Oxidative Stress-alleviating Strategies To Improve Recombinant ...

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Abstract

Large scale biopharmaceutical production of biologics relies on the overexpression of foreign proteins by cells cultivated in stirred tank bioreactors. It is well recognized and documented fact that protein overexpression may impact host cell metabolism and that factors associated with large scale culture, such as the hydrodynamic forces and inhomogeneities within the bioreactors, may promote cellular stress. The metabolic adaptations required to support the high-level expression of recombinant proteins include increased energy production and improved secretory capacity, which, in turn, can lead to a rise of reactive oxygen species (ROS) generated through the respiration metabolism and the interaction with media components. Oxidative stress is defined as the imbalance between the production of free radicals and the antioxidant response within the cells. Accumulation of intracellular ROS can interfere with the cellular activities and exert cytotoxic effects via the alternation of cellular components. In this context, strategies aiming to alleviate oxidative stress generated during the culture have been developed to improve cell growth, productivity, and reduce product microheterogeneity. In this review, we present a summary of the different approaches used to decrease the oxidative stress in Chinese hamster ovary cells and highlight media development and cell engineering as the main pathways through which ROS levels may be kept under control.

Keywords: CHO; Chinese hamster ovary cells; antioxidant; cell engineering; oxidative stress.

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Conflict of interest statement

V. Chevallier and L. Malphettes are employees of UCB Nordic A/S and UCB Pharma S.A., both of which carry out production activities in the area of interest. Mikael R Andersen does not have any conflict of interest.

Figures

Figure 1

Figure 1

Major enzymatic reactions involving glutathione.…

Figure 1

Major enzymatic reactions involving glutathione. Conjugation reactions with an electrophilic donor are catalyzed…

Figure 1 Major enzymatic reactions involving glutathione. Conjugation reactions with an electrophilic donor are catalyzed by glutathione‐S‐transferases (GST). Reduction of the substrate such as H2O2, lipid peroxide (LOOH), and peroxynitrite (ONOO−) are catalyzed by glutathione peroxidases (GPx). Disulfide bond reduction can be catalyzed by glutaredoxins (Grx). The reduction of glutathione disulfide (GSSG) to glutathione is catalyzed by the glutathione reductase (GR) and required NADPH
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References

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