Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies
The secretory capacity of Chinese hamster ovary (CHO) cells remains a fundamental bottleneck in the manufacturing of protein-based therapeutics. Unconventional biological drugs with complex structures and processing requirements are particularly problematic. Although engineered vector DNA elements c...
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S200103702400429X |
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| author | Ying Bai Ivan Domenech Mercadé Ramy Elgendy Giulia Lambiase Sew Peak-Chew Catarina Franco Steven W. Wingett Tim J. Stevens Luigi Grassi Noah Hitchcock Cristina Sayago Ferreira Diane Hatton Elizabeth A. Miller Rajesh K. Mistry |
| author_facet | Ying Bai Ivan Domenech Mercadé Ramy Elgendy Giulia Lambiase Sew Peak-Chew Catarina Franco Steven W. Wingett Tim J. Stevens Luigi Grassi Noah Hitchcock Cristina Sayago Ferreira Diane Hatton Elizabeth A. Miller Rajesh K. Mistry |
| author_sort | Ying Bai |
| collection | DOAJ |
| description | The secretory capacity of Chinese hamster ovary (CHO) cells remains a fundamental bottleneck in the manufacturing of protein-based therapeutics. Unconventional biological drugs with complex structures and processing requirements are particularly problematic. Although engineered vector DNA elements can achieve rapid and high-level therapeutic protein production, a high metabolic and protein folding burden is imposed on the host cell. Cellular adaptations to these conditions include differential gene expression profiles that can in turn influence the productivity and quality control of recombinant proteins. In this study, we used quantitative transcriptomic and proteomic analyses to investigate how biological pathways change with antibody titre. Gene and protein expression profiles of CHO cell pools and clones producing a panel of different monoclonal and bispecific antibodies were analysed during fed-batch production. Antibody-expressing CHO cell pools were heterogeneous, resulting in few discernible genetic signatures. Clonal cell lines derived from these pools, selected for high and low production, yielded a small number of differentially expressed proteins that correlated with productivity and were shared across the biotherapeutics. However, the dominant feature associated with higher protein production was transgene copy number and the resulting mRNA expression level. Moreover, variability between clonal cell lines suggested that the process of cellular adaptation is variable with diverse cellular changes associated with individual adaptation events. |
| format | Article |
| id | doaj-art-808e407dcb674f72af2e309420f393fc |
| institution | OA Journals |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-808e407dcb674f72af2e309420f393fc2025-08-20T01:59:30ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-0127173110.1016/j.csbj.2024.12.006Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodiesYing Bai0Ivan Domenech Mercadé1Ramy Elgendy2Giulia Lambiase3Sew Peak-Chew4Catarina Franco5Steven W. Wingett6Tim J. Stevens7Luigi Grassi8Noah Hitchcock9Cristina Sayago Ferreira10Diane Hatton11Elizabeth A. Miller12Rajesh K. Mistry13Cell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Cell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UKCell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Cell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UKTranslational Genomics, Discovery Sciences, BioPharmaceutical R&D, AstraZeneca, Gothenburg, SwedenAnalytical Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge, UKCell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UKCell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UKCell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UKCell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UKCell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UKCell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UKCell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UKCell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UKCell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Corresponding authors.Cell Culture and Fermentation Sciences, BioPharmaceutical Development, AstraZeneca, Cambridge UK; Corresponding authors.The secretory capacity of Chinese hamster ovary (CHO) cells remains a fundamental bottleneck in the manufacturing of protein-based therapeutics. Unconventional biological drugs with complex structures and processing requirements are particularly problematic. Although engineered vector DNA elements can achieve rapid and high-level therapeutic protein production, a high metabolic and protein folding burden is imposed on the host cell. Cellular adaptations to these conditions include differential gene expression profiles that can in turn influence the productivity and quality control of recombinant proteins. In this study, we used quantitative transcriptomic and proteomic analyses to investigate how biological pathways change with antibody titre. Gene and protein expression profiles of CHO cell pools and clones producing a panel of different monoclonal and bispecific antibodies were analysed during fed-batch production. Antibody-expressing CHO cell pools were heterogeneous, resulting in few discernible genetic signatures. Clonal cell lines derived from these pools, selected for high and low production, yielded a small number of differentially expressed proteins that correlated with productivity and were shared across the biotherapeutics. However, the dominant feature associated with higher protein production was transgene copy number and the resulting mRNA expression level. Moreover, variability between clonal cell lines suggested that the process of cellular adaptation is variable with diverse cellular changes associated with individual adaptation events.http://www.sciencedirect.com/science/article/pii/S200103702400429XMultiomicsChinese hamster ovary cellsBiotherapeutics |
| spellingShingle | Ying Bai Ivan Domenech Mercadé Ramy Elgendy Giulia Lambiase Sew Peak-Chew Catarina Franco Steven W. Wingett Tim J. Stevens Luigi Grassi Noah Hitchcock Cristina Sayago Ferreira Diane Hatton Elizabeth A. Miller Rajesh K. Mistry Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies Computational and Structural Biotechnology Journal Multiomics Chinese hamster ovary cells Biotherapeutics |
| title | Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies |
| title_full | Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies |
| title_fullStr | Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies |
| title_full_unstemmed | Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies |
| title_short | Identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies |
| title_sort | identification of cellular signatures associated with chinese hamster ovary cell adaptation for secretion of antibodies |
| topic | Multiomics Chinese hamster ovary cells Biotherapeutics |
| url | http://www.sciencedirect.com/science/article/pii/S200103702400429X |
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