Feasibility of Rapid Regulatory Differentiation of TNF Receptor 2-Fc Fusion Protein Products from Various Manufacturers in the Chinese Market Using a Novel Mass Spectrometry-Based Multi-attribute Method (MAM)

IF 2.7 2区 化学 Q2 BIOCHEMICAL RESEARCH METHODS
Mengjiao Xu, , , Mingming Xu, , , Tao Liu, , , Dan Mao, , , Chunguang Zheng, , , Wei Yu, , , Qingcheng Guo, , , Zhixin Li, , , Tianyu Gao, , , Yule Ren, , , Weifan Zhu, , , Huangzhen Zhuang, , , Zhiyuan Pan, , , Fugui Wang, , , Xinxin Fang, , , Shanshan Dong, , , Lankun Song, , , Xi Chen, , , Aiying Nie, , , Lusha Ji, , , Weizhu Qian, , , Sheng Hou, , , Jun Li, , , Yajun Guo*, , , Dapeng Zhang*, , , Jin Xu*, , , Hong Shao*, , and , Huaizu Guo*, 
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引用次数: 0

Abstract

Ensuring the quality of pharmaceutical products, particularly for complex recombinant protein drugs such as TNF receptor 2-Fc fusion proteins (TNFR2-Fc, Etanercept), poses significant public health challenges. These products, including biosimilars and follow-on versions, exhibit intricate glycosylation patterns and heterogeneous post-translational modifications, complicating their analytical assessment. The Chinese market, hosting four different TNFR2-Fc products, presents a unique regulatory challenge for rapid differentiation and quality control. This study developed a novel mass spectrometry-based multiattribute method (MAM) to address this challenge, enabling simultaneous monitoring of multiple quality attributes and effective differentiation among products from various manufacturers. Conventional techniques initially indicated high purity across all products, but these methods provided limited capabilities for differentiation. The improved MAM approach, involving desialylation, partial deglycosylation, and digestion steps, minimizes heterogeneity and simplifies analysis. This method successfully indicates differences in primary amino acid sequences and specific quality attributes, allowing for a clear differentiation among manufacturers. Notably, products from manufacturers A and B, as well as C and D, despite their high similarity, could be differentiated by their O-glycan profiles. Further activity evaluations revealed that the products from manufacturers C and D exhibited lower binding and biological activity, potentially due to differences in primary amino acid sequences or disulfide bond mismatches. Additionally, all products demonstrated similar Fc-effector functions. In conclusion, this study underscores the variability among TNFR2-Fc products in the Chinese market and the necessity for robust regulatory oversight. The MAM method developed herein serves as a rapid, accurate, and technologically advanced platform for quality control with significant implications for regulatory authorities, healthcare providers, and patients in ensuring access to safe and effective TNFR2-Fc products.

Abstract Image

利用一种基于质谱的多属性方法(MAM)对中国市场不同制造商TNF受体2-Fc融合蛋白产品进行快速调控分化的可行性
确保药品的质量,特别是复杂重组蛋白药物,如TNF受体2-Fc融合蛋白(TNFR2-Fc,依那西普),构成了重大的公共卫生挑战。这些产品,包括生物仿制药和后续版本,表现出复杂的糖基化模式和异质翻译后修饰,使其分析评估复杂化。中国市场拥有四种不同的TNFR2-Fc产品,对快速差异化和质量控制提出了独特的监管挑战。本研究开发了一种新的基于质谱的多属性方法(MAM)来解决这一挑战,能够同时监测多个质量属性,并有效区分来自不同制造商的产品。传统技术最初表明所有产品的纯度都很高,但这些方法提供的区分能力有限。改进的MAM方法,包括去糖基化、部分去糖基化和消化步骤,最大限度地减少了异质性,简化了分析。该方法成功地显示了初级氨基酸序列和特定质量属性的差异,允许制造商之间的明确区分。值得注意的是,A和B制造商的产品,以及C和D制造商的产品,尽管它们高度相似,但可以通过它们的o聚糖谱来区分。进一步的活性评价表明,C和D生产的产品具有较低的结合和生物活性,可能是由于初级氨基酸序列的差异或二硫键不匹配。此外,所有产品都显示出相似的fc效应功能。总之,本研究强调了中国市场上TNFR2-Fc产品的可变性以及加强监管的必要性。本文开发的MAM方法是一种快速、准确、技术先进的质量控制平台,对监管机构、医疗保健提供者和患者确保获得安全有效的TNFR2-Fc产品具有重要意义。
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来源期刊
CiteScore
5.50
自引率
9.40%
发文量
257
审稿时长
1 months
期刊介绍: The Journal of the American Society for Mass Spectrometry presents research papers covering all aspects of mass spectrometry, incorporating coverage of fields of scientific inquiry in which mass spectrometry can play a role. Comprehensive in scope, the journal publishes papers on both fundamentals and applications of mass spectrometry. Fundamental subjects include instrumentation principles, design, and demonstration, structures and chemical properties of gas-phase ions, studies of thermodynamic properties, ion spectroscopy, chemical kinetics, mechanisms of ionization, theories of ion fragmentation, cluster ions, and potential energy surfaces. In addition to full papers, the journal offers Communications, Application Notes, and Accounts and Perspectives
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