Abstract
The use of antioxidants in Chinese hamster ovary (CHO) cell cultures to improve monoclonal antibody production has been a topic of great interest. Nevertheless, the antioxidants do not have consistent benefits of production improvement, which might be cell line specific and/or process specific. In this work, we investigated how treatment with the antioxidant rosmarinic acid (RA) improved cell growth and titer in CHO cell cultures using transcriptomics. In particular, transcriptomics analysis indicated that RA treatment modified gene expression and strongly affected the MAPK and PI3K/Akt signaling pathways, which regulate cell survival and cell death. Moreover, it was observed that these signaling pathways, which had been identified to be up-regulated on day 2 and day 6 by RA, were also up-regulated over time (from initial growth phase day 2 to slow growth or protein production phase day 6) in both conditions. In summary, this transcriptomics analysis provides insights into the role of the antioxidant RA in industrial cell culture processes. The current study also represents an example in the industry of how omics can be applied to gain an in-depth understanding of CHO cell biology and to identify critical pathways that can contribute to cell culture process improvement and cell line engineering.
Highlights
Similar viable cell density (VCD) and viability profiles were observed under these two conditions until day 6, after which a decline was evident in the controls without rosmarinic acid (RA)
The use of antioxidants in Chinese hamster ovary (CHO) cell cultures to improve monoclonal antibody production has been a topic of great interest [8,33–39]
We utilized transcriptomics as a tool to elucidate potential factors that could have an impact on the cell culture growth and productivity due to RA treatment
Summary
To reduce manufacturing costs and, in turn, allow wider patient access, upstream titer improvement is still the primary focus of cell culture process development. The optimization of chemically defined media is essential for cell culture titer improvement and control of mAb quality attributes [4,5]. In addition to nutrients that are commonly optimized in chemically defined media, small molecule medium additives have shown great promise for titer improvement. The application of small molecule additives as new raw materials should be thoroughly evaluated to ensure raw material quality control, acceptable costs, and sufficient removal by downstream purification without affecting final product quality attributes. We have recently reported that rosmarinic acid (RA) shows particular promise, having doubled mAb titer during the manufacture of a clinical mAb with acceptable cost and comparable mAb quality attributes to the original manufacturing process without RA [8]. A systematic study on the detailed mechanism by which RA improves titer has not been reported in the literature
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