[pullquote]It’s 2018 — and you are competing in an automobile race. You wouldn’t jump behind the wheel of a Model T Ford and expect to win; you’d go for the sleekest, fastest roadster you were allowed to use. Yet, when it comes to the development, scale-up and production of biologic therapeutic drugs, the biopharmaceutical industry has been stuck in second gear for years.
The standard method of biologic manufacturing has been utilizing Chinese hamster ovary (CHO) cells since the 1980s. Although using CHO has proven to be a satisfactory strategy (and is still the focus of major investment among biopharma companies worldwide), it presents a clear set of drawbacks. Therapeutic protein production using CHO is very expensive, requiring costly upfront investments in manufacturing facilities and high material and production costs. Combined with the fact that there have been relatively few advances in CHO protein production processes during the last decade, this has resulted in minimum increases in CHO productivity.
In 2018, CHO productivity appears to have plateaued at an industry average of approximately 4 grams per liter in 14 days, which is inadequate to meet future commercial manufacturing demands for biologics. Yet, the favored industry solution involves building and operating more and ever-more-expensive CHO manufacturing plants.
How a Fungus Could Move Things Forward
A potential alternative to CHO involves a fungus called Myceliophthora thermophila. A genetically modified strain of this fungus, known as C1, has been envisioned as the basis of a gene expression system that can positively impact the development, production costs and performance of biologic vaccines and drugs at flexible commercial scales.
The novel structure of the C1 fungus allows the secretion of enzymes at a rate that has been made possible by beneficial serendipitous mutations. Although the enzymes produced by the fungal strain have initially been harnessed for various industrial applications — they were originally developed for use in the stonewashing of blue jeans — it seems to be the case that the C1 fungus could represent an attractive gene expression platform for producing a range of biologic drugs including antigens, vaccines, antibodies, enzymes and other therapeutic proteins, and primary and secondary metabolites.
For example, a drug platform utilizing the C1 fungal strain is already approaching 10 grams per liter in seven days, which is already far in excess of the industry average of approximately 4 grams per liter in 14 days. Because of the high productivity of the C1 fungal strain, an equivalent amount of drug may be able to be synthesized within a 2,000-liter bioreactor as is currently made using CHO with two 12,000-liter tanks. If so, the advantages the C1 fungus could hold for capital expenditure and operating costs are clear.
Some further potential advantages of the C1 fungal strain over CHO become evident if we examine more of C1’s properties. Not only does its morphology translate into higher yields of secreted protein; we believe there is also no risk of viral contamination, which eliminates two purification steps typically required in CHO production. With the C1 fungal strain, it is possible to develop cell lines at a rate of a gram per liter per day productivity in 15 weeks, representing a substantial savings of time compared to CHO. The C1 fungal strain also involves a fermentation cycle of four to seven days, which represents one-half to one-third the comparable period required with CHO. The C1 fungal strain has already received GRAS (Generally Recognized as Safe) designation from the U.S. Food and Drug Administration. Because the fungal production process is capable of being scaled up or down depending on the requirements of a specific manufacturer, it could offer a level of flexibility absent with CHO.
When it comes to winning the biologics race in the 21st century, forward-looking companies will find that the tried-and-true just isn’t enough to satisfy global payers’ and patients’ future needs — and that opting for a more productive, flexible alternative is a better bet for getting to the finish line.