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Article(id=1239250706977321371, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239250701583446236, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024.04.15, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=null, receivedDateStr=null, revisedDate=1709481600000, revisedDateStr=2024-03-04, acceptedDate=null, acceptedDateStr=null, onlineDate=1773389992707, onlineDateStr=2026-03-13, pubDate=1714406400000, pubDateStr=2024-04-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773389992707, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773389992707, creator=13701087609, updateTime=1773389992707, updator=13701087609, issue=Issue{id=1239250701583446236, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='4', pageStart='553', pageEnd='736', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773389991422, creator=13701087609, updateTime=1773390513217, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239252890213209050, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239250701583446236, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239252890213209051, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239250701583446236, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=678, endPage=688, ext={EN=ArticleExt(id=1239250707237368245, articleId=1239250706977321371, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Opalescence appearance of antibody formulation correlation with molecular size or aggregation propensity, columnId=1206272757852074373, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Safety Monitoring, runingTitle=null, highlight=null, articleAbstract=
Objective:

To explore the correlations between opalescence and molecular size, purity or aggregation tendency in the antibody formulation.

Methods:

Studied on the opalescence phenomena of various antibodies, including the influence of different concentrations, pH/buffer, excipients, as well as the influence of environmental factors such as temperature, light, freeze-thaw and agitation, and the correlations had been analyzed between opalescence and molecular size, purity (aggregation), KD or Tagg.

Results:

The degree of antibody opalescence was positively correlated with the molecular size, the deepening of the opalescence indicated that the molecular size was increased and the more tendency of molecular aggregation. For example, the opalescence of C molecule obviously enhanced under high temperature, and the result of turbidity changed from 3.3 NTU to 13.6 NTU, the molecular size changed from 13.1 nm to 40.6 nm, and the KD changed from positive to negative. The Tagg changed from 59.6 ℃ to below 50 ℃.

Conclusion:

The opalescence can be affected by buffer system, pH, excipients and ambient temperature, the degree of opalescence increased, indicating the stability become worse and the molecules prone to aggregate. This study provides important reference for the analysis and evaluation of opalescence in the antibody formulation development.

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目的：

对抗体制剂乳光现象与分子粒径、纯度及聚集倾向性的相关性进行系统研究。

方法：

通过研究多种抗体的乳光现象，其中包含不同浓度、pH/缓冲盐及辅料对乳光现象的影响，以及温度、光照、反复冻融及振荡等环境因素的影响，分析乳光现象与分子粒径、纯度(聚集体)、扩散相互作用指数(KD)及聚集温度(Tagg)之间的关联。

结果：

抗体制剂乳光与分子粒径大小呈正相关，乳光程度的加深表明分子粒径有所增加且分子聚集倾向性增加，如C分子在高温条件下，乳光现象明显加深，浊度由3.3 NTU变为13.6 NTU，粒径由13.1 nm变为40.6 nm，KD由正变负，Tagg由59.6 ℃变为50 ℃以下。

结论：

缓冲体系、pH及辅料等处方因素，以及温度等条件均会影响抗体制剂的乳光特性，乳光程度增加，预示制剂稳定性降低，更容易发生聚集。本研究为抗体药物制剂生产中乳光的检测评价提供重要参考。

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Tel：18862391213；E-mail：

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Tel：18862391213；E-mail：

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Tel：18862391213；E-mail：

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J Pharm Sci，2015，104(4)：1263, articleTitle=Opalescence in monoclonal antibody solutions and its correlation with intermolecular interactions in dilute and concentrated solutions, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1239250711939183272, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, xref=1., ext=[AuthorCompanyExt(id=1239250711943377577, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, companyId=1239250711939183272, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Suzhou Pro-heal Pharmaceuticals Technology Co., Ltd., Suzhou 215000, China), AuthorCompanyExt(id=1239250711951766188, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, companyId=1239250711939183272, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, 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caption=B分子在不同的缓冲体系中的浊度与粒径结果, figureFileSmall=4+P9LSF2C/eGU54SyXJlsg==, figureFileBig=pr4qrdSVzfpVg5cyYOmSSg==, tableContent=null), ArticleFig(id=1239250716334814029, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.3, caption=Turbidities and molecular sizes of E，H molecules, figureFileSmall=bQaN/sfps3gY7qyzGqIHQg==, figureFileBig=fFWhxwwFAy/EiV63aMoDBw==, tableContent=null), ArticleFig(id=1239250716456448849, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图3, caption=E和H分子的浊度和粒径结果, figureFileSmall=bQaN/sfps3gY7qyzGqIHQg==, figureFileBig=fFWhxwwFAy/EiV63aMoDBw==, tableContent=null), ArticleFig(id=1239250716561306453, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.4, caption=Turbidities and molecular sizes of A，C，D，F，G molecules, figureFileSmall=3gYhUY2E+i+C0/ptRZ1Z7Q==, 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journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.6, caption=HMW and turbidities of B molecule, figureFileSmall=nWD686F7jUpV0Dk2jQj4Lw==, figureFileBig=CeaGkOI2Rz6WGT35dLtOwQ==, tableContent=null), ArticleFig(id=1239250718448743275, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图6, caption=B分子在不同的缓冲体系中的聚集体与浊度结果, figureFileSmall=nWD686F7jUpV0Dk2jQj4Lw==, figureFileBig=CeaGkOI2Rz6WGT35dLtOwQ==, tableContent=null), ArticleFig(id=1239250718528435057, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.7, caption=HMW and turbidities of E，H molecules, figureFileSmall=M2JTk++IQmb/52oNNE13Xg==, figureFileBig=+3LqAq/hwT6VPM+0ldBSJQ==, tableContent=null), ArticleFig(id=1239250718612321143, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图7, caption=E和H分子的聚集体和浊度结果, 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tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图9, caption=C分子的KD检测曲线, figureFileSmall=aeWxABk46zPCiU1RawqvzQ==, figureFileBig=zxQyoipLtR/AHtB6g9Vepw==, tableContent=null), ArticleFig(id=1239250719140803467, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.10, caption=The KD curves of D molecule, figureFileSmall=6wfMCiKq1sDX0FWhAZnWOg==, figureFileBig=Fbud1Phf82yp8WLzeociSw==, tableContent=null), ArticleFig(id=1239250719224689551, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图10, caption=D分子的KD检测曲线, figureFileSmall=6wfMCiKq1sDX0FWhAZnWOg==, figureFileBig=Fbud1Phf82yp8WLzeociSw==, tableContent=null), ArticleFig(id=1239250719316964241, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.11, caption=The KD curves of H molecule, figureFileSmall=pilNt36y+DEhiU7vjs2kCw==, figureFileBig=dbdFjOJhd+iU+r0UKYUPEw==, tableContent=null), ArticleFig(id=1239250719409238936, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图11, caption=H分子的KD检测曲线, figureFileSmall=pilNt36y+DEhiU7vjs2kCw==, figureFileBig=dbdFjOJhd+iU+r0UKYUPEw==, tableContent=null), ArticleFig(id=1239250719509902235, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.12, caption=The Tagg curves of C molecule, figureFileSmall=jbQPIZpOBizxlSecH2E7SQ==, figureFileBig=MQXFPNCKwfw8w2Mo5hgX8g==, tableContent=null), ArticleFig(id=1239250719627342750, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图12, caption=C分子高温孵育后的Tagg检测曲线, figureFileSmall=jbQPIZpOBizxlSecH2E7SQ==, figureFileBig=MQXFPNCKwfw8w2Mo5hgX8g==, tableContent=null), ArticleFig(id=1239250719744783265, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.13, caption=The Tagg curves of G molecule after incubation at high temperature，strong light，freeze-thaw and agitation, figureFileSmall=HKaUof29kYFn9akAFBwMfg==, figureFileBig=0LHtdPEgUqhwIjsGBdiRkg==, tableContent=null), ArticleFig(id=1239250719853835172, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图13, caption=G分子在高温孵育、强光照、反复冻融和振荡后的Tagg检测曲线, figureFileSmall=HKaUof29kYFn9akAFBwMfg==, figureFileBig=0LHtdPEgUqhwIjsGBdiRkg==, tableContent=null), ArticleFig(id=1239250719925138343, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Fig.14, caption=The correlation among antibody opalescence，higher structure state and stability, figureFileSmall=qEiH9jYSx8alJBPaeO3S8A==, figureFileBig=kVyF7IM0aDDKrIUgg/IDow==, tableContent=null), ArticleFig(id=1239250720046773162, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=图14, caption=抗体制剂乳光现象与分子高级结构状态及稳定性的关联, figureFileSmall=qEiH9jYSx8alJBPaeO3S8A==, figureFileBig=kVyF7IM0aDDKrIUgg/IDow==, tableContent=null), ArticleFig(id=1239250720118076334, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.1, caption=

Informations of 8 antibody molecules

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		相对分子质量
(relative molecular mass)×103		C/(mg·mL-1)处方
(formulation)
A单抗(mAb)1505020 mol·L-1组氨酸(histidine)，145 mol·L-1盐酸精氨酸(arginine hydrochloride)，0.02%聚山梨酯80(polysorbate 80)，pH 6.0
BA5.0融合蛋白608020 mol·L-1醋酸(acetic acid)，pH 5.0
A5.5(fusion protein)20 mol·L-1醋酸(acetic acid)，pH 5.5
C5.020 mol·L-1柠檬酸(citric acid)，pH 5.0
C5.520 mol·L-1柠檬酸(citric acid)，pH 5.5
C6.020 mol·L-1柠檬酸(citric acid)，pH 6.0
H5.520 mol·L-1组氨酸(histidine)，pH 5.5
H6.020 mol·L-1组氨酸(histidine)，pH 6.0
H6.520 mol·L-1组氨酸(histidine)，pH 6.5
C单抗(mAb)1503020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.04%聚山梨酯80(polysorbate 80)，pH 6.0
D单抗(mAb)1501020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.02%聚山梨酯80(polysorbate 80)，0.002%EDTA，pH 5.5
EE-1单抗(mAb)1502020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.01%聚山梨酯80(polysorbate 80)，pH 6.0
E-2150140
F单抗(mAb)1503010 mol·L-1组氨酸(histidine)，8%海藻糖(trehalose)，0.02%聚山梨酯80(polysorbate 80)，pH 6.2
G双抗(biBody)1505020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.04%聚山梨酯80(polysorbate 80)，pH 6.0
HH-1双抗(biBody)1502040 mol·L-1柠檬酸(citric acid)，8%海藻糖(trehalose)，0.02%聚山梨酯80(polysorbate 80)，pH 6.0
H-21502040 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.02%聚山梨酯80(polysorbate 80)，pH 6.0
), ArticleFig(id=1239250720243905457, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=表1, caption=

8种抗体分子样品信息

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		相对分子质量
(relative molecular mass)×103		C/(mg·mL-1)处方
(formulation)
A单抗(mAb)1505020 mol·L-1组氨酸(histidine)，145 mol·L-1盐酸精氨酸(arginine hydrochloride)，0.02%聚山梨酯80(polysorbate 80)，pH 6.0
BA5.0融合蛋白608020 mol·L-1醋酸(acetic acid)，pH 5.0
A5.5(fusion protein)20 mol·L-1醋酸(acetic acid)，pH 5.5
C5.020 mol·L-1柠檬酸(citric acid)，pH 5.0
C5.520 mol·L-1柠檬酸(citric acid)，pH 5.5
C6.020 mol·L-1柠檬酸(citric acid)，pH 6.0
H5.520 mol·L-1组氨酸(histidine)，pH 5.5
H6.020 mol·L-1组氨酸(histidine)，pH 6.0
H6.520 mol·L-1组氨酸(histidine)，pH 6.5
C单抗(mAb)1503020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.04%聚山梨酯80(polysorbate 80)，pH 6.0
D单抗(mAb)1501020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.02%聚山梨酯80(polysorbate 80)，0.002%EDTA，pH 5.5
EE-1单抗(mAb)1502020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.01%聚山梨酯80(polysorbate 80)，pH 6.0
E-2150140
F单抗(mAb)1503010 mol·L-1组氨酸(histidine)，8%海藻糖(trehalose)，0.02%聚山梨酯80(polysorbate 80)，pH 6.2
G双抗(biBody)1505020 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.04%聚山梨酯80(polysorbate 80)，pH 6.0
HH-1双抗(biBody)1502040 mol·L-1柠檬酸(citric acid)，8%海藻糖(trehalose)，0.02%聚山梨酯80(polysorbate 80)，pH 6.0
H-21502040 mol·L-1组氨酸(histidine)，8%蔗糖(sucrose)，0.02%聚山梨酯80(polysorbate 80)，pH 6.0
), ArticleFig(id=1239250720340374452, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.2, caption=

Visual inspections of 8 antibody molecules at 40 ℃

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		目检 (visual inspection)备注
(comment)
T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)
A轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微加深
(slightly enhanced)
BA5.0澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
A5.5澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
C5.0轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		/轻微加深
(slightly enhanced)
C5.5轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		/轻微加深
(slightly enhanced)
C6.0轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		/轻微加深
(slightly enhanced)
H5.5澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
H6.0澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
H6.5澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
C轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		乳光(opalescence)乳光(opalescence)明显加深
(obviously enhanced)
D澄明(clear)澄明(clear)澄明(clear)澄明(clear)没有变化
(no change observed)
EE-1澄明(clear)澄明(clear)澄明(clear)轻微乳光
(slight opalescence)		轻微加深
(slightly enhanced)
E-2轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		没有变化
(no change observed)
F轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		乳光
(opalescence)		明显加深
(obviously enhanced)
G轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微加深
(slightly enhanced)
HH-1乳光(opalescence)乳光(opalescence)乳光(opalescence)乳光(opalescence)明显加深
(obviously enhanced)
H-2乳光(opalescence)乳光(opalescence)乳光(opalescence)乳光(opalescence)没有变化
(no change observed)
), ArticleFig(id=1239250720453620664, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=表2, caption=

8种抗体制剂溶液在40 ℃下的外观目检结果

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		目检 (visual inspection)备注
(comment)
T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)
A轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微加深
(slightly enhanced)
BA5.0澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
A5.5澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
C5.0轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		/轻微加深
(slightly enhanced)
C5.5轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		/轻微加深
(slightly enhanced)
C6.0轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		/轻微加深
(slightly enhanced)
H5.5澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
H6.0澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
H6.5澄明(clear)澄明(clear)澄明(clear)/没有变化
(no change observed)
C轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		乳光(opalescence)乳光(opalescence)明显加深
(obviously enhanced)
D澄明(clear)澄明(clear)澄明(clear)澄明(clear)没有变化
(no change observed)
EE-1澄明(clear)澄明(clear)澄明(clear)轻微乳光
(slight opalescence)		轻微加深
(slightly enhanced)
E-2轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		没有变化
(no change observed)
F轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		乳光
(opalescence)		明显加深
(obviously enhanced)
G轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微乳光
(slight opalescence)		轻微加深
(slightly enhanced)
HH-1乳光(opalescence)乳光(opalescence)乳光(opalescence)乳光(opalescence)明显加深
(obviously enhanced)
H-2乳光(opalescence)乳光(opalescence)乳光(opalescence)乳光(opalescence)没有变化
(no change observed)
), ArticleFig(id=1239250720558478268, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.3, caption=

Turbidities and molecular sizes of 8 antibodies at 40 ℃

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		浊度(turbidity)/NTU分子粒径(molecular size)/nm
T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)		T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)
A3.83.94.24.515.115.015.617.1
BA5.02.22.32.7/6.36.57.3/
A5.52.73.22.7/8.17.78.0/
C5.03.74.24.7/10.710.811.6/
C5.53.74.34.8/11.411.312.5/
C6.03.53.73.7/11.411.111.0/
H5.52.73.22.7/8.38.87.8/
H6.02.82.82.6/8.47.98.0/
H6.52.82.42.5/7.27.87.6/
C3.35.811.313.613.119.930.940.6
D1.41.81.72.411.711.711.815.7
EE-12.22.63.03.510.610.410.512.6
E-23.64.03.63.611.011.812.112.6
F3.74.45.56.815.717.721.823.4
G3.33.64.04.610.310.912.013.6
HH-14.96.17.28.016.823.426.527.3
H-210.510.510.010.333.932.334.034.3
), ArticleFig(id=1239250720654947260, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=表3, caption=

8种抗体制剂溶液在40 ℃下的浊度与粒径检测结果

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		浊度(turbidity)/NTU分子粒径(molecular size)/nm
T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)		T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)
A3.83.94.24.515.115.015.617.1
BA5.02.22.32.7/6.36.57.3/
A5.52.73.22.7/8.17.78.0/
C5.03.74.24.7/10.710.811.6/
C5.53.74.34.8/11.411.312.5/
C6.03.53.73.7/11.411.111.0/
H5.52.73.22.7/8.38.87.8/
H6.02.82.82.6/8.47.98.0/
H6.52.82.42.5/7.27.87.6/
C3.35.811.313.613.119.930.940.6
D1.41.81.72.411.711.711.815.7
EE-12.22.63.03.510.610.410.512.6
E-23.64.03.63.611.011.812.112.6
F3.74.45.56.815.717.721.823.4
G3.33.64.04.610.310.912.013.6
HH-14.96.17.28.016.823.426.527.3
H-210.510.510.010.333.932.334.034.3
), ArticleFig(id=1239250720759804862, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.4, caption=

Turbidities and molecular sizes of several antibodies under strong light，freeze-thaw & agitation

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		浊度(turbidity)/NTU分子粒径(molecular size)/nm
T0强光照2周
(strong light for 2 weeks)		冻融10次
(freeze-thaw 10 cycles)		振荡1周
(agitation for 1 week)		T0强光照2周
(strong light for 2 weeks)		冻融10次
(freeze-thaw 10 cycles)		振荡1周
(agitation for 1 week)
A3.84.03.83.915.116.215.715.9
C3.33.13.23.213.113.113.313.3
D1.41.71.81.511.711.811.811.9
E-12.22.62.32.310.611.710.810.6
E-23.63.83.93.711.011.411.111.2
H-110.510.810.610.933.932.131.833.7
H-24.95.24.35.116.817.316.116.8
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多种抗体制剂溶液在强光照、冻融和振荡条件下的浊度与粒径检测结果

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分子
(molecule)		浊度(turbidity)/NTU分子粒径(molecular size)/nm
T0强光照2周
(strong light for 2 weeks)		冻融10次
(freeze-thaw 10 cycles)		振荡1周
(agitation for 1 week)		T0强光照2周
(strong light for 2 weeks)		冻融10次
(freeze-thaw 10 cycles)		振荡1周
(agitation for 1 week)
A3.84.03.83.915.116.215.715.9
C3.33.13.23.213.113.113.313.3
D1.41.71.81.511.711.811.811.9
E-12.22.62.32.310.611.710.810.6
E-23.63.83.93.711.011.411.111.2
H-110.510.810.610.933.932.131.833.7
H-24.95.24.35.116.817.316.116.8
), ArticleFig(id=1239250720935965634, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.5, caption=

The purities of several antibodies under strong light，freeze-thaw & agitation

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分子
(molecule)		纯度(purity)/%
T0强光照2周(strong light for 2 weeks)冻融10次(freeze-thaw 10 cycles)振荡1周(agitation for 1 week)
A98.393.297.897.8
C98.598.098.398.1
D99.699.699.699.6
E-199.086.898.798.6
E-297.885.197.396.8
H-198.398.198.196.5
H-298.898.298.797.4
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多种抗体制剂经历强光照、反复冻融及振荡后的纯度

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		纯度(purity)/%
T0强光照2周(strong light for 2 weeks)冻融10次(freeze-thaw 10 cycles)振荡1周(agitation for 1 week)
A98.393.297.897.8
C98.598.098.398.1
D99.699.699.699.6
E-199.086.898.798.6
E-297.885.197.396.8
H-198.398.198.196.5
H-298.898.298.797.4
), ArticleFig(id=1239250721175040966, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.6, caption=

Results of KD

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		KD/(mL·mg-1)
T040 ℃ 1周(40 ℃ for 1 week)40 ℃ 2周(40 ℃ for 2 weeks)40 ℃ 4周(40 ℃ for 4 weeks)
A5.96×10-3-3.00×10-3-1.52×10-2-9.92×10-3
C-1.98×10-2/-2.04×10-2-2.14×10-2
D7.55×10-41.26×10-38.19×10-4-6.89×10-4
H-1-1.63×10-2///
H-2-7.93×10-3///
), ArticleFig(id=1239250721263121353, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=表6, caption=

扩散相互作用指数检测结果

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		KD/(mL·mg-1)
T040 ℃ 1周(40 ℃ for 1 week)40 ℃ 2周(40 ℃ for 2 weeks)40 ℃ 4周(40 ℃ for 4 weeks)
A5.96×10-3-3.00×10-3-1.52×10-2-9.92×10-3
C-1.98×10-2/-2.04×10-2-2.14×10-2
D7.55×10-41.26×10-38.19×10-4-6.89×10-4
H-1-1.63×10-2///
H-2-7.93×10-3///
), ArticleFig(id=1239250721359590345, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.7, caption=

Tagg of C molecule after incubation at high temperature

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		Tagg/℃
T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)
C59.6253.29NA
), ArticleFig(id=1239250721485419466, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=表7, caption=

C分子在高温孵育后的Tagg值

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		Tagg/℃
T040 ℃ 1周
(40 ℃ for 1 week)		40 ℃ 2周
(40 ℃ for 2 weeks)
C59.6253.29NA
), ArticleFig(id=1239250723003757515, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=EN, label=Tab.8, caption=

Tagg of G molecule after incubation at high temperature，strong light，freeze-thaw and agitation

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		Tagg/℃
T040 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)		强光照2周
(strong light for 2 weeks)		冻融10次
(freeze-thaw 10 cycles)		振荡1周
(agitation for 1 week)
G57.8251.7349.6356.8758.1258.81
), ArticleFig(id=1239250723096032204, tenantId=1146029695717560320, journalId=1205117023404326918, articleId=1239250706977321371, language=CN, label=表8, caption=

G分子在高温孵育、强光照、反复冻融和振荡后的Tagg值

, figureFileSmall=null, figureFileBig=null, tableContent=
分子
(molecule)		Tagg/℃
T040 ℃ 2周
(40 ℃ for 2 weeks)		40 ℃ 4周
(40 ℃ for 4 weeks)		强光照2周
(strong light for 2 weeks)		冻融10次
(freeze-thaw 10 cycles)		振荡1周
(agitation for 1 week)
G57.8251.7349.6356.8758.1258.81
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抗体制剂乳光现象与分子粒径及聚集倾向性研究
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周文超 1, 2 , 张雪莲 2 , 郭树华 1 , 马琳 1
药物分析杂志 | 安全监测 2024,44(4): 678-688
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药物分析杂志 | 安全监测 2024, 44(4): 678-688
抗体制剂乳光现象与分子粒径及聚集倾向性研究
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周文超1, 2 , 张雪莲2, 郭树华1, 马琳1
作者信息
  • 1.苏州普乐康医药科技有限公司，苏州 215000
  • 2.复旦大学生命科学学院，上海 200438

    • Tel：18862391213；E-mail：

Opalescence appearance of antibody formulation correlation with molecular size or aggregation propensity
Wen-chao ZHOU1, 2 , Xue-lian ZHANG2, Shu-hua GUO1, Lin MA1
Affiliations
  • 1.Suzhou Pro-heal Pharmaceuticals Technology Co., Ltd., Suzhou 215000, China
  • 2.School of Life Science, Fudan University, Shanghai 200438, China
出版时间: 2024-04-30 doi: 10.16155/j.0254-1793.2024.04.15
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摘要
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目的：

对抗体制剂乳光现象与分子粒径、纯度及聚集倾向性的相关性进行系统研究。

方法：

通过研究多种抗体的乳光现象，其中包含不同浓度、pH/缓冲盐及辅料对乳光现象的影响，以及温度、光照、反复冻融及振荡等环境因素的影响，分析乳光现象与分子粒径、纯度(聚集体)、扩散相互作用指数(KD)及聚集温度(Tagg)之间的关联。

结果：

抗体制剂乳光与分子粒径大小呈正相关，乳光程度的加深表明分子粒径有所增加且分子聚集倾向性增加，如C分子在高温条件下，乳光现象明显加深，浊度由3.3 NTU变为13.6 NTU，粒径由13.1 nm变为40.6 nm，KD由正变负，Tagg由59.6 ℃变为50 ℃以下。

结论：

缓冲体系、pH及辅料等处方因素，以及温度等条件均会影响抗体制剂的乳光特性，乳光程度增加，预示制剂稳定性降低，更容易发生聚集。本研究为抗体药物制剂生产中乳光的检测评价提供重要参考。

抗体制剂  /  乳光现象  /  分子粒径  /  高级结构  /  稳定性  /  聚集
Objective:

To explore the correlations between opalescence and molecular size, purity or aggregation tendency in the antibody formulation.

Methods:

Studied on the opalescence phenomena of various antibodies, including the influence of different concentrations, pH/buffer, excipients, as well as the influence of environmental factors such as temperature, light, freeze-thaw and agitation, and the correlations had been analyzed between opalescence and molecular size, purity (aggregation), KD or Tagg.

Results:

The degree of antibody opalescence was positively correlated with the molecular size, the deepening of the opalescence indicated that the molecular size was increased and the more tendency of molecular aggregation. For example, the opalescence of C molecule obviously enhanced under high temperature, and the result of turbidity changed from 3.3 NTU to 13.6 NTU, the molecular size changed from 13.1 nm to 40.6 nm, and the KD changed from positive to negative. The Tagg changed from 59.6 ℃ to below 50 ℃.

Conclusion:

The opalescence can be affected by buffer system, pH, excipients and ambient temperature, the degree of opalescence increased, indicating the stability become worse and the molecules prone to aggregate. This study provides important reference for the analysis and evaluation of opalescence in the antibody formulation development.

antibody formulation  /  opalescence  /  molecular size  /  high-lever structure  /  stability  /  aggregation
周文超, 张雪莲, 郭树华, 马琳. 抗体制剂乳光现象与分子粒径及聚集倾向性研究. 药物分析杂志, 2024 , 44 (4) : 678 -688 . DOI: 10.16155/j.0254-1793.2024.04.15
Wen-chao ZHOU, Xue-lian ZHANG, Shu-hua GUO, Lin MA. Opalescence appearance of antibody formulation correlation with molecular size or aggregation propensity[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (4) : 678 -688 . DOI: 10.16155/j.0254-1793.2024.04.15
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随着用于免疫治疗抗体制剂越来越多，在投入临床应用前应严格质量检测，以保证抗体制剂的安全(safety)、稳定(stable)及有效(effective)，这些检测包括外观、pH、可见异物、不溶性微粒、纯度、杂质、电荷异质体、无菌、异常毒性和活性等[1]。抗体药物制剂的剂型多以液体形式为主，对外观检测通常为灯检法(人工目检)观察液体是否带有颜色(如无色或淡黄色)，是否有颗粒(蛋白颗粒或外源颗粒)，以及是否澄清透明(澄明或微乳光)。当前行业内做法通常在成品完成加塞轧盖后，进行100%的目检，剔除外观不合格样品，如带有异物的样品。其中制剂外观的颜色和乳光现象，一般仅作为产品本身固有属性记录，如抗体溶液呈现淡黄色，多认为由原液中VB12结合CO3+，或其他残留金属离子，或残留宿主残留蛋白(HCP)导致，也可能由于成品中如组氨酸等辅料氧化，或某些氨基酸，如色氨酸氧化导致[2-4]。在实际应用中，乳光现象常被称为浊度(图1)，然而有时浊度多指溶液的浑浊程度，即光线与溶液中的白色悬浮颗粒相互作用，为光反射结果。而抗体制剂的乳光现象本质上是光散射引起，可以用瑞利散射解释，表示溶液中纳米级微粒对光的散射强度。散射光越强即溶液乳光现象越严重(浊度越大)。欧洲药典将抗体液体制剂的乳光程度分为4个等级：①澄清0~3 NTU；②微乳光3~6 NTU；③乳光6~18 NTU；④强乳光18~30 NTU[5]。目前，抗体溶液的乳光现象与样品的粒径、乳光、纯度以及样品聚集稳定性是否相关并不十分清楚。
本研究通过多种抗体分子，根据其不同处方、不同pH及不同孵育条件下的制剂乳光现象及变化程度，同时检测相应的分子粒径、纯度(聚集体)、扩散相互作用指数(diffusion interaction coefficient，KD)和聚集起始温度(Tagg)，多维角度地探究抗体乳光现象与其分子粒径、纯度(聚集体)、KD、Tagg等之间的关联性。在此研究基础上对抗体乳光现象的本质及其影响因素进行了讨论，为抗体药物制剂生产中乳光的检测评价提供重要参考，为抗体制剂开发过程中的稳定性研究提供思路。
1　仪器与试药
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1.1　仪器
YB-2澄明度检测仪(天大天发科技有限公司)；HACH-2100AN浊度仪(哈希公司)；Zetasizer Nano ZS型纳米粒度仪(马尔文仪器有限公司)；Agilent 1260高效液相色谱仪(安捷伦科技有限公司)；DynaPro动态激光粒度仪(怀雅特技术公司)。
1.2　样品及处方
共收集8种抗体制剂分子，分别以A、B、C、D、E、F、G、H进行命名，通过离心超滤形式，制备到相应处方体系，其中B分子、E分子和H分子制备了多种处方体系，以考察不同处方体系对抗体分子乳光的影响。所有制备样品进行无菌过滤后，分装至西林瓶中，完成实验样品的制备(见表1)。
2　方法与结果
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8种抗体分子制剂样品，分别进行(40±2) ℃的高温孵育考察，于起始点(T0)、1周、2周和4周进行取样检测。其中A、C、D、E、H分子还进行了反复冻融(-40 ℃至室温25 ℃)10次、强光照(5 000 lx)2周及振荡(300 r·min-1)1周的考察。
2.1　外观结果
在1 500 lx的澄明度仪光照条件下，水平目测所有样品的乳光现象，发现8种抗体分子的制剂乳光现象均是不相同的，即使同一分子在不同处方体系或不同浓度时，也会呈现不同的乳光现象(见表2)。如B分子在醋酸(A 5.0和A 5.5)和组氨酸(H 5.5、H 6.0和H 6.5)的缓冲体系中呈现澄清状态，且高温孵育后也没有明显的变化，而在柠檬酸(C 5.0、C 5.5和C 6.0)缓冲体系中呈现轻微乳光现象，并且在高温条件下其乳光程度轻微增强。另外，2种浓度的E分子溶液，其高浓度样品(E-2，140 mg·mL-1)乳光现象明显强于低浓度样品(E-1，20 mg·mL-1)。H分子在2种处方体系中均呈现典型的乳光现象，但组氨酸体系(H-2)中的乳光现象明显强于柠檬酸体系(H-1)。
通过高温孵育后，A、C、F、E-1、G和H-1的分子溶液，外观观测到的乳光现象均有所增强，尤其C分子溶液的乳光程度变化最为明显，其余分子则不能通过人眼辨别出乳光强度的变化。另外，通过反复冻融(-40 ℃至室温)、强光照(5 000 lx)及振荡(300 r·min-1)考察的几种分子，外观观测的乳光强度，均无明显变化。
2.2　浊度和粒径结果
通过浊度仪测量与照射样品入射光呈90 °的散射光强度，样品无需稀释，取2 mL置于样品瓶中，仔细擦去瓶壁印记，放入检测池，检测并记录结果，以NTU作为浊度单位。通过纳米粒度仪的动态光散射技术(DLS)对抗体进行粒径检测，样品无需稀释，取50 μL放入样品池，避免气泡，平衡温度25 ℃，选择检测角度173 °，测量粒子的流体力学半径(指动态的水合/溶剂化粒子的表观粒径)[6]。结果显示8种抗体分子溶液的浊度与分子粒径均是不相同的，即使同一分子在不同处方体系或不同浓度时，也会呈现不同的浊度值与粒径值(见表3)。如B分子在不同的pH缓冲体系中，浊度和粒径是有差异的(见图2)，在柠檬酸体系中的浊度值和分子粒径值，均比在醋酸和组氨酸体系大，并且高温孵育后，也只有柠檬酸体系中的浊度值和粒径值轻微增加，该结果与外观观测的乳光现象一致，推断该分子在柠檬酸体系中是不稳定的。另外，2种浓度的E分子溶液，其高浓度E-2溶液的浊度值和粒径值，均大于低浓度的E-1溶液；H分子在2种处方体系中的浊度值与分子粒径值差别较大，在柠檬酸体系(H-1)中，浊度和粒径值的表现均小于组氨酸体系(H-2)，但高温孵育后，柠檬酸体系(H-1)的浊度值与分子粒径值更容易发生变化(见图3)。
经过分析，发现高温孵育后，A、C、D、F和G 5种分子溶液，其浊度和分子粒径值也呈现出明显的增加趋势(见图4)，其中最明显的C分子，其浊度由3.3 NTU增加至13.6 NTU，相应的分子粒径由13.1 nm变为40.6 nm。另外，通过强光照(5 000 lx)、反复冻融(-40 ℃至室温)及振荡(300 r·min-1)的考察的几种分子，浊度和粒径值均无明显变化(见表4)，与外观观测的乳光现象一致。
通过浊度与分子粒径的数据，表明了在高温条件下观测出的乳光现象增强现象或不同处方体系中呈现出不同的乳光现象，本质上均是分子粒径不同导致。在强光照、反复冻融和振荡条件下，考察的多种抗体分子粒径保持稳定，其乳光现象也无明显变化。
2.3　纯度结果
采用Agilent 1260高效液相色谱仪和TSKgel G3000SWXL (300 mm×7.8 mm，5 μm)色谱柱，以50 mol·L-1磷酸缓冲液-300 mol·L-1氯化钠溶液(pH 6.8±0.1)为流动相，流速1.0 mL·min-1，等度洗脱20 min，柱温20 ℃，检测波长280 nm，流动相稀释样品至1.0 mg·mL-1，进样体积100 μL，进行分离检测。通过体积排阻色谱(size exclusion chromatography，SEC)法，依据分子量大小的差异来获得单体纯度。结果显示在高温条件下，所有分子纯度均发生了不同程度的下降，片段峰有所增加，但更多体现是聚集体(HMW)增加，其中F分子聚集体增加最明显，从1.1%增加至21.6%；C分子聚集体从1.4%增加至3.8%(见图5)；B分子在柠檬酸体系(C 5.0~C 6.0)中，聚集体增加最明显(见图6)。高浓度E分子(E-2，140 mg·mL-1)溶液浊度和聚集体，均大于低浓度E-1溶液(30 mg·mL-1)，E-2聚集体呈现增加的趋势，但浊度则基本无明显变化；H分子在柠檬酸体系(H-1)中的聚集体随着浊度上升而增加，在组氨酸体系(H-2)中的浊度虽无明显变化，但聚集体则明显增加(见图7)。
综合分析溶液浊度、分子粒径和聚集体结果，当浊度与粒径增大时，往往会引起聚集体的增加。但不同分子，本身稳定性存在差异，则聚集体增加程度会有所不同，如F分子，当浊度与粒径发生变化时，其纯度也会发生明显变化。通过E-2和H-2的结果，表明聚集体也可能由分子自身稳定性或其他因素(如浓度、温度等)导致，即聚集体的增加不一定会通过浊度与粒径的变化体现。另外，通过反复冻融(-40 ℃至室温)、强光照(5 000 lx)及振荡(300 r·min-1)考察的几种分子，A分子和E分子在强光照条件下的纯度明显下降，其他条件下的所有分子纯度均无明显变化(见表5)，表明了在乳光程度或分子粒径未发生变化的情况下，纯度也可能由光照或其他因素导致下降。
2.4　聚集倾向性检测
2.4.1　扩散相互作用指数
抗体分子的聚集倾向性可预测产品稳定性，通过动态激光粒度仪测定样品的浓度与扩散系数间的关系，得出分子间的KD，该值可反映分子间的弱相互作用，当KD>0时，表示分子间存在弱相互排斥力，预测样品较稳定；当KD<0时，表示分子间存在弱相互吸引力，预测样品处于不稳定状态[7]。根据样品浓度，用相应处方（见表1）稀释至5个梯度的浓度样品(如A分子分别稀释至4、8、16、24、30 mg·mL-1)，分别添加30 μL至384样品板中，2 000 r·min-1离心5 min去除气泡，放入样品槽中，温度设置25 ℃，选择KD检测模式。
A、C、D和H共4种分子KD值检测结果见表6，其中A分子在高温条件下，随着浊度与粒径的增加，40 ℃ 2周和40 ℃ 4周的KD变为负值(图8)，表明分子已由稳定状态转为不稳定状态，而在反复冻融、光照和振荡条件下的浊度、粒径与KD值，均没有发生明显变化；C分子则从T0开始，40 ℃ 2周和40 ℃ 4周的KD值均为负值(图9)，表明C分子的不稳定性，其浊度与粒径检测结果也变化较大；D分子则在T0、40 ℃ 1周和40 ℃ 2周的KD值为正值，40 ℃ 4周时，KD值转为负值(图10)；H分子在2种体系下(H-1和H-2)的KD均为负值(图11)，但H-2的斜率明显更大，表明H分子在柠檬酸和组氨酸2种体系中均是不稳定的，但在组氨酸体系中的稳定性更差，在浊度、粒径与纯度结果中也有相应的体现。
通过分析KD值及相应的浊度、分子粒径结果，可知抗体分子溶液在浊度值和粒径值增大时，分子间的弱相互间作用力也会发生变化。
2.4.2　聚集温度
抗体蛋白分子Tagg目前已被作为抗体胶体热稳定性的特征参数之一，较低的Tagg往往是预示着低热稳定性和低胶体稳定性的标志，基于颗粒的光散射效应，对蛋白分子进行逐步和连续的加热，通过DynaPro动态激光粒度仪分析出抗体分子的粒径尺寸及变化情况，从而获得随着温度变化，抗体分子聚集的形成趋势，分析出样品的Tagg[7-8]。样品无需稀释，添加30 μL至384样品板中，2 000 r·min-1离心5 min去除气泡，再缓慢加入15 μL石蜡油进行密封，防止样品加热过程中挥发，放入样品槽中后，温度设置25至70 ℃，升温速率为1 ℃·h-1，选择Tagg检测模式。
高温孵育后的C分子Tagg检测结果见表7，该分子T0的Tagg为59.6 ℃，高温孵育1周的Tagg为53.3 ℃，高温孵育2周后的Tagg已无法通过软件计算给出，但通过图谱分析可判断其Tagg在50 ℃以下(见图12)。
同样G分子也进行了高温孵育后的Tagg检测，及强光照2周、反复冻融10次和振荡1周的Tagg检测，结果见表8。结果显示，G分子在强光照、反复冻融或振荡后的Tagg与起始点(T0)相比，均没有明显变化，保持在58 ℃上下。但高温孵育2周和4周的样品，其Tagg明显发生了下降，分别为51.73 ℃和49.63 ℃，表明G分子在高温孵育后，其分子构象受热力学影响发生了变化，不仅导致溶液浊度升高及分子粒径变大，其Tagg也变低了(见图13)。
通过分析C分子与G分子的Tagg值及相应的浊度、分子粒径结果，可知抗体分子溶液在浊度值和粒径值增大时，分子更容易发生聚集。
3　讨论
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抗体制剂溶液呈现的乳光程度，本质因素是抗体分子本身的高级结构状态及其浓度的影响，其中以抗体分子高级结构状态为主要因素。从本研究结果可见，抗体制剂溶液乳光现象的变化是与分子粒径及聚集倾向性有关联的，甚至与抗体分子长期的稳定性有关。
总结本研究，多方面的因素会引起溶液乳光现象的变化：①抗体分子浓度的增加，会使溶液乳光程度增加，但通常并不会使乳光程度明显增强，否则表明在该分子的高浓度状态下分子之间的相互作用力已经促使分子构象发生了变化，即此状态下的分子是不稳定的，很容易发生聚集；②缓冲盐的影响，如组氨酸和柠檬酸2种缓冲体系，根据作者行业经验，多数抗体分子在柠檬酸体系中容易形成明显的乳光现象，稳定性也相对较差，但不是绝对的，如H分子；③其他处方中的因子，如辅料或pH，也可能会影响抗体溶液的乳光程度；④当溶液体系确定下来时，常规的光照、反复冻融和振荡等条件对抗体溶液乳光现象产生影响较小，但如高温则通常可导致抗体溶液乳光现象发生明显变化[9-13]。推测在高温条件下，抗体分子结构容易从“紧密”状态变为“膨松”状态，甚至为“伸展”的状态，即抗体分子的粒径变大，从而引起更强的光散射，导致溶液的乳光程度增加[14-15]。根据乳光现象、分子粒径及KD和Tagg的关联性研究，推测出以下3种模型(图14)：
1)稳定态(stable)：即抗体分子的天然状态，其高级结构受缚于疏水作用力，疏水的非极性氨基酸大多包埋于分子构象内部，外部水合层相对稳定，整体的分子高级结构呈现“紧密”的状态，此时溶液外观基本为澄清或微乳光的状态[16-17]。
2)亚稳态(metastability)：在热力学驱动力下，抗体分子构象内部的部分疏水氨基酸不再完全受缚于疏水作用力，趋于暴露在结构表面，原先的外部水合层也发生相应变化，导致其高级结构呈现相对“膨松”的状态，此时溶液外观基本为微乳光或乳光的状态[18]。
3)变性态(denature)：受热力学的强力驱动，抗体分子构象内部的大多数或所有疏水氨基酸，已不再“屈服”于疏水作用力，完全从分子内部暴露出来，分子高级结构呈现“伸展”的状态，此时溶液基本为乳光或强乳光状态，该状态下极易发生分子间的聚集[19]。
因此，在抗体制剂处方筛选阶段，若溶液乳光现象较为明显，可以尝试优化盐类辅料、不同种类的缓冲盐及pH等条件，后期工艺开发也建议温和的工艺参数，尽量保证分子构象上的稳定性[20-21]。若在稳定性考察过程中发现乳光程度有所变化，往往意味着抗体分子的高级结构状态发生变化，但当该变化较小时，即抗体分子的高级结构处于亚稳态时，很可能该分子的其他检测指标是无明显差异或无明显变化的，因为这时候的抗体可能依然处于活性状态[22]。另外需要说明的是，稳定态和亚稳态，这2种抗体分子高级结构状态，并不能等同于可逆的分子状态，更不能看作可逆聚集的状态。
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2024年第44卷第4期
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doi: 10.16155/j.0254-1793.2024.04.15
  • 首发时间：2026-03-13
  • 出版时间：2024-04-30
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    1.苏州普乐康医药科技有限公司，苏州 215000
    2.复旦大学生命科学学院，上海 200438
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2种不同金属材料的力学参数
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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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