不同单克隆抗体聚集与断裂行为的多维分析

Q511; 采用尺寸排阻色谱法和分析型超速离心法对ZG154和ZG187抗体的分子大小变异体进行正交分析,系统解析了造成聚集和断裂的因素.结果表明,40℃时ZG154样品在天冬酰胺 329位点发生脱酰胺修饰的比例增加了 30.7%,通过增加分子间相互作用,相关修饰加速了聚集,并导致断裂的发生;40℃时ZG187样品在蛋氨酸 430位点发生氧化修饰的比例增加了36.9%,相关修饰降低了蛋白的稳定性,导致了断裂的发生.研究结果为上述药物研发和生产过程中的聚集与断裂问题提供了检测和分析方法....

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Published in华东理工大学学报（自然科学版） Vol. 51; no. 1; pp. 42 - 49
Main Authors 陆治锦, 文玺凯, 刘鲁杰, 王宜冰, 沈春雷, 伍维, 沈智勇, 赵黎明
Format Journal Article
LanguageChinese
Published 上海臻格生物技术有限公司,上海 201413%华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237 2025
上海市细胞代谢光遗传学技术前沿科学研究基地,上海 200237%上海臻格生物技术有限公司,上海 201413
华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237%华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237
Subjects
deamidation
氧化
oxidation
断裂
aggregation
聚集
脱酰胺
单克隆抗体
fragmentation
monoclonal antibodies
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Abstract Q511; 采用尺寸排阻色谱法和分析型超速离心法对ZG154和ZG187抗体的分子大小变异体进行正交分析,系统解析了造成聚集和断裂的因素.结果表明,40℃时ZG154样品在天冬酰胺 329位点发生脱酰胺修饰的比例增加了 30.7%,通过增加分子间相互作用,相关修饰加速了聚集,并导致断裂的发生;40℃时ZG187样品在蛋氨酸 430位点发生氧化修饰的比例增加了36.9%,相关修饰降低了蛋白的稳定性,导致了断裂的发生.研究结果为上述药物研发和生产过程中的聚集与断裂问题提供了检测和分析方法.
AbstractList Q511; 采用尺寸排阻色谱法和分析型超速离心法对ZG154和ZG187抗体的分子大小变异体进行正交分析,系统解析了造成聚集和断裂的因素.结果表明,40℃时ZG154样品在天冬酰胺 329位点发生脱酰胺修饰的比例增加了 30.7%,通过增加分子间相互作用,相关修饰加速了聚集,并导致断裂的发生;40℃时ZG187样品在蛋氨酸 430位点发生氧化修饰的比例增加了36.9%,相关修饰降低了蛋白的稳定性,导致了断裂的发生.研究结果为上述药物研发和生产过程中的聚集与断裂问题提供了检测和分析方法.
Abstract_FL This paper used size exclusion chromatography and analytical ultracentrifugation techniques to perform orthogonal analysis of the molecular size variants of ZG154 and ZG187 antibodies.Moreover,liquid chromatography-mass spectrometry,circular dichroism spectroscopy,dynamic light scattering and differential scanning fluorescence techniques were used to systematically analyze the factors causing aggregation and fragmentation.The results showed a 30.7%increase in the deamidation modification at the 329 site of asparagine in the ZG154 sample when stored at 40℃.The related modifications did not alter the secondary and tertiary structures,as well as the stability of the protein,but accelerated aggregation by increasing intermolecular interactions and led to fragmentation due to the production of succinimide.Moreover,there was a 36.9%increase in the oxidative modification at the lysine 430 site in the ZG187 sample when stored at 40℃,which reduced the stability of the protein and led to fragmentation.However,it did not change the secondary and tertiary structures of the protein,and the molecules always exhibited mutually exclusive interactions,thus not leading to aggregation.Furthermore,the changes in the sedimentation coefficient of ZG154 dimer and the non-covalent interactions between ZG187 molecular fragments were revealed through analytical ultracentrifugation sedimentation velocity analysis.These results describe suitable detection methods which can be combined to resolve the aggregation and fragmentation problems in the development and production of the above-mentioned drugs.
Author 陆治锦
刘鲁杰
沈智勇
王宜冰
赵黎明
文玺凯
伍维
沈春雷
AuthorAffiliation 华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237%华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237;上海臻格生物技术有限公司,上海 201413%华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237;上海市细胞代谢光遗传学技术前沿科学研究基地,上海 200237%上海臻格生物技术有限公司,上海 201413
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Author_FL LU Zhijin
SHEN Chunlei
WANG Yibing
SHEN Zhiyong
ZHAO Liming
WU Wei
LIU Lujie
WEN Xikai
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DocumentTitle_FL Multi-Tiered Analysis of Aggregation and Fragmentation Behavior of Different Monoclonal Antibodies
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Keywords deamidation
氧化
oxidation
断裂
aggregation
聚集
脱酰胺
单克隆抗体
fragmentation
monoclonal antibodies
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PublicationTitle 华东理工大学学报（自然科学版）
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PublicationYear 2025
Publisher 上海臻格生物技术有限公司,上海 201413%华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237
上海市细胞代谢光遗传学技术前沿科学研究基地,上海 200237%上海臻格生物技术有限公司,上海 201413
华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237%华东理工大学生物工程学院,生物反应器工程国家重点实验室,上海 200237
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Snippet Q511; 采用尺寸排阻色谱法和分析型超速离心法对ZG154和ZG187抗体的分子大小变异体进行正交分析,系统解析了造成聚集和断裂的因素.结果表明,40℃时ZG154样品在天冬酰胺 329位点发生脱酰胺修饰的比例增加了...
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StartPage 42
Title 不同单克隆抗体聚集与断裂行为的多维分析
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