How to Use Mechanistic Metabolic Modeling to Ensure High Quality Glycoprotein Production

• Published in: Computer Aided Chemical Engineering Vol. 40; pp. 2839 - 2844
• Main Authors: Ehsani, Alireza, Niedenfuehr, Sebastian, Eissing, Thomas, Behnken, Swantje, Schuppert, Andreas
• Format: Book Chapter
• Language: English
• Published: 01.01.2017
• Subjects: Bioprocess optimization; Glycoprotein; Glycosylation; Mammalian cell culture; Metabolic modeling; Glycosylation; Bioprocess optimization; Metabolic modeling; Mammalian cell culture; Glycoprotein
• ISBN: 9780444639653; 0444639659
• ISSN: 1570-7946
• DOI: 10.1016/B978-0-444-63965-3.50475-X

Glycosylation is one of the most important quality attributes directly affecting the activity of bio-therapeutics produced by cell culture technology. In our study, a metabolic model has been developed to find strategies to deal with the reduced sialylation of glycoforms which has an important role in plasma half-life of glycoproteins. Our model is comprised of three major layers including a bioprocess model, as well as kinetic reaction networks representing cellular metabolism and glycosylation inside Golgi apparatus. The kinetic parameters were estimated performing a scatter search optimization. The estimated parameter set of the model is capable of reproducing glycoforms measured by in vitro experiments. In order to evaluate significance of different parts of the model, a global sensitivity analysis was conducted and the results were interpreted with respect to glycoform sialylation. This study thereby increases understanding of the formation of glycoforms and reveals complex interactions of different compartments within mammalian cells acting on the maturation of produced proteins of interest. The built model helps to clearly identify conditions for the bioprocess that ensure meeting the desired specifications of quality and, thus, make it more robust.