Quantitative biochemical response profiling as a methodology for comparing biosimilar compounds

生物技术产品的一个主要市场领域是单克隆抗体，它可用作诊断工具、药物和分子生物学试剂。然而，用于产生单克隆抗体的方法通常不产生单一类型的生物分子，而是产生密切相关的生物分子的集合体，其可以具有糖基化模式和其他次要特征的差异。这可能导致单克隆抗体生物学效应的细微差异。因此，开发用于鉴定单克隆抗体的生物学效应的潜在变化的方法具有相当大的实际重要性。可能受到这些变化影响的一个领域是 包括生物仿制药和可互换生物制剂在内的进口药品，它们是已建立药品的类似物。为了证明这些化合物与原研生物制剂等效，制造商必须满足涉及严格的统计等效性测试的法规要求。这对于复杂的生物分子如单克隆抗体可能具有挑战性，因为包括糖基化在内的次要特征对于原研药和生物仿制药化合物而言通常是可变的。因此，需要新的方法来满足等效性的统计学要求，特别是在效价和免疫功能受聚糖影响的情况下。该项目将开发定量方法，通过使用高通量表达分析，评估和比较生物仿制药和原研药的生化作用。本研究将探讨高通量基因和蛋白表达分析作为比较生物仿制药与相应原研药生物学效应的工具的有效性 生物制品该项目中用作模型的特定靶标是曲妥珠单抗（赫赛汀），这是一种干扰HER 2/neu受体的单克隆抗体，在某些癌症中不受调节。将研究对曲妥珠单抗生物类似药的反应，其将在适当范围内显示效果等效性，或可能揭示可能指向新生物学影响的非预期效果。

A major market area for biotechnology products is monoclonal antibodies, which have applications as diagnostic tools, pharmaceuticals and molecular biology reagents. However, methods for producing monoclonal antibodies do not typically produce a single type of biomolecule, but instead produce an assemblage of closely related biomolecules that can have differences in glycosylation patterns and other secondary features. This may result in subtle differences in biological effects of the monoclonal antibody. Developing methods for identifying potential variations of biological effects of monoclonal antibodies is therefore of considerable practical importance. One area that is potentially impacted by these variations is subsequent-entry pharmaceuticals including biosimilars and interchangeable biologics, which are analogs of established pharmaceuticals. To demonstrate that these compounds are equivalent to originator biologics, manufacturers must satisfy regulatory requirements that involve rigourous tests of statistical equivalence. This can be challenging for complex biomolecules such as monoclonal antibodies, as secondary features including glycosylation are often variable for both the originator and biosimilar compound. Novel approaches are therefore needed to meet statistical requirements of equivalency, especially where potency and immunological function are influenced by glycans. This project will develop quantitative methodology, through the use of high-throughput expression analysis, to assess and compare biochemical effects of biosimilars and originator compounds. The proposed study will investigate the effectiveness of high-throughput gene and protein expression analysis as tools to compare the biological effects of biosimilars with corresponding originator biologics. The specific target used as a model within this project is Trastuzumab (Herceptin), a monoclonal antibody that interferes with the HER2/neu receptor, which is unregulated in certain cancers. Responses to trastuzumab biosimilars will be investigated, which will either show equivalence of effect within appropriate margins, or may reveal unexpected effects that could point to novel biological impacts.