Modeling of copy number variability in Pichia pastoris
Name
10.1002-bit.27698.pdf
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3.85 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Lu, Amos E.
Maloney, Andrew J.
Dalvie, Neil C.
Brady, Joseph R.
Love, Kerry R.
Love, J. Christopher
Braatz, Richard D.
Date Issued
February 2, 2021
Journal
Biotechnology and Bioengineering
Publisher
Wiley
Citation
Lu, A. E., Maloney, A. J., Dalvie, N. C., et al. Modeling of copy number variability in Pichia pastoris. Biotechnology and Bioengineering. 2021; 118: 1832– 1839.
Version
Author's final manuscript
Abstract
Development of continuous biopharmaceutical manufacturing processes is an area of active research. This study considers the long-term transgene copy number stability of Pichia pastoris in continuous bioreactors. We propose a model of copy number loss that quantifies population heterogeneity. An analytical solution is derived and compared with existing experimental data. The model is then used to provide guidance for stable operating timescales. The model is extended to consider copy number dependent growth such as in the case of Zeocin supplementation. The model is also extended to analyze a continuous seeding strategy. This study is a critical step towards understanding the impact of continuous processing on the stability of Pichia pastoris and the resultant products.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1002/bit.27698
