The biopharmaceutical industry relies on a few organisms and cell lines for production. The most common are CHO, E. coli, and S. cerevisiae, which are well characterized and can achieve acceptable yields. In other words, drug firms use expression systems that are proven to work.
But it is time to consider alternatives, according to Christopher Love, PhD, professor of chemical engineering at MIT, who says with synthetic biology scientists can modify organisms so they can make more protein in less time and more simply than traditional cell lines.
“The processes required to manufacture biologic medicines are intimately linked to the biology of the host selected: the overall productivity and purity of the products is shaped by the features of the host selected,” he explains.
“New hosts can help simplify manufacturing processes, which in turn could enable fast development for clinical testing and reduced costs in manufacturing these medicines.”
The possible benefits are considerable. Love says new hosts could eliminate time consuming and costly processing steps like viral inactivation, reduce buffer requirements, and simplify chromatographic protocols.
“Alternative hosts can offer potential savings in time and costs for development and manufacturing…These advantages are borne from differences in their growth rates, simplicity in genome engineering, and the potential for process intensification by reducing manufacturing operations required,” continues Love.
“The advances in synthetic biology and gene editing make holistic process development—which includes the host biology appropriate to support manufacturing—accessible in ways it has not been in the past when other hosts have been considered.”
Also, as industry shifts towards new types of therapies, the need to efficiently transition molecules from the lab to the clinic and beyond is increasingly important for businesses, Love adds.
Genome engineering
Love and colleagues from MIT’s AltHost Consortium—a group using genome engineering to create production strains—set out the potential benefits alternative hosts in a recent study. The team used the approach to develop production strains to help advance clinical stage vaccines for SARS-CoV-2, the virus that causes COVID-19.
“As the current pandemic has demonstrated, additional manufacturing capabilities could help forward access, equity, and robustness in manufacturing in response to situations like this one,” says Love.
Other organizations are also advancing novel hosts they offer for use by biopharmaceutical firms and CDMOs, notes Love, describing such work as a requirement for a healthy manufacturing ecosystem.
“This approach allows for shared learning on the biology of hosts that can inform the design of ‘fit-for-purpose’ strains, like ones that have appropriate post-translational modifications like glycans or competitive productivities,” he points out.
And the approach has even wider application, according to Love, who says “This new model is using principles common in the software industry for open-source development, which are known to promote innovation and expand knowledge in the industry.”
Greater industry adoption of alternative hosts like Pichia pastoris—which is gaining in popularity for vaccine production—would foster innovation in the process technology space, Love tells GEN.
“Beyond the host itself, there are opportunities to advance technologies for intensified processes for alternative hosts like continuous manufacturing and single-use technologies that have been developed for CHO successfully,” he says.
“Innovations in processes and hosts could take advantage of the best of both engineering and biological systems to enable next-generation manufacturing solutions for speed and costs, and potentially further simplify technology transfers for platform-like processes for other types of molecules beyond monoclonal antibodies.”
Securing regulatory backing for processes that use an alternative host is likely to be straightforward, according to Love, who says the FDA has already shown it is willing to approve drugs made using novel systems.
“Regulatory agencies like the FDA license products on the basis of their safety, efficacy, and on the expected reliability of supply to the market. These same principles apply to any host,” he explains. “There are already biologics approved in the United States for chronic indications like migraines (Lundbeck’s eptinezumab)and diabetes— (Biocon’s insulin), that are manufactured in what is considered an alternative host, the yeast Komagataella phaffii.
“Millions of patients globally receive medicines produced in this host already, and it represents an example of how alternative hosts could be used for supplying safe and efficacious products.”
