a Shanghai Henlius Biotech, Inc ., Shanghai , China.
MAbs. 2019 Apr;11(3):606-620. doi: 10.1080/19420862.2019.1578147. Epub 2019 Feb 22.
Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China's Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, efficacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.
在过去的十年中，中国的生物治疗药物发展呈指数级增长。然而，由于缺乏国家生物类似药监管指导原则，中国尚未批准任何生物类似药。HLX01 是在中国按照欧洲药品管理局生物类似药指导原则和要求开发的利妥昔单抗生物类似药，是中国第一个提交监管审查的此类药物，预计将作为生物类似药产品在中国获得批准。为了证明 HLX01、CN-利妥昔单抗（中国来源但在欧洲生产）和 EU-利妥昔单抗（欧洲来源和生产）的分析相似性，根据中国药品评价中心最近发布的相似性要求指南，采用一系列正交和最先进的技术进行了广泛的 3 路物理化学和功能相似性评估。相似性研究的结果表明，HLX01 与参比药物 MabThera®的蛋白氨基酸序列完全相同，一级结构高度相似，高级结构、效价、完整性、纯度和杂质谱、生物学和免疫结合功能以及在应激条件下的降解行为也高度相似。此外，HLX01 的聚集体略低于参比药物，光稳定性略好。尽管糖基部分的相对丰度和重链 C 末端赖氨酸修饰略有变化，但参比药物和 HLX01 之间的生物学活性和免疫原性没有差异。总之，HLX01 在理化性质和生物学活性方面与 CN 和 EU 来源的参比药物高度相似，提示其具有相似的产品质量、疗效和安全性。对 HLX01 上市申请进行的分析相似性评估所采用的监管要求为中国生物类似药产品的分析相似性评估树立了先例。
