According to BioPlan Associates’ 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, industry continues to favour mammalian cell lines to make biologics over novel-type expression systems like fungi, algae, and insect, opting in particular for CHO (Chinese hamster ovary) expression systems due to its “proven and safe nature (particularly in regulatory terms).”
But according to Mark Emalfarb, CEO and founder of Dyadic International, as biopharma looks to increase productivity for its multi-specific antibodies and biological vaccine pipelines, it will need to turn its back on the CHO cell line.
Genentech’s plasminogen activator Activase became the first human therapeutic product produced using CHO cells in 1987.
Since then the cell line has become an expression system of choice for biomanufacturers and is used to make best-selling monoclonal antibodies Rituxan, Humira and Enbrel, to name a few.
“Industry is starting to painfully experience the limitations of CHO expression yields for the next wave of biologics, bi-specific and tri-specific antibodies,” he told Biopharma-Reporter. “The already low yields and high cost of producing biologics with CHO appear to make CHO unsustainable and commercially unaffordable for producing these more complex molecules.”
High yielding, low-cost alternatives
Dyadic sold its industrial biotech business to DuPont for $75m in December 2015 but retained the right to apply its C1 fungal expression system to human and animal biopharma applications.
The platform is based on Myceliopthora thermophila fungus and involves “straight forward” fermentation that can be scaled-up to various commercial levels with a purification process Emalfarb said is easier and less costly than with a CHO platform.
“CHO is likely the last cell line one would have chosen if the industry would have had the foresight to see the future 30 years ago,” he said, adding: “Our cell line data lead us to believe that our C1 cell line has a great potential to deliver what has been coined a ‘CHO Stopper.’”
In the biofuel space, the platform has achieved production productivity of around 80 g/l of a single enzyme with high purity, and Dyadic hopes to bring the same success to biopharma.
“Abengoa, BASF, DuPont and others are utilising C1 to produce biofuel and other enzymes at up to 38 times the scale of [a typical biopharma stainless steel] 13,000 litre fermenter, in 50% or less the time, with 2-10 times the protein yield, with a fraction of the media cost and projected higher purity and simpler downstream processing,” Emalfarb said.
Industry shift
“There is a definite movement in place to find an alternative to CHO, and it is gaining momentum quickly,” Emalfarb told us.
Biogen, for example, said earlier this year it is looking at a “radical departure from the CHO platform” through research into fungal, algae and trypanosome systems.
And Dyadic itself has agreements with two undisclosed Big Pharma companies involving the expression of monoclonal antibodies through the C1 platform, and Emalfarb said there is interest from a number of other large multinationals engaged in therapeutics that have a high-dose regimen looking for a more cost-effective production cell line.
Obsolete capacity
The uptake of C1 and other hyper producing cell lines will disrupt the biomanufacturing infrastructure, Emalfarb warned, with recent investments made in commercial-scale mammalian cell culture capacity by CMOs – such as Samsung Biologics and Boehringer-Ingelheim – to become quickly outmoded.
“When C1 delivers on its promise in biopharma, as it did in industrial biotech… the tank infrastructure will choke [the biomanufacturers] and make their fermentation facilities and investment obsolete in the long run.”
The future of bioproduction is “not about more tanks and marginal competitive costs by scale, it's about high yielding cell lines,” he added.