Increased MSX level improves biological productivity and production stability in multiple recombinant GS CHO cell lines
Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality co...
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| Published in | Engineering in life sciences Vol. 20; no. 3-4; pp. 112 - 125 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Germany
John Wiley and Sons Inc
01.03.2020
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1618-0240 1618-2863 |
| DOI | 10.1002/elsc.201900124 |
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| Abstract | Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality comparable to the original process. In this study, we report that three different GS−/− CHO cell lines developed in media containing a standard concentration of the selection agent methionine sulfoximine (MSX), but then exposed to increased MSX concentrations during seed train expansion, achieved titer increases of 10–19%. This result was observed in processes already considerably optimized. Expanding the cells with a higher MSX concentration improved cell line production stability with increased culture age. Production cultures in 500‐L and 1000‐L bioreactors replicated laboratory results using 5‐L bioreactors, demonstrating process robustness and scalability. Furthermore, product quality attributes of the final drug substance using the higher MSX process were comparable with those from cells expanded in media with the standard selection MSX concentration. Subsequent mechanistic investigations confirmed that the cells were not altered at the genetic level in terms of integration profiles or gene copy number, nor transcriptional levels of glutamine synthetase, heavy chain, or light chain genes. This study provides an effective and applicable strategy to improve the productivity of therapeutic proteins for biologics manufacturing. |
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| AbstractList | Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality comparable to the original process. In this study, we report that three different GS
CHO cell lines developed in media containing a standard concentration of the selection agent methionine sulfoximine (MSX), but then exposed to increased MSX concentrations during seed train expansion, achieved titer increases of 10-19%. This result was observed in processes already considerably optimized. Expanding the cells with a higher MSX concentration improved cell line production stability with increased culture age. Production cultures in 500-L and 1000-L bioreactors replicated laboratory results using 5-L bioreactors, demonstrating process robustness and scalability. Furthermore, product quality attributes of the final drug substance using the higher MSX process were comparable with those from cells expanded in media with the standard selection MSX concentration. Subsequent mechanistic investigations confirmed that the cells were not altered at the genetic level in terms of integration profiles or gene copy number, nor transcriptional levels of glutamine synthetase, heavy chain, or light chain genes. This study provides an effective and applicable strategy to improve the productivity of therapeutic proteins for biologics manufacturing. Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality comparable to the original process. In this study, we report that three different GS−/− CHO cell lines developed in media containing a standard concentration of the selection agent methionine sulfoximine (MSX), but then exposed to increased MSX concentrations during seed train expansion, achieved titer increases of 10–19%. This result was observed in processes already considerably optimized. Expanding the cells with a higher MSX concentration improved cell line production stability with increased culture age. Production cultures in 500‐L and 1000‐L bioreactors replicated laboratory results using 5‐L bioreactors, demonstrating process robustness and scalability. Furthermore, product quality attributes of the final drug substance using the higher MSX process were comparable with those from cells expanded in media with the standard selection MSX concentration. Subsequent mechanistic investigations confirmed that the cells were not altered at the genetic level in terms of integration profiles or gene copy number, nor transcriptional levels of glutamine synthetase, heavy chain, or light chain genes. This study provides an effective and applicable strategy to improve the productivity of therapeutic proteins for biologics manufacturing. Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality comparable to the original process. In this study, we report that three different GS −/− CHO cell lines developed in media containing a standard concentration of the selection agent methionine sulfoximine (MSX), but then exposed to increased MSX concentrations during seed train expansion, achieved titer increases of 10–19%. This result was observed in processes already considerably optimized. Expanding the cells with a higher MSX concentration improved cell line production stability with increased culture age. Production cultures in 500‐L and 1000‐L bioreactors replicated laboratory results using 5‐L bioreactors, demonstrating process robustness and scalability. Furthermore, product quality attributes of the final drug substance using the higher MSX process were comparable with those from cells expanded in media with the standard selection MSX concentration. Subsequent mechanistic investigations confirmed that the cells were not altered at the genetic level in terms of integration profiles or gene copy number, nor transcriptional levels of glutamine synthetase, heavy chain, or light chain genes. This study provides an effective and applicable strategy to improve the productivity of therapeutic proteins for biologics manufacturing. Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality comparable to the original process. In this study, we report that three different GS-/- CHO cell lines developed in media containing a standard concentration of the selection agent methionine sulfoximine (MSX), but then exposed to increased MSX concentrations during seed train expansion, achieved titer increases of 10-19%. This result was observed in processes already considerably optimized. Expanding the cells with a higher MSX concentration improved cell line production stability with increased culture age. Production cultures in 500-L and 1000-L bioreactors replicated laboratory results using 5-L bioreactors, demonstrating process robustness and scalability. Furthermore, product quality attributes of the final drug substance using the higher MSX process were comparable with those from cells expanded in media with the standard selection MSX concentration. Subsequent mechanistic investigations confirmed that the cells were not altered at the genetic level in terms of integration profiles or gene copy number, nor transcriptional levels of glutamine synthetase, heavy chain, or light chain genes. This study provides an effective and applicable strategy to improve the productivity of therapeutic proteins for biologics manufacturing.Increasing cell culture productivity of recombinant proteins via process improvements is the primary focus for research groups within biologics manufacturing. Any recommendations to improve a manufacturing process obviously must be effective, but also be robust, scalable, and with product quality comparable to the original process. In this study, we report that three different GS-/- CHO cell lines developed in media containing a standard concentration of the selection agent methionine sulfoximine (MSX), but then exposed to increased MSX concentrations during seed train expansion, achieved titer increases of 10-19%. This result was observed in processes already considerably optimized. Expanding the cells with a higher MSX concentration improved cell line production stability with increased culture age. Production cultures in 500-L and 1000-L bioreactors replicated laboratory results using 5-L bioreactors, demonstrating process robustness and scalability. Furthermore, product quality attributes of the final drug substance using the higher MSX process were comparable with those from cells expanded in media with the standard selection MSX concentration. Subsequent mechanistic investigations confirmed that the cells were not altered at the genetic level in terms of integration profiles or gene copy number, nor transcriptional levels of glutamine synthetase, heavy chain, or light chain genes. This study provides an effective and applicable strategy to improve the productivity of therapeutic proteins for biologics manufacturing. |
| Author | Qian, Yueming Langsdorf, Erik Oliveira, Christopher Li, Zheng Jian Egan, Susan Xu, Jianlin Tian, Jun He, Qin Qian, Nan‐Xin Reily, Michael Aranibar, Nelly Borys, Michael Warrack, Bethanne |
| AuthorAffiliation | 2 Molecular & Cellular Science Bristol‐Myers Squibb Company Princeton NJ USA 1 Biologics Process Development Global Product Development and Supply, Bristol‐Myers Squibb Company Devens MA USA 3 Drug Development and Preclinical Studies Bristol‐Myers Squibb Company Princeton NJ USA |
| AuthorAffiliation_xml | – name: 1 Biologics Process Development Global Product Development and Supply, Bristol‐Myers Squibb Company Devens MA USA – name: 3 Drug Development and Preclinical Studies Bristol‐Myers Squibb Company Princeton NJ USA – name: 2 Molecular & Cellular Science Bristol‐Myers Squibb Company Princeton NJ USA |
| Author_xml | – sequence: 1 givenname: Jun surname: Tian fullname: Tian, Jun organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 2 givenname: Qin surname: He fullname: He, Qin email: qin.he@bms.com organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 3 givenname: Christopher surname: Oliveira fullname: Oliveira, Christopher organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 4 givenname: Yueming surname: Qian fullname: Qian, Yueming organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 5 givenname: Susan surname: Egan fullname: Egan, Susan organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 6 givenname: Jianlin surname: Xu fullname: Xu, Jianlin organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 7 givenname: Nan‐Xin surname: Qian fullname: Qian, Nan‐Xin organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 8 givenname: Erik surname: Langsdorf fullname: Langsdorf, Erik organization: Bristol‐Myers Squibb Company – sequence: 9 givenname: Bethanne surname: Warrack fullname: Warrack, Bethanne organization: Bristol‐Myers Squibb Company – sequence: 10 givenname: Nelly surname: Aranibar fullname: Aranibar, Nelly organization: Bristol‐Myers Squibb Company – sequence: 11 givenname: Michael surname: Reily fullname: Reily, Michael organization: Bristol‐Myers Squibb Company – sequence: 12 givenname: Michael surname: Borys fullname: Borys, Michael organization: Global Product Development and Supply, Bristol‐Myers Squibb Company – sequence: 13 givenname: Zheng Jian orcidid: 0000-0002-1941-4145 surname: Li fullname: Li, Zheng Jian organization: Global Product Development and Supply, Bristol‐Myers Squibb Company |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32874175$$D View this record in MEDLINE/PubMed |
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| Title | Increased MSX level improves biological productivity and production stability in multiple recombinant GS CHO cell lines |
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