On the model based optimization of secreting mammalian cell cultures via minimal glucose provision
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abstract
Commercial synthesis of monoclonal antibodies (MAB) represents one of the most important products in the biopharmaceutical industry because of their diagnostic and clinical applications. However, the production of industrial scale quantities of MAB is an expensive and challenging task. Thus far most model based approaches have focused on maximisation of final mAb titre by manipulating the input of Glucose alone. The omission of other significant nutrients from such model based approaches leads to an overestimation of the required Glucose in an attempt to compensate for the modelling simplification. However, the work of [1] illustrated that excessive feeding of glucose is not the best means towards higher product titres, since it shifts metabolism towards energy inefficient pathways. A truly optimal feeding profile should be derived based on the provision of adequate yet not excessive amounts of energy through controlled quantities of Glucose. Herein we present a dynamic model that successfully correlates cellular growth and mAb production of GS-NS0 cells to the availability of Glucose, Glutamate and ATP. Following The model parameters are derived from a batch experiment and the validity of the model is tested against two independent batch experiments. Consequently the significant model parameters are identified through Global Sensitivity Analysis (GSA) and an optimal fed-batch experiment is designed in order to adjust the model to fed-batch culture conditions. The model is utilised in order to derive an optimal feeding profile that maximises final mAb titre via minimal Glucose provision. The resulting optimal feeding profile is then experimentally validated in order to prove the applicability of our novel energy - based approach. 2011 Elsevier B.V.
