As the pipeline of biologics matures, the pharmaceutical industry is expected to see new biotherapeutics that offer improved efficacy. Pressure from the current healthcare environment, however, is pushing the pharmaceutical industry toward lower-cost therapies and faster times to market.
The CHO standard
Biologic drug development has traditionally depended on the use of Chinese hamster ovary (CHO) cells. Over the past three decades, the CHO cell line has become the automatic choice of expression system for biomanufacturers, notes Mark Emalfarb, CEO of Dyadic International, a biotechnology company focused on developing biologic vaccines and biologic drugs.
Emalfarb notes that the pharmaceutical industry is nonetheless experiencing the limitations that CHO expression yields present, which is complicated by pressures to develop affordable drugs quickly. “These [limitations] are particularly evident for the next wave of biologics, bi-specific, and tri-specific antibodies. The relatively low yields and relatively high costs of producing biologics with CHO appear to make it less sustainable and less commercially affordable for producing these more complex molecules,” Emalfarb says. “In a way, using CHO cells to develop and manufacture biologics is a bit like driving a 1900s model car in a 2020 Tesla world.”
Using CHO cells as the industry standard for biologic drug development has several major drawbacks, adds Mario DiPaola, PhD, senior scientific director at Charles River Laboratories, a contract research organization. The most significant drawback is product yield, which is typically less than one gram per liter, followed by costs related to the extensive cell-line development and limited cell viability for production.
“CHO expression systems work reasonably well for expression of less complex glycoproteins, but not well for new product modalities. For instance, in the case of AAV [adeno-associated virus]-like particle-based products, many developers are relying on HEK293 cell lines. Aside from yield and cost issues, the CHO cell-based expression system has other limitations related to glycosylation,” DiPaola explains. “The introduction of the immunogenic Galactose-alpha 1,3–Galactose linkage or N-glycolylneuraminic acid into glycan moieties of glycoproteins lacks certain transferases such as alpha 2,6 sialyltransferase, and it fails to produce any glycan with alpha 2,6 sialic acid.”
Driving innovation behind better biologic drug development is decreasing the cost of these therapies, which is quite high for most biologic drugs, DiPaola comments. “It is important to drive the costs down through innovations in order to lower both the costs of development and costs of production. It is interesting to note that over the course of the past two decades the time from patent filing to market has increased from an average of 130 months to about 150 months, and the cost of getting a biologic approved has gone from approximately $650 in 1996 to more than $2 billion in 2018,” DiPaola says. “Clearly, these trends must be reversed so that more patients can benefit from these drugs at reasonable costs.”
In addition, there is a separate need for more complex drugs, including more effective antibody drug conjugates (ADCs), multi-valent antibodies, and gene/cell therapies, “all of which industry to ensure success,” according to DiPaolo.
Emalfarb further comments to say that “‘better, faster, more affordable’ is a mantra we should all take to heart as we pursue the knowledge that could—at least potentially—make it easier to make the drugs that could save lives more affordably.”
“It is the responsibility of those working in the industry to enhance pharma companies’ ability to develop and make drugs efficiently and more cost-effectively. A large part of this entails encouraging pharmaceutical companies to study the potential of viable alternatives to CHO and to Escherichia coli (E. coli). Working together, government, regulatory agencies, academia, and pharma and biotech companies can indeed change things for the better,” Emalfarb says.
Exploring a new expression system
A cell source being explored as the basis of a new expression system for biologic building blocks is the fungus Myceliophthora thermophila, nicknamed C1, which Dyadic has been developing for the past two decades. C1 technology is a fungal expression system for gene discovery, development, and production of enzymes and other proteins.
Known as the C1 Expression System, Dyadic’s technology turns genes into a broad range of products and helps to overcome some of the inadequacies inherent in existing expression technologies used for gene discovery, product development, and commercialization.