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Research ArticleResearch

Studies of Protein Oxidation as a Product Quality Attribute on a Scale-Down Model for Cell Culture Process Development

Nacole D. Lee, Bhargavi Kondragunta, Shaunak Uplekar, Jose Vallejos, Antonio Moreira and Govind Rao
PDA Journal of Pharmaceutical Science and Technology March 2015, 69 (2) 236-247; DOI: https://doi.org/10.5731/pdajpst.2015.01035
Nacole D. Lee
1Department of Biomedical Sciences, Hood College, Frederick, MD; Currently at MedImmune, Inc., Gaithersburg, MD;
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  • For correspondence: LeeND@MedImmune.com
Bhargavi Kondragunta
2Center for Advanced Sensor Technology and Department of Chemical, Biochemical and Environmental Engineering; University of Maryland, Baltimore County; Baltimore, MD;
3Currently at Vaccine Research Center, NIH; and
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Shaunak Uplekar
2Center for Advanced Sensor Technology and Department of Chemical, Biochemical and Environmental Engineering; University of Maryland, Baltimore County; Baltimore, MD;
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Jose Vallejos
2Center for Advanced Sensor Technology and Department of Chemical, Biochemical and Environmental Engineering; University of Maryland, Baltimore County; Baltimore, MD;
4Currently at MS&T-AstraZeneca, Frederick, MD
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Antonio Moreira
2Center for Advanced Sensor Technology and Department of Chemical, Biochemical and Environmental Engineering; University of Maryland, Baltimore County; Baltimore, MD;
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Govind Rao
2Center for Advanced Sensor Technology and Department of Chemical, Biochemical and Environmental Engineering; University of Maryland, Baltimore County; Baltimore, MD;
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Abstract

Of importance to the biological properties of proteins produced in cell culture systems are the complex post-translational modifications that are affected by variations in process conditions. Protein oxidation, oxidative modification to intracellular proteins that involves cleavage of the polypeptide chain, and modifications of the amino acid side chains can be affected by such process variations. Dissolved oxygen is a parameter of increasing interest since studies have shown that despite the necessity of oxygen for respiration, there may also be some detrimental effects of oxygen to the cell. Production and accumulation of reactive oxygen species can cause damage to proteins as a result of oxidation of the cell and cellular components. Variation, or changes to cell culture products, can affect function, clearance rate, immunogenicity, and specific activity, which translates into clinical implications. The effect of increasing dissolved oxygen on protein oxidation in immunoglobulin G3–producing mouse hybridoma cells was studied using 50 mL high-throughput mini-bioreactors that employ non-invasive optical sensor technology for monitoring and closed feedback control of pH and dissolved oxygen. Relative protein carbonyl concentration of proteins produced under varying levels of dissolved oxygen was measured by enzyme-linked immunosorbent assay and used as an indicator of oxidative damage. A trend of increasing protein carbonyl content in response to increasing dissolved oxygen levels under controlled conditions was observed.

LAY ABSTRACT: Protein oxidation, oxidative modification to intracellular proteins that involves cleavage of the polypeptide chain, and modifications of the amino acid side chains can be affected by variations in dissolved oxygen levels in cell culture systems. Studies have shown that despite the necessity of oxygen for respiration, there may be detrimental effects of oxygen to the cell. Production and accumulation of reactive oxygen species can cause damage to proteins as a result of oxidation of the cell and cellular components, affecting function, clearance rate, immunogenicity, and specific activity, which translates into clinical implications. The effect of increasing dissolved oxygen on protein oxidation in immunoglobulin G3–producing mouse hybridoma cells was studied using 50 mL high-throughput mini-bioreactors that employ non-invasive optical sensor technology for monitoring and closed feedback control of pH and dissolved oxygen. Protein carbonyl concentration of proteins produced under varying levels of dissolved oxygen was measured by enzyme-linked immunosorbent assay and used as an indicator of oxidative damage. A trend of increasing protein carbonyl content in response to increasing dissolved oxygen levels under controlled conditions was observed.

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PDA Journal of Pharmaceutical Science and Technology: 69 (2)
PDA Journal of Pharmaceutical Science and Technology
Vol. 69, Issue 2
March/April 2015
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Studies of Protein Oxidation as a Product Quality Attribute on a Scale-Down Model for Cell Culture Process Development
Nacole D. Lee, Bhargavi Kondragunta, Shaunak Uplekar, Jose Vallejos, Antonio Moreira, Govind Rao
PDA Journal of Pharmaceutical Science and Technology Mar 2015, 69 (2) 236-247; DOI: 10.5731/pdajpst.2015.01035

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Studies of Protein Oxidation as a Product Quality Attribute on a Scale-Down Model for Cell Culture Process Development
Nacole D. Lee, Bhargavi Kondragunta, Shaunak Uplekar, Jose Vallejos, Antonio Moreira, Govind Rao
PDA Journal of Pharmaceutical Science and Technology Mar 2015, 69 (2) 236-247; DOI: 10.5731/pdajpst.2015.01035
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