<  Back to the Polytechnique Montréal portal

Analyzing Clonal Variation of Monoclonal Antibody-Producing CHO Cell Lines Using an In Silico Metabolomic Platform

Atefeh Ghorbaniaghdam, Jingkui Chen, Olivier Henry and Mario Jolicoeur

Article (2014)

Open Acess document in PolyPublie and at official publisher
Open Access to the full text of this document
Published Version
Terms of Use: Creative Commons Attribution
Download (1MB)
Show abstract
Hide abstract


Monoclonal antibody producing Chinese hamster ovary (CHO) cells have been shown to undergo metabolic changes when engineered to produce high titers of recombinant proteins. In this work, we have studied the distinct metabolism of CHO cell clones harboring an efficient inducible expression system, based on the cumate gene switch, and displaying different expression levels, high and low productivities, compared to that of the parental cells from which they were derived. A kinetic model for CHO cell metabolism was further developed to include metabolic regulation. Model calibration was performed using intracellular and extracellular metabolite profiles obtained from shake flask batch cultures. Model simulations of intracellular fluxes and ratios known as biomarkers revealed significant changes correlated with clonal variation but not to the recombinant protein expression level. Metabolic flux distribution mostly differs in the reactions involving pyruvate metabolism, with an increased net flux of pyruvate into the tricarboxylic acid (TCA) cycle in the high-producer clone, either being induced or non-induced with cumate. More specifically, CHO cell metabolism in this clone was characterized by an efficient utilization of glucose and a high pyruvate dehydrogenase flux. Moreover, the high-producer clone shows a high rate of anaplerosis from pyruvate to oxaloacetate, through pyruvate carboxylase and from glutamate to a-ketoglutarate, through glutamate dehydrogenase, and a reduced rate of cataplerosis from malate to pyruvate, through malic enzyme. Indeed, the increase of flux through pyruvate carboxylase was not driven by an increased anabolic demand. It is in fact linked to an increase of the TCA cycle global flux, which allows better regulation of higher redox and more efficient metabolic states. To the best of our knowledge, this is the first time a dynamic in silico platform is proposed to analyze and compare the metabolomic behavior of different CHO clones.

Uncontrolled Keywords

Animals; Antibodies, Monoclonal; CHO Cells; Citric Acid Cycle; Cricetulus; Ketoglutaric Acids; Metabolomics; Models, Theoretical; Pyruvate Decarboxylase; Pyruvic Acid; Antibodies, Monoclonal; Ketoglutaric Acids; Pyruvic Acid; alpha-ketoglutaric acid; Pyruvate Decarboxylase

Subjects: 1800 Chemical engineering > 1800 Chemical engineering
1900 Biomedical engineering > 1900 Biomedical engineering
Department: Department of Chemical Engineering
Funders: CRSNG / NSERC, Canadian Foundation for Innovation (CFI), Viropro International Inc.
PolyPublie URL: https://publications.polymtl.ca/3461/
Journal Title: PLOS One (vol. 9, no. 3)
Publisher: PLOS
DOI: 10.1371/journal.pone.0090832
Official URL: https://doi.org/10.1371/journal.pone.0090832
Date Deposited: 22 Nov 2018 15:28
Last Modified: 10 Apr 2024 02:19
Cite in APA 7: Ghorbaniaghdam, A., Chen, J., Henry, O., & Jolicoeur, M. (2014). Analyzing Clonal Variation of Monoclonal Antibody-Producing CHO Cell Lines Using an In Silico Metabolomic Platform. PLOS One, 9(3). https://doi.org/10.1371/journal.pone.0090832


Total downloads

Downloads per month in the last year

Origin of downloads


Repository Staff Only

View Item View Item