CHO cell factory modelling

Process development is typically based on existing platform processes developed for mAb production, which give a starting point for high titres based on an earlier selection of high-producing clones. Further process optimisation results in often pre-designed operational (primarily reactor feeding) strategies applicable to the cell line/product in question. The optimisation process is typically empirical and the associated capability lies within a few individuals in an organisation. In academia and increasingly in industry, mathematical models are used to rapidly explore different operating strategies and expedite process optimisation. Structured and knowledge-based modelling strategies would be transferrable across different cell lines and process conditions to enable fully rational decision-making during bioprocess development and operation. An example is the recently proposed kinetic model of cell growth, mAb productivity and glycosylation developed by Imperial College London and MedImmune (Kotidis et al., 2019, Biotechnology and Bioengineering, 116(7):1612-1626). The model was used to screen over 8,000 sets of process conditions computationally to identify the subspace the met two constraints (minimum titre and extent of galactosylation) and the findings were verified experimentally (Kotidis et al., 2019, Computers & Chemical Engineering, 125: 558-568). Although the model successfully predicted whether the constraints were met or not, we found that it is not fully quantitatively predictive. This is somewhat unsurprising because the model, like all kinetic models, is fixed in its structure and parameter values, when it is known that the metabolic behaviour of producer cells is not constant throughout the culture period.
Our goal is to generate a modular cell factory modelling platform that integrates kinetic models with flux balance analysis to quantitatively and accurately describe (i) how the stoichiometric relationships between extracellular and intracellular metabolites vary during cell culture processes, (ii) how these shifts in stoichiometry influence the dynamics of CHO cell growth, and (iii) how cellular metabolism, product biosynthesis, assembly and secretion, all combine to yield different productivity levels and mAb product glycosylation.