(418a) Towards Energy-Based Dynamic Optimisation of Monoclonal Antibody-Producing GS-NS0 Cultures

Mammalian cell culture systems produce clinically important high-value biologics, such as monoclonal antibodies (MAb). A complete framework that interlinks model-based design of experiments (DOE) and model-based control and optimisation to the actual industrial bioprocess could assist experimentation, hence reducing time and costs. Previously, we have presented the development of a systematic framework for modelling of mammalian cell bioprocesses (Sidoli et al. 2005, Kontoravdi et al. 2005 & 2007, Ho et al. 2006, Lam et al. 2007). Herein, we present the development of a dynamic model describing the growth and monoclonal antibody formation in GS-NS0 cell cultures that interlinks productivity in each cell cycle phase to the available energy (ATP/ADP) balance with time. This allows the investigation of cellular energy requirements at each cell cycle, which can be utilised to optimise feeding strategies in order to increase MAb productivity and cell viability. The first step in the systematic framework employs Global Sensitivity Analysis (GSA) techniques to identify model parameters that significantly affect the model output. Next, the values of the significant model parameters are obtained experimentally through a limited (and DOE-derived) set of batch experiments, while the remaining model parameters are set at their nominal values. Finally, using dynamic optimisation algorithms the optimal feeding strategies that maximise MAb production are determined in silico and are subsequently validated experimentally. This novel work aims to achieve model-based optimisation of mammalian cell culture systems based on energy levels.

REFERENCES

[1] Sidoli F.R., Mantalaris A., Asprey S.P., Toward Global Parametric Estimability of a Large-Scale Kinetic Single-Cell Model for Mammalian Cell Culture, Ind. Eng. Chem. Res., 44 (4), 868 -878, 2005

[2] Kontoravdi C., Asprey S.P., Pistikopoulos E.N., Mantalaris A., Application of Global Sensitivity Analysis to Determine Goals for Design of Experiments: An Example Study on Antibody-Producing Cell Cultures, Biotechnol. Prog., 21 (4), 1128 -1135, 2005

[3] Kontoravdi C., Asprey S.P., Pistikopoulos,Athanasios E.N., Mantalaris A, Development of a dynamic model of monoclonal antibody production and glycosylation for product quality monitoring, Computers & Chemical Engineering 31, 392-400, 2007

[4] Ho Y., Varley J., Mantalaris A., Development and analysis of a mathematical model for antibody-producing GS-NS0 cells under normal and hyperosmotic culture conditions, Biotechnol Prog, v. 22(6), 1560-9, 2006

[5] Lam C.M., Wong D.C.F., Yap M.G.S., Pistikopoulos E.N., Mantalaris A., Dynamic Optimisation of a CHO-IFNγ Fed-Batch Cell Culture Time-Profile, Proceedings of the 20th European Society for Cell Animal Technology Meeting. Dresden, Germany. June 2007.