Towards Controlling the Glycoform: A Model Framework Linking Extracellular Metabolites to Antibody Glycosylation
Towards Controlling the Glycoform: A Model Framework Linking Extracellular Metabolites to Antibody Glycosylation
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DOI：
10.3390/ijms15034492
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发表时间：
2014-03-01
影响因子：
5.6
通讯作者：
Kontoravdi, Cleo
中科院分区：
文献类型：
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作者：
Jedrzejewski, Philip M.;del Val, Ioscani Jimenez;Kontoravdi, Cleo
糖蛋白代表了越来越多的生物衍生药物中最大的一组。已知相关聚糖结构及其分布对药代动力学有很大影响。开发了一个建模框架，以提供从细胞外环境及其对细胞内代谢物的影响到抗体产物恒定区上聚糖分布的联系。这项工作的主要重点是通过34种物质的质量平衡和所涉及的60个代谢反应的饱和动力学速率，对核苷酸糖供体（NSD）代谢网络进行计算机模拟重建。NSD是高尔基体中糖基化过程的共底物，其模拟的动态细胞内浓度曲线与描述抗体恒定区N-连接聚糖结构分布的现有模型相关。建模框架还描述了通过修改的莫诺动力学的细胞群体的生长动力学。模拟结果匹配以及从鼠杂交瘤细胞系的实验数据。其结果是一个建模平台，能够描述基于细胞外条件的产物糖型。它代表了生物素糖型计算机预测的第一步，并为优化生物工艺条件提供了一个平台，以提高产品质量。
Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD) metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality.