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Using MVDA with Stoichiometric Balances to Optimize Amino Acid Concentrations in Chemically Defined CHO Cell Culture Medium for Improved Culture Performance
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  • Taha Salim,
  • Gaurav Chauhan,
  • Neil Templeton,
  • Wai Lam Ling
Taha Salim
Merck & Co Inc
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Gaurav Chauhan
Merck & Co Inc
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Neil Templeton
Merck and Co Inc West Point
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Wai Lam Ling
Merck & Co Inc
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Abstract

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.

Peer review status:IN REVISION

02 Jul 2021Submitted to Biotechnology and Bioengineering
03 Jul 2021Assigned to Editor
03 Jul 2021Submission Checks Completed
08 Jul 2021Reviewer(s) Assigned
23 Aug 2021Review(s) Completed, Editorial Evaluation Pending
23 Aug 2021Editorial Decision: Revise Minor