November 30, 2017
I have recently read a couple of industry articles around cell line development that claim the Chinese hamster ovary (CHO) cell line is not the future of biomanufacturing and that alternative non-mammalian platforms, such as fungal, algae and plant systems, will offer the low-cost solutions that CHO cannot. Make no mistake, it will be a very long time before CHO cells are replaced as the manufacturing system of choice for most of the novel and sophisticated biotherapeutics (such as Fc fusions, bi-specifics, new scaffolds, etc.) being developed today. While there are examples where these alternative systems can be used to make therapeutics and vaccines, these systems are not able to cope with large natural protein therapeutics (e.g., MAbs), engineered protein therapeutics (e.g., Fc fusions, bi-specifics), therapeutic proteins with complex folding requirements (e.g., blood coagulation factors) or post-translational modifications. Furthermore, it is not yet clear whether the secretory capabilities of any of these non-mammalian systems can ever be fully modified to express recombinant protein drugs with low or no immunogenicity if injected in a human body.
The CHO cell line has been the workhorse of mammalian cell production since 1987, starting with the approval of Genentech’s ACTIVASE® (alteplase) for treating patients with acute ischemic stroke (AIS), which is caused by a blood clot in the brain’s blood vessels. In those days, it took approximately 12 to 16 months to make a cell line. The cells were grown in serum-containing media and the yields were around 100 mg/L. When we fast forward 30 years and countless cycles of innovation, we are now able to generate a high-expressing clonal cell line in less than four months, with cells grown in a chemically defined and serum-free media with titer levels between 2000-7000 mg/L (mainly for MAbs).
And the innovation continues… The CHO genome and transcriptome have been extensively analyzed and used to create novel CHO cell lines with improved biochemical pathways leading to the generation of clonal cell lines expressing difficult to express proteins (e.g., recombinant vaccines). At Selexis for example, using the data from our proprietary CHO K1 cell line genome and transcriptome, we are now able to determine levels of key enzymes critical for transcription, translation, secretion and metabolism and modify them to improve secretion, post-translational modifications, and – ultimately – productivity for difficult-to-express proteins. Furthermore, advances in how we identify and select clones from cell populations are also providing new avenues for identifying high-producing manufacturing clones. In any transfected population, only a small percentage of those cells have the optimal transcriptional, translational, metabolic and secretory machinery capable of supporting very high levels of production. We now have technologies that allow us to capture those rare events.
CONSLUSION The relevance of CHO cells to the production of emerging biologic therapeutics in the next 30 years will be just as important as it has been in the past 30 years. CHO cells are here to stay thanks to the wealth of experience in using these lines; in-depth understanding of the mammalian genome, transcriptome and metabolome of such cell lines; and, the on-going innovation that is allowing us to produce better, faster and more efficiently.