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.