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Tuning monoclonal antibody galactosylation using Raman spectroscopy‐controlled lactic acid feeding
Biotechnology Progress ( IF 2.9 ) Pub Date : 2020-09-24 , DOI: 10.1002/btpr.3085
Thomas W Eyster 1 , Sameer Talwar 1 , Janice Fernandez 1 , Shelby Foster 1 , James Hayes 1 , Randal Allen 1 , Scot Reidinger 1 , Boyong Wan 1 , Xiaodan Ji 1 , Juan Aon 1 , Pramthesh Patel 1 , Diana B Ritz 1
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A key aspect of large‐scale production of biotherapeutics is a well‐designed and consistently‐executed upstream cell culture process. Process analytical technology tools provide enhanced monitoring and control capabilities to support consistent process execution, and also have potential to aid in maintenance of product quality at desired levels. One such tool, Raman spectroscopy, has matured as a useful technique to achieve real‐time monitoring and control of key cell culture process attributes. We developed a Raman spectroscopy‐based nutrient control strategy to enable dual control of lactate and glucose levels for a fed‐batch CHO cell culture process for monoclonal antibody (mAb) production. To achieve this, partial least squares‐based chemometric models for real‐time prediction of glucose and lactate concentrations were developed and deployed in feedback control loops. In particular, feeding of lactic acid post‐metabolic shift was investigated based on previous work that has shown the impact of lactate levels on ammonium as well as mAb product quality. Three feeding strategies were assessed for impact on cell metabolism, productivity, and product quality: bolus‐fed glucose, glucose control at 4 g/L, or simultaneous glucose control at 4 g/L and lactate control at 2 g/L. The third feeding strategy resulted in a significant reduction in ammonium levels (68%) while increasing mAb galactosylation levels by approximately 50%. This work demonstrated that when deployed in a cell culture process, Raman spectroscopy is an effective technique for simultaneous control of multiple nutrient feeds, and that lactic acid feeding can have a positive impact on both cell metabolism and mAb product quality.

中文翻译:

使用拉曼光谱控制的乳酸进料调节单克隆抗体半乳糖基化

大规模生产生物治疗药物的一个关键方面是精心设计和始终如一地执行的上游细胞培养过程。过程分析技术工具提供增强的监视和控制能力以支持一致的过程执行,并且还具有帮助将产品质量保持在所需水平的潜力。其中一种工具,拉曼光谱,已经成熟为一种有用的技术,可以实现对关键细胞培养过程属性的实时监测和控制。我们开发了一种基于拉曼光谱的营养控制策略,以实现对用于单克隆抗体 (mAb) 生产的分批补料 CHO 细胞培养过程的乳酸和葡萄糖水平的双重控制。为达到这个,开发了基于偏最小二乘的化学计量模型,用于实时预测葡萄糖和乳酸浓度,并将其部署在反馈控制回路中。特别是,根据先前的工作研究了乳酸代谢后转变的喂养,该工作表明乳酸水平对铵和 mAb 产品质量的影响。评估了三种喂养策略对细胞代谢、生产力和产品质量的影响:推注葡萄糖、4 g/L 的葡萄糖控制或 4 g/L 的同时葡萄糖控制和 2 g/L 的乳酸控制。第三种喂养策略导致铵水平显着降低 (68%),同时将 mAb 半乳糖基化水平提高了约 50%。这项工作表明,当部署在细胞培养过程中时,
更新日期:2020-09-24
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