Mammalian cells have been the major workhorse to produce therapeutic proteins owing to their capability to perform complex post-translation modifications that are essential to the pharmacological activities of these proteins. The performance of mammalian cell culture is greatly affected by cell metabolism, while the robustness of glycosylation patterns of the product proteins still needs improvement. A meta-analysis of cell culture bioprocess data revealed a correlation between lactate metabolism, productivity, and glycosylation patterns. In this study, we develop an integrated platform for generation and visualization of the O-glycosylation network. The platform was used to explore the heterogeneity of O-glycans produced in mammalian cells. In addition, we use a kinetic model of energy metabolism to explain the mechanism behind the increase in lactate production during the late stage of fed-batch cultures. Such a metabolic behavior of lactate can have negative impacts on the culture productivity and potentially, product quality because it occurs during the main production phase. Insights from this study can be helpful in contriving strategies for more robust control of cell metabolism and obtaining consistent glycan patterns of biologics.
University of Minnesota Ph.D. dissertation. May 2018. Major: Chemical Engineering. Advisor: Wei-Shou Hu. 1 computer file (PDF); xi, 159 pages.
Systems Analysis In Mammalian Cell Biomanufacturing - Linking Energy Metabolism And Glycosylation.
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