Going Beyond CHO: Is there a bright future for alternative eukaryotic expression systems?
The recent approval of ELELYSO™, the Pfizer/Protalix product for long-term treatment of type 1 Gaucher disease that is produced in genetically engineered carrot cells, made us wonder about the future of mammalian cell culture for production of complex biopharmaceuticals that cannot be manufactured in microbial systems. In particular, we wondered if the dominance of CHO cells in biopharmaceutical production was about to come to an end and if CHO cells would be rapidly replaced with newer mammalian cell lines, plant cells, insect cells, or even yeast. In a recent bioPulse™ survey we explored the prevailing attitudes towards this myriad of eukaryotic expression systems that are being offered as superior alternatives to CHO cells.
We found that in the self-selected respondents who participated in the survey, about half said they were using CHO cell lines for the production of their therapeutic products. If one takes a “glass half empty” viewpoint, this means that half the industry is using or considering alternatives to the cell line that has become the workhorse of the industry. Almost one quarter of the survey respondents said they were using the human cell lines HEK293 and PER.C6® (17% and 6%, respectively) for production with the remaining quarter split between murine cell lines and other technologies. While we don’t know whether our respondents’ products are commercial or in clinical trials, we could surmise that the use of older technologies represented by various murine cell lines occurs primarily in marketed or late stage clinical products, while the newer human production cell lines such as Per.C6 and HEK293 are used to produce emerging products in early clinical development. Of the other cell lines mentioned in the survey, most (A549, Cap and Cap-T, Vero, and MDCK) are known to be used primarily for vaccine production and minimally for production of therapeutic proteins and antibodies.
By looking at these results with a “glass half full” mentality, one immediately notes that no cell line other than CHO is in use by half the respondents, and in fact our own data shows that 70% of mammalian-produced products in development today are produced using CHO cells. And while some of the newer production cell lines were hailed by our respondents as producing proteins that are easier to purify or that have a better glycosylation profile, we do not think there is strong data to support these assertions. In fact, the majority of our respondents agree that human-derived production cell lines do not have any advantage over CHO cells and with over 25 years of experience in treating patients effectively with CHO-produced products, most companies are not excited about testing alternatives if they don’t have to. When asked what non-mammalian systems would be used if a candidate therapeutic protein could not be expressed in a mammalian cell line (human, murine, or CHO), the dominant alternatives were about equally split between avian, insect, and yeast cells, with a minority of just 14% suggesting plant cells. We wonder if the approval of a plant-produced product will tip the scale in favor of plant cells as a low-risk alternative to mammalian cell culture, but along with over 66% of our respondents, we believe that the dominance of CHO cells will continue through the next decade and the titers, product quality, and purity of CHO-derived products will only improve as we continue to build infrastructure around culturing and manipulating CHO cells. As a conservative and risk-averse industry, biotechnology will not migrate quickly to any new platform, especially when the old one is working so well for so many people.