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Title: Mathematical modelling and experimental validation for optimisation and control of mammalian cell culture systems
Author: Quiroga Campano, Ana
ISNI:       0000 0004 7657 0990
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Monoclonal antibodies (mAbs) exhibit remarkable properties that make them suitable for a wide range of diagnostic and therapeutic applications. The main manufacturing platform used to produce mAbs is mammalian cell cultures due to their capacity for post-translational modifications, which are essential for the mAbs functionality (Zhu, 2012). Unfortunately, mammalian cell cultures present low yield, slow growth, and require expensive medium components. Model-based techniques could be industrially applied to overcome these limitations, e.g., implementing model-based optimisation strategies that identify feeding regimes to maximise mAbs titre in GS-NS0 cultures (Kiparissides et al., 2011). However, existing feeding strategies depend mainly on glucose and glutamate supply neglecting the exhaustion of essential amino acids and cell's energy requirements not only for proliferation and maintenance but also for mAbs production. In this work, cell and product compositions, and energy requirements for proliferation, maintenance and production, have been considered in the development of a novel dynamic predictive model for GS-NS0 cells producing cB72.3 mAbs, in modified DMEM medium supplemented with 10% serum or in a serum-free CD-Hybridoma medium. The model describes growth kinetics, nutrient metabolism, mAbs secretion and the adenosine triphosphate (ATP) balance based on glucose/amino acids energy metabolic networks, in batch and fed-batch cultures; and it successfully predicts the number cells, and the concentrations of ATP, glucose, amino acids and lactate throughout the culture. The successful coupling of growth kinetics equations and stoichiometric balances, and the in vitro/in silico approach has enabled us to develop the first dynamic model that predicts the intracellular ATP content in mammalian cell cultures. Additionally, this experimentally validated model was utilised to design a tailor-made and low-cost supplemental medium and implement an optimised fed-batch schedule that maximises the mAbs production and extends the longevity of the culture. This integrated model-based approach has the potential to be applied for media development, upstream optimisation and the development of control strategies for a wide range of biopharmaceutical products.
Supervisor: Mantalaris, Athanasios ; Pistikopoulos, Efstratios Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral