基于NMR 指纹谱相关分析的生物类似药高级结构评价

doi:10.11938/cjmr20150216

波谱学杂志 ›› 2015, Vol. 32 ›› Issue (2): 342-353.doi: 10.11938/cjmr20150216

基于NMR 指纹谱相关分析的生物类似药高级结构评价

许美凤，方均建，董芳霆，颜贤忠*

国家生物医学分析中心，北京 100850

收稿日期:2015-02-16 修回日期:2015-05-08 出版日期:2015-06-05 在线发表日期:2015-06-05
作者简介:*通讯联系人：颜贤忠，电话：+86-10-66930305，E-mail：yanxz@proteomics.cn.
基金资助:
The National Science and Technology Major Projects (2014ZX09304311-001, 2012ZX09301003-001-010).

Higher Order Structure Assessment of Biosimilars Based on the Correlation of NMR Spectral Fingerprints

XU Mei-feng，FANG Jun-jian，DONG Fang-ting，YAN Xian-zhong*

National Center of Biomedical Analysis, Beijing 100850

Received:2015-02-16 Revised:2015-05-08 Published:2015-06-05 Online:2015-06-05
About author:XU Mei-feng (1986-), female, born in Fujian, Master, her research focuses on liquid NMR, Tel: +86-10-66931443, Fax: +86-10-68246161, E-mail: xumeifeng103@126.com. *Corresponding author: YAN Xian-zhong, Tel: +86-10-66930305, E-mail:yanxz@proteomics.cn.
Supported by:
The National Science and Technology Major Projects (2014ZX09304311-001, 2012ZX09301003-001-010).

摘要/Abstract

摘要：

建立了基于¹H NMR 指纹技术的生物类似药高级结构相似性分析方法，利用相关系数r 和决定系数R2 定量评估生物类似药与其原研药的结构相似度．将该方法应
用在一种分子量为1 620 的抗菌性脂肽达托霉素上，比较了其类似药的活性原料成分(API)、类似药制剂与原研药克必信的高级结构相似性．实验结果显示，3 个达托霉素样品的谱图存在显著差异，表明达托霉素类似药与其原研药在水溶液中存在结构差异．将该方法应用在分子量为145 423 的单克隆抗体药物曲妥珠单抗的高级结构比对上．对1个批次的赫赛汀原研药、4 个批次的类似药的¹H NMR 谱进行相似性分析，相关系数r和决定系数R² 的结果显示，曲妥珠单抗的类似药与赫赛汀原研药相似度很高；进一步采用局部相关系数进行谱图分析，得到了曲妥珠单抗类似药与赫赛汀原研药之间的微小差异．研究表明，有效结合NMR 指纹分析技术和统计分析方法，将在生物类似药质量控制中发挥重大的作用．

关键词: NMR 指纹技术, 生物类似药, 相似度评价, 高级结构

Abstract:

A procedure based on the ¹H NMR fingerprints of biologics was established for the assessment of higher order structure of biosimilar samples. The global correlation coefficients r and R² of binned NMR spectra were used to quantify structural similarity between biosimilars and originators, and a local correlation analysis method was used to find out the specific regions that contribute to the structure differences. This method was applied to the quantitative
assessment of daptomycin, a lipopeptide antibiotic with a molecular weight of 1 620, by comparing the higher order structure of the biosimilar active pharmaceutical ingredient (API), its injection and originator injection Cubicin. The results showed that there were significant spectral differences among daptomycin samples, indicating structural differences between daptomycin originator and its biosimilars. Local correlation analysis further revealed the specific spectral regions that contributed to these differences. The method was also applied to a monoclonal antibody drug Trastuzumab, which is a large protein with a molecular weight of 145 423. ¹H NMR spectra of the originator drug Herceptin and four lots of its biosimilar were recorded and binned for statistical analysis. The correlation coefficients r and R2 showed that Trastuzumab biosimilars seem to be highly similar to Herceptin. These results demonstrated that the combination of NMR fingerprints and statistical analysis is a powerful and robust technique in biosimilar quality control.

Key words: NMR fingerprint, biosimilar, similarity assessment, higher order structure

中图分类号:

O482.53

许美凤，方均建，董芳霆，颜贤忠*. 基于NMR 指纹谱相关分析的生物类似药高级结构评价[J]. 波谱学杂志, 2015, 32(2): 342-353.

XU Mei-feng，FANG Jun-jian，DONG Fang-ting，YAN Xian-zhong*. Higher Order Structure Assessment of Biosimilars Based on the Correlation of NMR Spectral Fingerprints[J]. Chinese Journal of Magnetic Resonance, 2015, 32(2): 342-353.

参考文献

[1] Walsh G. Biopharmaceutical benchmarks 2014[J]. Nat Biotech, 2014, 32(10): 992－1 000.

[2] European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing monoclonal antibodies-non-clinical and clinical issues[OL]. London: European Medicines Agency; 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf.

[3] Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference product[OL]. Rockville: Food and Drug Administration; 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.

[4] Berkowitz S A, Engen J R, Mazzeo J R, et al. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars[J]. Nat Rev Drug Discov, 2012, 11(7): 527－540.

[5] Falconer R J, Jackson-Matthews D, Mahler S M. Analytical strategies for assessing comparability of biosimilars[J]. J Chem Technol Biotechnol, 2011, 86(7): 915－922.

[6] Federici M, Lubiniecki A, Manikwar P, et al. Analytical lessons learned from selected therapeutic protein drug comparability studies[J]. Biologicals, 2013, 41(3): 131－147.

[7] Houde D, Berkowitz S A, Engen J R. The utility of hydrogen/deuterium exchange mass spectrometry in biopharmaceutical comparability studies[J]. J Pharm Sci, 2011, 100(6): 2 071－2 086.

[8] Amezcua C A, Szabo C M. Assessment of higher order structure comparability in therapeutic proteins using nuclear magnetic resonance spectroscopy[J]. J Pharm Sci, 2013, 102(6): 1 724－1 733.

[9] Wishart D S. Characterization of biopharmaceuticals by NMR spectroscopy[J]. TrAC-Trends Anal Chem, 2013, 48: 96－111.

[10] Quinternet M, Starck J P, Delsuc M A, et al. Heteronuclear NMR provides an accurate assessment of therapeutic insulin's quality[J]. J Pharm Biomed Anal, 2013, 78/79: 252－254.

[11] Jin X, Kang S, Kwon H, et al. Heteronuclear NMR as a 4-in-1 analytical platform for detecting modification-specific signatures of therapeutic insulin formulations[J]. Anal Chem, 2014, 86(4): 2 050－2 056.

[12] Panjwani N, Hodgson D J, Sauve S, et al. Assessment of the effects of pH, formulation and deformulation on the conformation of interferon alpha-2 by NMR[J]. J Pharm Sci, 2010, 99(8): 3 334－3 342.

[13] Sauve S, Gingras G, Aubin Y. Assessment of the three-dimensional structure of recombinant protein therapeutics by NMR fingerprinting: demonstration on recombinant human granulocyte macrophage-colony stimulation factor[J]. Biomol NMR Assign, 2008, 2(1): 5－7.

[14] Visser J, Feuerstein I, Stangler T, et al. Physicochemical and functional comparability between the proposed biosimilar Rituximab GP2013 and originator Rituximab[J]. Biodrugs, 2013, 27(5): 495－507.

[15] Vu B K, Walsh J D, Dimitrov D S, et al. Dynamics of antibody domains studied by solution NMR[J]. Methods Mol Biol, 2009, 525:533－543, xv.

[16] Poppe L, Jordan J B, Lawson K, et al. Profiling formulated monoclonal antibodies by 1H NMR spectroscopy[J]. Anal Chem, 2013, 85(20): 9 623－9 629.

基于NMR 指纹谱相关分析的生物类似药高级结构评价

Higher Order Structure Assessment of Biosimilars Based on the Correlation of NMR Spectral Fingerprints

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