Optimization of bioprocess conditions improves production of a CHO cell-derived, bioengineered heparin

Baik, Jong Youn
Dahodwala, Hussain
Oduah, Eziafa
Talman, Lee
Gemmill, Trent R.
Gasimli, Leyla
Datta, Payel
Yang, Bo
Li, Guoyun
Zhang, Fuming
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Optimization of bioprocess conditions improves production of a CHO cell-derived, bioengineered heparin, J. Y. Baik, H. Dahodwala, E. Oduah, L. Talman, T. R. Gemmill, L. Gasimli, P. Datta, B. Yang, G. Li, F. Zhang, L. Li, R. J. Linhardt, A. M. Campbell, S.F. Gorfien, S. T. Sharfstein, Biotechnology Journal,10, 1067–1081, 2015.
Heparin is the most widely used anticoagulant drug in the world today. Heparin is currently produced from animal tissues, primarily porcine intestines. A recent contamination crisis motivated development of a non-animal-derived source of this critical drug. We hypothesized that Chinese hamster ovary (CHO) cells could be metabolically engineered to produce a bioengineered heparin, equivalent to current pharmaceutical heparin. We previously engineered CHO-S cells to overexpress two exogenous enzymes from the heparin/heparan sulfate biosynthetic pathway, increasing the anticoagulant activity ∼100-fold and the heparin/heparan sulfate yield ∼10-fold. Here, we explored the effects of bioprocess parameters on the yield and anticoagulant activity of the bioengineered GAGs. Fed-batch shaker-flask studies using a proprietary, chemically-defined feed, resulted in ∼two-fold increase in integrated viable cell density and a 70% increase in specific productivity, resulting in nearly three-fold increase in product titer. Transferring the process to a stirred-tank bioreactor increased the productivity further, yielding a final product concentration of ∼90 μg/mL. Unfortunately, the product composition still differs from pharmaceutical heparin, suggesting that additional metabolic engineering will be required. However, these studies clearly demonstrate bioprocess optimization, in parallel with metabolic engineering refinements, will play a substantial role in developing a bioengineered heparin to replace the current animal-derived drug.
Biotechnology Journal,10, 1067–1081
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
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Rensselaer Polytechnic Institute, Troy, NY
Biotechnology Journal
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