Transcriptomics and cell painting analysis reveals molecular and morphological features associated with fed-batch production performance in CHO recombinant clones

Stable, highly productive mammalian cells are critical for manufacturing affordable and effective biological medicines. Establishing a rational design of optimal biotherapeutic expression systems requires understanding how cells support the high demand for efficient biologics production. To that end...

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Bibliographic Details
Published in:Biotechnology and bioengineering 2023-11, Vol.120 (11), p.3177-3190
Main Authors: Nelson, Luke, Veling, Mike, Farhangdoust, Fatemeh, Cai, Xuezhu, Huhn, Steve, Soloveva, Veronica, Chang, Meiping
Format: Article
Language:English
Subjects:
Antibodies
Batch production
Biological activity
Biological effects
Cell density
Cloning
Epigenetics
Gene expression
Genes
Glutathione
L-Lactate dehydrogenase
Lactate dehydrogenase
Mammalian cells
Metabolism
Morphology
Organelles
Productivity
System effectiveness
Transcriptomics
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Summary:Stable, highly productive mammalian cells are critical for manufacturing affordable and effective biological medicines. Establishing a rational design of optimal biotherapeutic expression systems requires understanding how cells support the high demand for efficient biologics production. To that end, we performed transcriptomics and high-throughput imaging studies to identify putative genes and morphological features that underpin differences in antibody productivity among clones from a Chinese hamster ovary cell line. During log phase growth, we found that the expression of genes involved in biological processes related to cellular morphology varied significantly between clones with high specific productivity (qP > 35 pg/cell/day) and low specific productivity (qP < 20 pg/cell/day). At Day 10 of a fed-batch production run, near peak viable cell density, differences in gene expression related to metabolism, epigenetic regulation, and proliferation became prominent. Furthermore, we identified a subset of genes whose expression predicted overall productivity, including glutathione synthetase (Gss) and lactate dehydrogenase A (LDHA). Finally, we demonstrated the feasibility of cell painting coupled with high-throughput imaging to assess the morphological properties of intracellular organelles in relation to growth and productivity in fed-batch production. Our efforts lay the groundwork for systematic elucidation of clone performance using a multiomics approach that can guide future process design strategies.
ISSN:0006-3592
1097-0290
DOI:10.1002/bit.28518