Release date: 2017-04-18
Chinese hamster ovary cells (CHO cells) are often used to make biological agents, protein-based drugs, that can be used to treat cancer, autoimmune diseases, and many other diseases. Today, more than half of the best-selling biologics on the market are produced by CHO cells. For example, adalimumab (Humira), bevacizumab (Avastin) and rituximab (Rituxan).
Despite its widespread use, researchers face the challenge of optimizing biologics using CHO cells. For example, the protein production of CHO cells is sometimes low, which leads to higher costs for these drugs.
Researchers from the CHO System Biology Center at the University of California, San Diego (hereinafter referred to as the CHO Center) pioneered efforts to gain a deeper understanding of CHO cells and advance cell engineering research. CHO Center researchers and researchers from the University of California, San Diego, Jacobs School of Engineering, the University of California, San Diego School of Medicine, and the Sanford Burnham Prebys Medical Discovery Institute Build an interdisciplinary team.
Increase product output
In a paper published last year in the journal Cell Systems, CHO Center researchers worked with several teams around the world to develop a comprehensive genome-wide CHO cell metabolism model and identify specifics that maximize protein production. way. The project was led by Nathan Lewis, co-director of the CHO Center and a professor of pediatrics at the University of California, San Diego.
Researchers use this model to predict how much protein CHO cells can actually produce when subjected to two treatments that are often used in the industry to increase protein production. One treatment involves lowering the culture temperature, and another treatment involves adding sodium butyrate to the culture medium.
This model predicts that these treatments are less powerful in increasing protein production, but at the expense of cell growth. Lewis said, "This trade-off is very inefficient," because cell growth is only a small increase in protein production.
The researchers used this model to simulate other changes in CHO cells. In particular, they studied the effects of genetic changes on the flow of secretory pathways in CHO cells, which produce therapeutic proteins and release these proteins out of the cell. This model predicts that these cellular changes can increase protein production three times more than the industry treatments often used.
Lewis said, "This finding confirms that this secretory pathway is an important pipeline in cellular machinery, and we can modify it to produce more protein."
In a study published earlier this year in the journal Scientific Reports, Lewis and colleagues demonstrated that a different approach can increase protein production and increase cell growth rates. This method involves mapping the activity of all ribosomes in CHO cells when they produce a therapeutic antibody. In this process, the researchers found that silencing a gene not only improved cell growth, but also led to an 18% increase in antibody production.
QC
Glycosylation, the attachment of sugar chains to proteins, is another cellular process that CHO researchers are investigating. Controlling glycosylation, such as which sugar molecules or how many sugar molecules are added to the desired protein, is critical to producing high quality pharmaceutical products, but it is extremely challenging.
In a study published in the journal Biotechnology Journal, researchers developed an algorithm to predict how they can modify CHO cells to achieve the desired glycosylation pattern when making biologics and their biosimilars. Lewis said the study could accelerate efforts to significantly reduce the cost of major protein drugs.
Ongoing research
CHO Center researchers are developing and improving other first-rate resources to rationally design and optimize CHO cell lines for drug development. These resources include high-quality genomic sequences from CHO cell lines, next-generation genome editing technology, an ever-increasing library of engineered CHO cell lines, improved "clean" CHO cell lines without contaminants, and "safe harbor" integration sites (ie Sites on the CHO cell genome, capable of safely inserting human genes into these sites to improve protein expression), and complex methods for analyzing and understanding omics data.
Source: Bio Valley
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