Abstract Based on elementary flux mode (EFM) analysis, a novel approach is presented for monoclonal antibody (MAb) production by GS-CHO cells. A kinetic model is developed on the basis of a set of macro-reactions, which can predict the time-dependent concentrations of metabolites, cell growth, and MAb productivity over a range of culture conditions. The model incorporates energy metabolism with biomass and MAb formation, with the specific ATP production rate being decided by the central carbon metabolism and used for estimation of biomass and MAb synthesis rates. The reaction rate expressions are represented by Michaelis–Menten kinetics based on extracellular metabolite concentrations, which determine ATP production by glycolysis and respiratory chain. Glutamine and asparagine are considered as regulatory metabolites for GS-CHO cells. Glutamine determines asparagine utilization route and energetic state of cells, while asparagine regulates the uptake rates of aspartate and glutamate. The model was calibrated for glutamine-free and glutamine-available cases and validated for fed-batch cultures supplied with glutamine. Unoptimized fed-batch cultures have been simulated for daily and constant feeding. The model predictions are in good agreement with the experimental data reported in literature.

中文翻译：

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基于动态 EFM 的抗体生产细胞系模型和基于模型的分批补料评估

摘要 基于基本通量模式 (EFM) 分析，提出了一种通过 GS-CHO 细胞生产单克隆抗体 (MAb) 的新方法。动力学模型是在一组宏观反应的基础上开发的，可以预测代谢物的时间依赖性浓度、细胞生长和 MAb 生产力在一系列培养条件下。该模型将能量代谢与生物量和 MAb 的形成结合起来，具体的 ATP 生成速率由中心碳代谢决定，并用于估计生物量和 MAb 合成速率。反应速率表达式由基于细胞外代谢物浓度的 Michaelis-Menten 动力学表示，它决定了糖酵解和呼吸链产生的 ATP。谷氨酰胺和天冬酰胺被认为是 GS-CHO 细胞的调节代谢物。谷氨酰胺决定天冬酰胺的利用途径和细胞的能量状态，而天冬酰胺调节天冬氨酸和谷氨酸的摄取率。该模型针对无谷氨酰胺和有谷氨酰胺的情况进行了校准，并针对提供谷氨酰胺的分批补料培养物进行了验证。未优化的分批补料培养已被模拟为每日和持续补料。模型预测与文献报道的实验数据非常吻合。