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Addition of Valproic Acid to CHO Cell Fed-Batch Cultures Improves Monoclonal Antibody Titers

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Abstract

Improving the productivity of a biopharmaceutical Chinese hamster ovary (CHO) fed-batch cell culture can enable cost savings and more efficient manufacturing capacity utilization. One method for increasing CHO cell productivity is the addition of histone deacetylase (HDAC) inhibitors to the cell culture process. In this study, we examined the effect of valproic acid (VPA, 2-propylpentanoic acid), a branched-chain carboxylic acid HDAC inhibitor, on the productivity of three of our CHO cell lines that stably express monoclonal antibodies. Fed-batch shake flask VPA titrations on the three different CHO cell lines yielded cell line-specific results. Cell line A responded highly positively, cell line B responded mildly positively, and cell line C did not respond. We then performed factorial experiments to identify the optimal VPA concentration and day of addition for cell line A. After identifying the optimal conditions for cell line A, we performed verification experiments in fed-batch bioreactors for cell lines A and B. These experiments confirmed that a high dose of VPA late in the culture can increase harvest titer >20 % without greatly changing antibody aggregation, charge heterogeneity, and N-linked glycosylation profiles. Our results suggest that VPA is an attractive and viable small molecule enhancer of protein production for biopharmaceutical CHO cell culture processes.

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Acknowledgments

The authors would like to thank Biogen Idec Analytical Development and the Biogen Idec High Throughput Analytical Group for performing the Protein G and product quality analyses. We would also like to thank Kevin Ramer for review of the manuscript.

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Authors and Affiliations

  1. Cell Culture Development, Biogen Idec, Inc., 5000 Davis Drive, Research Triangle Park, NC, 27709, USA

    William C. Yang, Jiuyi Lu, Ngan B. Nguyen, An Zhang, Nicholas V. Healy & Yao-Ming Huang

  2. Cell Culture Development, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA, 02142, USA

    Rashmi Kshirsagar & Thomas Ryll

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  1. William C. Yang
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  2. Jiuyi Lu
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  3. Ngan B. Nguyen
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Correspondence to William C. Yang.

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Yang, W.C., Lu, J., Nguyen, N.B. et al. Addition of Valproic Acid to CHO Cell Fed-Batch Cultures Improves Monoclonal Antibody Titers. Mol Biotechnol 56, 421–428 (2014). https://doi.org/10.1007/s12033-013-9725-x

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