Production of an antibody can be doubled without loss in quality by genetically modifying special cells to overexpress heat shock protein 27 (HSP27), a Singaporean research team has shown, bringing efficient production of therapeutics a step closer.
Cultures of Chinese hamster ovary (CHO) cells are used to produce large quantities of biological medicines known as recombinant biologics. DNA is artificially constructed with specially chosen gene sequences and inserted into CHO cells. The 'recombinant DNA' instructs the cells to produce proteins that are then used for medical purposes.
Scientists from A*STAR's Bioprocessing Technology Institute (BTI) and the National University of Singapore have now genetically modified CHO cells to overexpress heat shock protein 27. Under typical conditions, CHO cells die in culture, due to build-up of waste by-products, which limits the amount of recombinant biologics they can produce.
By studying gene and protein expression in CHO cultures BTI researchers previously found that HSP27 levels were low when the growth of CHO cells was slow. "We speculated that more HSP27 in the CHO cells could prolong the culture's life and accordingly increase the concentrations of the biologics they produce," says BTI bioprocess scientist Janice Tan Gek Ling.
To demonstrate the concept, the team overexpressed HSP27 in CHO cells engineered to produce an antibody that binds to an antigen, called Rh factor, which is commonly present on red blood cells. This antibody can prevent Rh disease, where Rh incompatibility between a pregnant mother and her fetus can lead to a dangerous breakdown in the newborn baby's red blood cells—acute cases can kill the baby in utero.
Together with their previous study that used CHO cells engineered to produce recombinant human interferon gamma—a therapy for hereditary immune and bone diseases — the team has shown that use of overexpressed HSP27 can improve the production of different recombinant biologics.
"Companies developing new biologic products can choose to implement this technology by using a host cell line designed to overexpress HSP27," says BTI Staff Scientist Ng Say Kong. In future, rather than having to engineer the cell lines from scratch, there could be new additives to add to CHO cultures which would simplify using this technology in existing manufacturing plants.
The team is now pursuing a more in-depth understanding of how HSP27 works. "With this knowledge, we can further engineer the CHO cell cultures to have an even longer culture life and higher cell growth leading to higher production of biologics," says Ng.
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Janice G.L. Tan et al. Heat shock protein 27 overexpression in CHO cells modulates apoptosis pathways and delays activation of caspases to improve recombinant monoclonal antibody titre in fed-batch bioreactors, Biotechnology Journal (2015). DOI: 10.1002/biot.201400764