2019BS010)
广西高校中青年教师科研基础能力提升项目(2020KY0747)
广西中医药大学自然科学研究面上项目(2020MS002)
作者信息
    1.青岛市即墨区人民医院，山东 青岛　266228
    2.广西中医药大学，广西 南宁　530200

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唐海玲
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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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