Grant: Strategic Projects - Group

Mammalian cell culture comprises a major platform for producing a number of high-value biopharmaceuticals,including enzymes, monoclonal antibodies (Mabs), viral vaccines, hormones and immuno-regulators. Thisproposal deals with the development of a novel based optimal bioprocessing methodology for the production ofMab by the Chinese hamster ovary (CHO) cell line using fed batch culture. The optimization will be based on adetailed model of the process that will describe both the extracellular metabolite fluxes and the signaltransduction pathways in the cell. The objective will be to find an optimal feeding profile and optimal operatingconditions, including nutrient and temperature profile, to be implemented during the fed-batch process. Thekey issue for optimizing the system is the prevention or delay of programmed cell death referred to asapoptosis. Previous studies have proposed only partial models of the system. Some researchers only modelledthe signal transduction pathways related to apoptosis whereas others only modelled the metabolic extracellularfluxes during the process.The current research intends to elucidate the mechanisms leading to apoptosis by accounting for both theevolution of extracellular metabolite fluxes and their specific interaction with the cellular transductionpathways responsible for apoptosis. This comprehensive mathematical model, to be used for optimization, willbe validated by experimental monitoring of the levels of metabolites, intracellular and extracellular proteins aswell as the proportions of viable, necrotic and apoptotic cells during the Mab production process.It is expected that by investigating and addressing the interaction between the extracellular fluxes and thesignal transduction pathways realted to apoptosis, a systematic methodology for obtaining novel optimalprotocols for biopharmaceutical production will result. This will bring about a significant cost saving to thepublic regarding currently expensive biopharmaceuticals.