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<p>N-glycosylation heterogeneity has a significant impact on the clinical safety, efficacy, pharmacokinetics (PK), and pharmacodynamics of monoclonal antibody (mAb) drugs, thus becoming a critical quality attribute (CQA) of great concern. In the registration quality standards for bevacizumab produced by different manufacturers, either lacking supervision of N-glycosylation or the detection methods and criteria vary greatly among manufacturers, leading to compromised comparability of results. Besides, the existing quality control system pays insufficient attention to the correlation between glyco-relevant physicochemical properties and glycosylated modification. In this study, a standardized hydrophilic interaction liquid chromatography-fluorescence detection (HILIC-FLD) N-glycan profiling method was developed, which had been proven to be more time-saving and easier to operate and was used for the parallel analysis of N-glycan profiles in bevacizumab products provided by 8 different manufacturers. We also paid attention to the glycosylation-related CQAs including charge heterogeneity, isoelectric point, non-glycosylated heavy chain (NGHC) and aggregates. Results revealed obvious difference in N-glycosylation, NGHC and aggregates among manufacturers. Among all the mAbs, the abundance of major glycoforms showed similar order yet the percentage of the same glycoform varies greatly. In summary, the standardized method could offer a reliable, efficient and practical approach for the parallel analysis and comparison of glycosylation and related CQA heterogeneity among manufacturers, providing a reference for more effective quality control of mAb drugs.</p>

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Standardized HILIC-FLD N-Glycan Analysis for Assessing N-Glycosylation Heterogeneity and Glycosylation-Related Quality Attributes in Bevacizumab from Multiple Manufacturers

  • 期刊论文

  • 发表日期：

    2025年4月11日

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  • Doudou Lou,
  • Yuan Zhu,
  • Jingke Fan,
  • Lin Fan,
  • Qingfu Zhu,
  • Yihong Lu,
  • Shuqiang Zhao

摘要

N-glycosylation heterogeneity has a significant impact on the clinical safety, efficacy, pharmacokinetics (PK), and pharmacodynamics of monoclonal antibody (mAb) drugs, thus becoming a critical quality attribute (CQA) of great concern. In the registration quality standards for bevacizumab produced by different manufacturers, either lacking supervision of N-glycosylation or the detection methods and criteria vary greatly among manufacturers, leading to compromised comparability of results. Besides, the existing quality control system pays insufficient attention to the correlation between glyco-relevant physicochemical properties and glycosylated modification. In this study, a standardized hydrophilic interaction liquid chromatography-fluorescence detection (HILIC-FLD) N-glycan profiling method was developed, which had been proven to be more time-saving and easier to operate and was used for the parallel analysis of N-glycan profiles in bevacizumab products provided by 8 different manufacturers. We also paid attention to the glycosylation-related CQAs including charge heterogeneity, isoelectric point, non-glycosylated heavy chain (NGHC) and aggregates. Results revealed obvious difference in N-glycosylation, NGHC and aggregates among manufacturers. Among all the mAbs, the abundance of major glycoforms showed similar order yet the percentage of the same glycoform varies greatly. In summary, the standardized method could offer a reliable, efficient and practical approach for the parallel analysis and comparison of glycosylation and related CQA heterogeneity among manufacturers, providing a reference for more effective quality control of mAb drugs.