In recent years, leveraging biology and engineering has led to incredible strides in combating human disease. In particular, we are able to develop and use antibodies to target a range of conditions, from cancer and cardiovascular ailments to skin disease and Ebola. Immunotherapy is rapidly becoming the most promising approach to eliminate cancerous cells. Indeed, the immunotherapy and antibody-drug conjugate market — based on blockbuster monoclonal antibodies — is worth USD $100 billion.
Monoclonal antibodies are just one type of glycoprotein — a diverse class of molecules that are just like regular proteins but with short chains of glycans (sugars) attached to them. Glycoproteins perform tasks critical for the human body’s reproductive, digestive, endocrine, and immune systems. Whether the glycoprotein is erythropoietin (stimulating red blood cell production in bone marrow) or a B-cell-bound antibody (driving immune responses), this class of molecules holds vast potential to be leveraged for engineering and advancing human health — something that has been clearly demonstrated by the current multitude of candidate COVID-19 antibody therapeutics.
While therapeutic glycoproteins are a critical key for further developing promising immunotherapies, the development and production of these molecules has been stubbornly limited due to their complex structures. The challenges of glycoprotein synthesis are varied. It is often difficult to determine the structure of the glycoproteins’ carbohydrates and separate the various forms into pure components because of the heterogeneity of these side chains. Glycosylation is a more diverse and complex posttranslational change compared to various other functional group reactions; coupling this with glycoproteins’ large size (typically over 15 kilodaltons) and the branched structure of carbohydrate chains, these molecules are chemically challenging targets. These factors have limited the commercial glycoprotein industry to fragile mammalian cell systems that are next to impossible to scale to the same levels as are employed by more cost-sensitive industries.
Until now, that is. The synthetic biology techniques of today are making this problem much more tractable.
Coaxing microbes to make glycoproteins at scale
Last August, Conagen, a vertically integrated synthetic biology company located in Boston’s biotech corridor, announced that it acquired a fermentation-based technology for the production of therapeutically useful glycoproteins, including several patents covering the platform. This is significant because glycoproteins are anything but straightforward to make.
There are two major types of glycans which are bound to glycoproteins: N-linked and O-linked, each of which can exist in a variety of forms and which differ in their locations on a glycoprotein. It is this structural divergence that leads not only to the diverse functional capabilities and distinctions between different glycoproteins, but often to different functions of the same glycoprotein when comprised of different glycans. It is also what has made it difficult to produce glycoproteins via industrial fermentation thus far; engineering a microbe to express glycoproteins with the necessary and optimal glycostructures and to do it robustly and at scale has been a nearly impossible task. But Conagen is uniquely positioned to be the first company to crack the code.
Most antibody-based therapies use monoclonal antibodies to target a wide array of diseases including cancer, neurodegeneration, autoimmune disorders, and infectious diseases like COVID-19. Traditionally, these antibodies are commercially produced in mammalian systems, such as Chinese hamster ovary (CHO) cells. Some improved technologies have made it possible to exceed productivities of 2 g/L/day in CHO cells producing some antibodies. However, remaining challenges still include high production costs, long optimization time and quality concerns.
Conagen’s new proprietary Conamax(TM) platform promises to achieve productivity upward of 1 g/L/day in a fast and sustainable way. Production of several therapeutic monoclonal antibodies has already been demonstrated in the system. Furthermore, the increased efficiency resulting from the greater scalability and robustness of this novel platform will also translate to surprisingly lower production costs, reducing the economic burden for the patients who need these critical treatments — a necessary focus as the high price of biopharmaceuticals and other drugs dominate news cycles and elections.
“The Conamax(TM) platform is uniquely suited for making antibodies. One of the most exciting features of this host organism is its ability to express glycoproteins harboring homogenous glycostructures which promote the desired immune cell functions,” says Vice President of Innovation, Casey Lippmeier. “This is a very unusual feature to find in a robustly fermentable microbe. It is also advantaged by its ability to tolerate the engineering required to customize these glycostructures while preserving the microbe’s robustness.”
At present, Conagen plans to expand this technology and others towards large-scale manufacturing of solutions to combat COVID-19. “We are thinking of a much higher production scale than what is currently achievable,” said Lippmeier, as a key panelist in SynBioBeta’s COVID-19 antibodies roundtable on April 17, 2020.
Expertise rooted in plants
It should come as no surprise that Conagen is making waves in this space. The company has a deep-rooted history in the biochemistry of botanical product biosynthesis and is driven by an unwavering motivation to uncover metabolic pathways for developing natural products and molecules closest to what nature produces. Much of the company’s innovation is facilitated by its extensive microbial platforms, which leverage synthetic biology to rationally engineer and improve upon nature. The company’s vertically integrated systems allow for the rapid movement of microbial strains to the metric-ton scale, effectively and efficiently controlling quality, cost, and purity—not an easy feat for most fermentation labs.
Their platform has already seen the introduction of the next generation of rebaudioside-based sweeteners, is enabling chemical giant BASF to scale fermentation of vanillin, and is also being leveraged to produce natural molecules that may promote healthy aging. With this newest addition to their portfolio, the company can now address one of the most significant challenges to realizing promising new glycoprotein-based therapeutics for a range of conditions.
The increased efficiency resulting from increased scales will also translate to reduced production costs, reducing the economic burden for the patients who need these critical treatments—a necessary focus as pharmaceutical companies and predatory drug pricing dominate news cycles and elections. This concern is more evident than ever, especially as the development and manufacturing of antibodies to treat COVID-19 demand the utmost speed; Conagen’s Conamax(TM) platform presents a tantalizing opportunity to disrupt traditionally slower production timelines and therefore bring drugs to market as fast as possible to better serve patients.
Partnering with nature for an innovative, bright future
Conagen has an established history of bringing new innovations to market. The company’s ethos rooted in sustainability extends its future and potential far beyond rebaudiosides, vanillin, or even glycoproteins. Its world-scale production capabilities, unique microbial fermentation platforms, and products already on the market will ensure its continued growth and success for years to come. Conagen will continue to innovate the future of biotechnology, producing molecules closest to what nature develops at the nexus of science, the earth, and health.0