Kozue Okamura, Sara Badr, Yusuke Ichida, Akira Yamada, Hirokazu Sugiyama
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引用次数: 0
摘要
对单克隆抗体(mAbs)的需求正在迅速增长。为了实现更高的生产率,细胞系、操作模式、培养基和培养条件都有了改进。需要有代表性的数学模型来缩小日益增多的工艺选择范围。以往的研究提出了一些机理模型来描述细胞新陈代谢的转变(如乳酸的产生到消耗)。然而,这些模型尚未完全纳入某些操作条件变化的影响。本文提供了一种新的机理模型,考虑了溶解氧和谷氨酰胺耗竭对细胞代谢的影响,并将其应用于一种新型的中国仓鼠卵巢(CHO)细胞系。为搅拌罐和摇床反应器制定了乳酸盐产生、谷氨酰胺消耗和 mAb 生产的特定速率表达式。在不同的实验条件组合下,对乳酸盐代谢转变有了更深入的了解。在溶解氧较高、谷氨酰胺浓度较低的条件下,乳酸消耗更为明显。该模型提供了有助于设计先进运行策略的机理见解。它可用于设计空间生成和工艺优化,以提高生产率和产品质量。
Modeling of cell cultivation for monoclonal antibody production processes considering lactate metabolic shifts.
Demand for monoclonal antibodies (mAbs) is rapidly increasing. To achieve higher productivity, there have been improvements to cell lines, operating modes, media, and cultivation conditions. Representative mathematical models are needed to narrow down the growing number of process alternatives. Previous studies have proposed mechanistic models to depict cell metabolic shifts (e.g., lactate production to consumption). However, the impacts of variations of some operating conditions have not yet been fully incorporated in such models. This paper offers a new mechanistic model considering variations in dissolved oxygen and glutamine depletion on cell metabolism applied to a novel Chinese hamster ovary (CHO) cell line. Expressions for the specific rates of lactate production, glutamine consumption, and mAb production were formulated for stirred and shaken-tank reactors. A deeper understanding of lactate metabolic shifts was obtained under different combinations of experimental conditions. Lactate consumption was more pronounced in conditions with higher DO and low glutamine concentrations. The model offers mechanistic insights that are useful for designing advanced operation strategies. It can be used in design space generation and process optimization for better productivity and product quality.
期刊介绍:
Biotechnology Progress , an official, bimonthly publication of the American Institute of Chemical Engineers and its technological community, the Society for Biological Engineering, features peer-reviewed research articles, reviews, and descriptions of emerging techniques for the development and design of new processes, products, and devices for the biotechnology, biopharmaceutical and bioprocess industries.
Widespread interest includes application of biological and engineering principles in fields such as applied cellular physiology and metabolic engineering, biocatalysis and bioreactor design, bioseparations and downstream processing, cell culture and tissue engineering, biosensors and process control, bioinformatics and systems biology, biomaterials and artificial organs, stem cell biology and genetics, and plant biology and food science. Manuscripts concerning the design of related processes, products, or devices are also encouraged. Four types of manuscripts are printed in the Journal: Research Papers, Topical or Review Papers, Letters to the Editor, and R & D Notes.