A dynamic EFM-based model for antibody producing cell lines and model based evaluation of fed-batch processes

摘要

Based on elementary flux mode (EFM) analysis, a novel approach is presented for monoclonal antibody (MAb) production by GS-CHO cells. A kinetic model is developed on the basis of a set of macro-reactions, which can predict the time-dependent concentrations of metabolites, cell growth, and MAb productivity over a range of culture conditions. The model incorporates energy metabolism with biomass and MAb formation, with the specific ATP production rate being decided by the central carbon metabolism and used for estimation of biomass and MAb synthesis rates. The reaction rate expressions are represented by Michaelis-Menten kinetics based on extracellular metabolite concentrations, which determine ATP production by glycolysis and respiratory chain. Glutamine and asparagine are considered as regulatory metabolites for GS-CHO cells. Glutamine determines asparagine utilization route and energetic state of cells, while asparagine regulates the uptake rates of aspartate and glutamate. The model was calibrated for glutamine-free and glutamine-available cases and validated for fed-batch cultures supplied with glutamine. Unoptimized fed-batch cultures have been simulated for daily and constant feeding. The model predictions are in good agreement with the experimental data reported in literature.