Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule

总结 该提案的总体目标是开发综合数学算法，以评估 比较多批两种不同复合物分子的分析表征数据。第一，多个 生物聚合物-药物缀合物（透明质酸-顺铂）和药学相关糖蛋白的批次 （IgG1-Fc）。对于IgG 1-Fc分子，我们利用技术生产六种不同的，良好的- 定义的糖型，其可以单独表征，然后以不同的比例混合在一起， 不同水平的Fc受体结合活性，用于后续的分析可比性测试。 第二，将使用一种新的方法来监测这两种复杂分子的生物、化学和物理特性。 广泛的分析技术，包括在加速稳定性试验期间阐明相关性 物理化学变化和生物活性之间的关系。第三，我们将结合目前的 可用的数据可视化工具使用我们的实验室，沿着新的数学算法， 在本提案中开发，以整合结构和生物学数据， 关键质量属性（CQA）。最后，数学算法评估整体性能的能力 将使用适当的阳性和阴性药物来验证每种复杂生物药物的多个批次的相似性， 阴性对照，因此提供了分析可比性的总体评估。

Summary The overall goal of this proposal is to develop integrated mathematical algorithms to assess the similarity of analytical characterization data comparing multiple batches of two different complex molecules. First, multiple batches of a biopolymer-drug conjugate (hyaluronic acid-cisplatin) and a pharmaceutically relevant glycoprotein (IgG1-Fc) will be prepared. For the IgG1-Fc molecules, we utilize technology to produce six different, well- defined glycoforms, which can be characterized individually and then mixed together in different ratios resulting in varying levels of binding activity to various Fc receptors for subsequent analytical comparability testing. Second, the biological, chemical and physical properties of both complex molecules will be monitored using a wide range of analytical technologies, including during accelerated stability testing to elucidate correlations between physicochemical changes and biological activity. Third, we will then employ a combination of currently available data visualization tools used our laboratories, along with novel mathematical algorithms to be developed in this proposal, to integrate the structural and biological data to provide an overall assessment of their critical quality attributes (CQAs). Finally, the ability of the mathematical algorithm(s) to assess the overall similarity of multiple lots of each complex biopharmaceutical will be validated using appropriate positive and negative controls, and therefore, provide an overall assessment of analytical comparability.