Amino acid degradation pathway inhibitory by‐products trigger apoptosis in CHO cells

Author:

Martínez Verónica S.1ORCID,Rodriguez Karen1,McCubbin Timothy2,Tong Junjie1,Mahler Stephen1,Shave Evan13,Baker Kym13,Munro Trent P.14,Marcellin Esteban12

Affiliation:

1. ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland St Lucia Queensland Australia

2. Queensland Metabolomics and Proteomics (Q‐MAP) The University of Queensland St Lucia Queensland Australia

3. Patheon, by Thermo Fisher Scientific Woolloongabba Queensland Australia

4. National Biologics Facility The University of Queensland St Lucia Queensland Australia

Abstract

AbstractChinese hamster ovary (CHO) cells are widely used to produce complex biopharmaceuticals. Improving their productivity is necessary to fulfill the growing demand for such products. One way to enhance productivity is by cultivating cells at high densities, but inhibitory by‐products, such as metabolite derivatives from amino acid degradation, can hinder achieving high cell densities. This research examines the impact of these inhibitory by‐products on high‐density cultures. We cultured X1 and X2 CHO cell lines in a small‐scale semi‐perfusion system and introduced a mix of inhibitory by‐products on day 10. The X1 and X2 cell lines were chosen for their varied responses to the by‐products; X2 was susceptible, while X1 survived. Proteomics revealed that the X2 cell line presented changes in the proteins linked to apoptosis regulation, cell building block synthesis, cell growth, DNA repair, and energy metabolism. We later used the AB cell line, an apoptosis‐resistant cell line, to validate the results. AB behaved similar to X1 under stress. We confirmed the activation of apoptosis in X2 using a caspase assay. This research provides insights into the mechanisms of cell death triggered by inhibitory by‐products and can guide the optimization of CHO cell culture for biopharmaceutical manufacturing.

Funder

Therapeutic Innovation Australia

Publisher

Wiley

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