How this protein expression system can help fight future pandemics

Mark Emalfarb, CEO of Dyadic, explains how a protein expression platform C1 may offer science and society a better way to stop viral pandemics.

As the current pandemic is demonstrating across the world, the pharma industry is capable of responding robustly to the global health crisis but at a cost that society may not be able to sustain under current bioprocessing development and manufacturing models.

Centuries of detecting, responding and treating global pandemics have taught us that if a virus (or any biologic threat) is extremely infectious and transmittable, it can spread quickly and propagate in vast numbers of people, quickly jumping social distance, borders and the ability of healthcare systems to treat the sick. Now in a global market where ‘carriers’ travel so extensively across continents– we need a rapid and affordable vaccine more than eve. 

Facing what’s to come

When confronted with such threats, the speed in which therapeutic or preventative solutions can be developed is critical, as is the ability to manufacture enough doses at an affordable cost to affect outcomes. 

With the challenge of trying to reach billions of patients, the economics of protein expression becomes even more critical to the equation. When you consider delivering these medications to the world, the problems this magnitude of scale highlights is clear. 

Better suited for small populations and the rhythms of seasonal flu, the long timelines and high costs of pharma’s current methods may no longer be sustainable or adequate enough to respond to neither the current or next global health crisis. 

A vaccine is only the means to an end 

However, if the goal is to stop a disease like Covid-19 as well as future viral threats to come, finding a vaccine is one thing. In turn, manufacturing it in quantity and distributing it to patients globally, is entirely another. Demand for a Covid-19 vaccine is likely to hit billions of doses—under current best commercial practice. Do the economics of manufacturing and distribution seem practical?  

The way vaccines are developed and rolled out today is about the same as it has been for the past several decades. Currently the world mainly relies on Chinese Hamster Ovary (CHO) cells or insect cells for expression as the gold standard, but its expense and processing complexity is driving developers to consider emerging cell line (hosts in which to express these proteins and vaccines) alternatives. 

Despite commercial pharma’s best efforts, it’s become clear it is time to move past deep-rooted thinking and centralised dedicated CHO and baculovirus models and exploit the advances of synthetic biology and apply it to more efficient cell lines - like Dyadic’s hyper productive C1 cell line.

Compelling science and production economies

Dyadic has been dedicated to leveraging science in pursuit of industrial and pharmaceutical process quality, economy and efficiency. For the past three decades, Dyadic has been taking compelling science and turning it into production efficiency for some of the most prominent names globally.

In the wake of intensive research and development, we have developed a commercially viable expression platform for biopharma that’s proving it can improve yields, quality and quantifiably accelerate vaccine and biologics development timelines.

A next-generation expression platform as a worthy opponent 

C1, named Thermothelomyces heterothallica, is a fungus originally isolated from Russian soil. Dyadic’s scientists using state of the art methodologies including advanced molecular toolset took advantage of a serendipitous mutation that prompted a several 100-fold increase in protein productivity by the C1 filamentous fungus.

Since 2016, Dyadic’s expression platform, the C1 technology, has developed a commercially viable expression platform for biopharma that’s proving it can improve yields, quality, affordability and quantifiably accelerate vaccine and biologics development timelines. For example, C1 has a two-hour doubling time compared to roughly 20 hours for CHO cells. The system also uses defined synthetic media, which is far less costly as well as avoids a viral inactivation step required for CHO cells. 

Ready for emerging pharmacoeconomics and payer environments

Today, a broad range of biopharmaceuticals, vaccines and biosimilars are being produced via less efficient CHO and baculovirus cells. With Dyadic’s hyper productive C1 cells, manufacturers can produce remarkably more doses in a shorter time, and at a fraction of the cost compared to the average CHO and baculovirus productivity the industry reports.

Because C1 secretes its product into the surrounding cell media (essentially well-defined salts and sugars of the cheapest kind), the down-stream protein harvesting steps are also simpler than those in other next generation systems including E. coli expression systems that require lysing of cells, purifying product from cell fractions and more, all of which add costly complexity. 

More development routes, better yields

Dyadic’s C1 platform can also reliably express full-length monoclonal antibodies (mAbs), antibody heavy and light chains, Fc-fusion proteins, Fabs (antigen-binding fragments), bispecific antibodies, and vaccines. C1 can also make virus-like particles (VLPs), which theoretically are a more potent type of vaccine and difficult to express in general. 

Our R&D teams are also engineering C1 to express human-like glycosylation in different forms. That means pharmaceutical developers can evaluate potential candidates faster and more efficiently. Unlike CHO cells, C1 cells are monoclonal cells which have the potential to produce more consistent, more homogeneous glycostructures for companies to test and evaluate to find the best performers. 

Although both E. coli and the fungus-based C1 expression systems share advantages, such as not requiring the expensive viral clearance steps needed in CHO cells, the speed, quantity, purity, safety and transferability of the Dyadic C1 cell line system are optimal for processing commercial volumes of biopharmaceuticals economically. 

C1 is an agnostic platform – it expresses in high quantities, the proteins it is told to and does not prejudice against any known disease or target element. C1 is a highly scalable solution capable of bringing down the high costs associated with health care and manufacturing vaccines on a global basis. 

A proven technology now responding to Covid-19

In order to help combat the Covid-19 outbreak Dyadic recently developed a hyper productive C1 cell line that produces a SARS-CoV-2 Receptor Binding Domain (RBD) antigen from the Dyadic C1 gene expression platform that expresses the RBD antigen at three grams per liter (3.5 g/l) in only four days.  

Currently, the proprietary C1 expressed receptor binding domain (RBD) of the SARS-CoV-2 spike protein is being used in animal trials by seven research groups, governmental agencies and biopharma companies, including the Israel Institute for Biological Research (IIBR) and a collaboration of European Union scientists participating in the ZAPI programme. 

These institutions and companies are testing the C1 expressed RBD vaccine candidate(s) in animal trials on a stand-alone basis as well as testing the C1 RBD with nanoparticles and adjuvants.  Dyadic currently expects up to 10 animal trials to be completed by the end of 2020.  

Data generated by a number of these expert third parties confirmed that the C1 expressed RBD has the correct structure resulting in high binding and neutralising capacity. Additionally, a recently concluded IIBR mice study shows that the C1 RBD has the potential to generate excellent immunogenicity responses with very high titers and neutralising antibodies against the SARS-CoV-2 coronavirus. 

We are now moving to the next level of development aiming to conduct Toxicology test and the producing the C1 expressed SARS-CoV-2 RBD antigen under cGMP condition for Phase 1 and 2 clinical trials. 

Recently we expressed a SARS-CoV-2 mAb in collaboration with a biotech company who is developing promising new antibody cocktails to treat COVID-19 patients. 

We can and need to do better now

Dyadic is already hard at work to make the change happen: in Europe teaming with ZAPI – created for speed and coordinated response to diseases as soon as they emerge. With the Israeli Institute for Biologic Research (IIBR). And chosen by Frederick National Laboratory in the US to engineer C1 cell lines for vaccine candidates to be utilised by the Vaccine Research Center and at the National Institute of Health. 

Although pharma’s manufacturers are compelled as much by sunk costs as they are by entrenched industrial practice to trust their current vaccine production processes, the industry should consider a parallel processing strategy, investing in alternative expression technologies like C1 to hedge its bets. The US government and political players need to be open to new technology while exerting the necessary influence to push this solution and financial support to move the industry as a whole forward and to help make healthcare more accessible and affordable for patients globally 

During this pandemic, the pharmaceutical industry in the US received more than $10 billion in government support to find a vaccine. That certainly helped this time, but at a cost that is simply unsustainable using processes that will not meet the huge global demands if another outbreak were to occur and really isn’t moving the needle to making healthcare an inalienable right to citizens globally.