Chemically defined (CD) media are routinely used in the production of
biologics in Chinese Hamster Ovary (CHO) cell culture and provide
enhanced raw material control. Nutrient optimized CD media is an
important path to increase cell growth and monoclonal antibody (mAb)
productivity in recombinant CHO cell lines. However, nutrient
optimization efforts for CD media typically rely on multi-factorial and
experimental design of experiment (DoE) approaches or complex
mathematical models of cellular metabolism or gene expression systems.
Moreover, the majority of these efforts are aimed at amino acids since
they constitute essential nutrients in CD media as they directly
contribute to biomass and protein production. In this study, we
demonstrate the utilization of multi-variate data analytics (MVDA)
coupled with amino acid stoichiometric balances (SBs) to increased cell
growth and mAb productivity in efforts to reduce CD media development
efforts. SBs measure the difference between theoretical demand of amino
acids and the empirically measured fluxes to identify metabolic states
of the cell. When coupled with MVDA, the statistical models were not
only able to highlight key amino acids towards cell growth or
productivity, but also provided direction on metabolic favorability of
the amino acid. Experimental validation of our approach resulted in a
55% increase in total cell growth and about an 80% increase in total
mAb productivity. Increased specific consumption of stoichiometrically
balanced amino acids and decreased specific consumption of glucose was
also observed in optimized CD media suggesting favorable consumption of
desired nutrients and a potential for energy redistribution towards
increased cellular growth or mAb productivity.
Poly-pathway model, a novel approach to simulate multiple metabolic states by reaction network-based model – Application to amino acid depletion in CHO cell culture