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Multi-omics profiling of a CHO cell culture system unravels the effect of culture pH on cell growth, antibody titer and product quality
  • +16
  • Alison Lee,
  • Yee Jiun Kok,
  • Meiyappan Lakshmanan,
  • Dawn Leong,
  • Lu Zheng,
  • Hsueh Lee Lim,
  • Shuwen Chen,
  • Shi Ya Mak,
  • Kok Siong Ang,
  • Neil Templeton,
  • Taha Salim,
  • Xiaona Wei,
  • Eric Gifford,
  • Andy Hee-Meng Tan,
  • Xuezhi Bi,
  • Say Kong Ng,
  • Dong-Yup Lee,
  • Wai Lam Ling,
  • Ying Swan Ho
Alison Lee
Bioprocessing Technology Institute, A*STAR
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Yee Jiun Kok
Bioprocessing Technology Institute, A*STAR
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Meiyappan Lakshmanan
Bioprocessing Technology Institute, A*STAR
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Dawn Leong
Bioprocessing Technology Institute, A*STAR
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Lu Zheng
Bioprocessing Technology Institute, A*STAR
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Hsueh Lee Lim
Bioprocessing Technology Institute, A*STAR
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Shuwen Chen
Bioprocessing Technology Institute, A*STAR
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Shi Ya Mak
Bioprocessing Technology institute, A*STAR
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Kok Siong Ang
Bioprocessing Technology institute, A*STAR
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Neil Templeton
Merck and Co Inc
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Taha Salim
Merck and Co Inc
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Xiaona Wei
MSD International GmbH (Singapore Branch)
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Eric Gifford
MSD International GmbH (Singapore Branch)
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Andy Hee-Meng Tan
Bioprocessing Technology Institute, A*STAR
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Xuezhi Bi
Bioprocessing Technology Institute, A*STAR
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Say Kong Ng
Bioprocessing Technology Institute, A*STAR
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Dong-Yup Lee
Sungkyunkwan University
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Wai Lam Ling
Merck Research Labs
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Ying Swan Ho
Bioprocessing Technology Insitute, A*STAR
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Abstract

A robust monoclonal antibody (mAb) bioprocess requires physiological parameters such as temperature, pH, or dissolved oxygen (DO) to be well-controlled as even small variations in them could potentially impact the final product quality. For instance, pH substantially affects N-glycosylation, protein aggregation and charge variant profiles, as well as mAb productivity. However, relatively less is known about how pH jointly influences product quality and titer. In this study, we investigated the effect of pH on culture performance, product titer and quality profiles by applying longitudinal multi-omics profiling, including transcriptomics, proteomics, metabolomics and glycomics, at three different culture pH set points. The subsequent systematic analysis of multi-omics data showed that pH set points differentially regulated various intracellular pathways including intracellular vesicular trafficking, cell cycle, and apoptosis, thereby resulting in differences in specific productivity, product titer and quality profiles. In addition, a time-dependent variation in mAb N-glycosylation profiles, independent of pH was identified to be mainly due to the accumulation of mAb proteins in the endoplasmic reticulum (ER) over culture time, disrupting cellular homeostasis. Overall, this multi-omics-based study provides an in-depth understanding of the intracellular processes in mAb-producing CHO cell line under varied pH conditions and could serve as a baseline for enabling the quality optimization and control of mAb production.

Peer review status:IN REVISION

17 Feb 2021Submitted to Biotechnology and Bioengineering
17 Feb 2021Assigned to Editor
17 Feb 2021Submission Checks Completed
03 Mar 2021Reviewer(s) Assigned
31 Mar 2021Review(s) Completed, Editorial Evaluation Pending
31 Mar 2021Editorial Decision: Revise Major