CHO cells the 1900s model car in a 2020 Tesla world, says Dyadic
According to Dyadic International, the C1 production platform develops cell lines in approximately three months, as opposed to the six months requires to make Chinese hamster ovary (CHO)-based cell lines.
In addition, “C1’s doubling time – rate of cell growth – is two hours, versus 20 hours for CHO cells,” CEO Mark Emalfarb told us.
“Based on the large difference of media cost needed for production using CHO, C1 achieves higher productivity using lower cost-defined synthetic media estimated to offer a cost savings of five to 10 times over CHO media,” he added.
Biopharma-Reporter (BPR) spoke with CEO of Dyadic International, Mark Emalfarb (ME), to discuss how the C1 platform works, why industry is looking for an alternative to traditional CHO cell lines, and what Dyadic has planned for the future of cell line production.
BPR: What are some of the major drawbacks of using CHO as the industry standard for biologic drug development?
ME: In a way, using CHO cells to develop and manufacture biologics at affordable costs is a bit like driving a 1900s model car in a 2020 Tesla world.
We, and others within the pharmaceutical and biotech industry, believe that there are numerous reasons why less than two percent of Americans use biologics, yet biologics account for 40 percent of total spending on prescription drugs. One of these reasons could be a result of pricing, and one way to bring down costs could lie in finding an alternative to using CHO cell lines to develop and manufacture biologics.
As Albert Einstein reportedly said, the definition of insanity is doing the same thing over and over and expecting different results. If drastic changes are not implemented in the biomanufacturing of biologics, we believe this problem will continue to worsen, as we are living longer; since biologics represented 70 percent of the growth in drug spending from 2010 to 2015 and are expected to be the fastest-growing segment of drug spending, the current healthcare model is unsustainable.
Data show that it takes about twice as long to create biologic drugs using CHO cell lines compared with microbial cell lines and about twice as long to get the cells ready to go into a fermenter. Dyadic has created a proprietary protein expression platform based on a genetically modified strain of the Myceliophthora thermophila fungus, nicknamed C1, which has been shown to be able to produce proteins faster, in higher amounts and at a lower cost than CHO.
C1’s doubling time – or rate of cell growth – is two hours versus 20 hours for CHO cells. With regard to the creation of monoclonal antibodies (mAbs), CHO entails a higher capital expenditure and operating expenditure than using microbial cell lines, and larger fermentation vessels are needed with CHO to obtain an equal output of mAbs. In addition to its lower yield and longer cycle time, CHO requires expensive, enriched growth media and viral purification steps that are not required with Dyadic’s C1 cell line.
BPR: How and why was C1 initially developed?
ME: Dyadic’s scientists originally searched for a microorganism to produce a cellulase enzyme for use in the manufacturing process for stonewashed jeans. This search eventually led them to isolate the C1 fungus from the alkaline soil of a forest in the far east of Russia. Dyadic scientists took the C1 fungus back to their labs and started selectively breeding it for higher expression of the desired cellulase protein. To propagate new characteristics in the fungal cells, they exposed them to ultraviolet light in a process called UV mutagenesis and expanded and reinforced beneficial mutations in a line of cells designed for lower-cost, large-scale manufacturing that the company named C1. During this process, two serendipitous mutations occurred. One of them was a drastic change in the shape of C1, from long, spaghetti-like, filamentous strands to short, grain-sized sections. This profound change in morphology resulted in multiple unexpected benefits in terms of industrial production of proteins.
Since C1 fungal cells secrete enzymes from the ends of the filaments, there were more secreting ends, multiplying the potential total yield of enzymes. Furthermore, due to its new shape, C1 became easier to grow in large tanks. The first commercial cellulase enzyme produced from C1 was launched in 1996 and since then, Dyadic and certain of its licensees such as Abengoa Bioenergy, BASF, Codexis/Shell and DuPont have been using C1 to develop and produce a variety of different enzymes for use in diverse applications including biofuels.
BPR: How was the potential of a protein expression platform based on C1 envisioned as a basis for next-generation production of biologics and other drugs?
ME: C1 has been shown to offer a shorter production time for mAbs and other proteins than CHO, requires significantly smaller production facilities and does not require viral purification. When C1-expressed proteins are secreted from the cells, they come out in a purer form than CHO-produced mAbs. For these reasons, we believe C1 may one day be a safe and efficient expression system that may help speed up the development, lower the production costs and improve the performance of biologic vaccines and drugs at flexible commercial scales. We believe it may also potentially enable the development and commercialisation of more complex genes that are difficult to express at reasonable yields in CHO and other cell lines. It might also be able to produce larger amounts of protein to enable drug discovery and development to move forward faster.
BPR: What interest has the C1 production platform attracted in the biopharma industry so far?
Dyadic has, and is, receiving research funds from several top-tier pharma companies to conduct certain proof-of-concept studies. Although restricted in some cases from being able to name such collaborators, some of these have been made public, such as the following research collaborations:
- Mitsubishi Tanabe Pharma: To help Mitsubishi Tanabe overcome specific gene expression challenges of two important therapeutic compounds using C1 technology.
- Israel Institute for Biological Research (IIBR): To further advance C1 for the development and manufacture of recombinant vaccines and neutralizing agents comprising targeted antigens and monoclonal antibodies to combat emerging disease and threats.
- ZAPI (Zoonoses Anticipation and Preparedness Initiative): Preliminary results indicated that the C1-produced antigen generated an immune response in mice that protected them and did not have negative effects on their health.
BPR: What are the next steps in the development of the C1 production platform?
ME: Dyadic will seek to continue to improve the productivity yield of mAB, Fab and multi-specific antibodies, FC-Fusion proteins, vaccines, antigens, VLPs and other types of proteins for animal and human use utilising the C1 platform. The company will also continue to look for R&D collaborations with pharmaceutical companies that are looking to speed up the development and lower the cost of manufacturing biologic vaccines and drugs.
Mark Emalfarb founded Dyadic in 1979. He has been a member of Dyadic’s board of directors since 2004, and heading the board as chairman, as well as president and CEO, from October 2004 until April 2007. Emalfarb took up these responsibilities for a second time, from June 2008 until the present.