Researchers at Lumen Bioscience report in Nature Biotechnology genetic engineering methods to highly express bioactive proteins in spirulina using what they say are large-scale cultivation and processing methods appropriate for biopharmaceutical manufacturing.
The company describes it as a rapid, low-cost drug development approach to orally delivering biologics.
Previous attempts to convert Spirulina, a photosynthetic cyanobacterium, into a biomanufacturing platform have proven futile, said the Lumen team.
The paper also summarizes preclinical and early-stage clinical testing of Lumen’s orally delivered spirulina-expressed antibody targeting campylobacter.
Beyond campylobacter, the spirulina-based technology offers promising treatment options for conditions such as C. difficile, inflammatory bowel disease, and certain metabolic diseases, said Lumen CEO and cofounder, Brian Finrow.
The challenge
It took outside intervention, however, for the company to realize the benefits of focusing its spirulina platform on such targets, he told us.
It was a prompt from the Gates Foundation, which is located just across the lake from Lumen’s facility in Seattle, that initiated the company’s current R&D programs and strategy: “The Gates Foundation team approached us ten weeks after we incorporated and introduced us to this idea of directly delivering monoclonal antibodies and other protein therapeutics to diseased tissue and particularly to the GI tract.”
The non-profit organization maintained that delivering antibody drugs orally to prevent and treat highly prevalent gastrointestinal diseases rather than by injection would make them safer. However, orally delivered antibodies require repeat dosing, and antibodies made with traditional technologies such as CHO cell fermentation, which typically cost $100-$200 per gram, are too expensive to manufacture in the quantities necessary for oral delivery.
Looking at injectables, very little of the antibody, when delivered that way, actually goes to the site of the disease, in the mucosal epithelium, said Finrow. “You have to overwhelm the system with a huge dose,” he added.
“The Gates Foundation educated us that if you come from the top down, as we do, by eating the antibody, you can achieve much higher concentrations at the site of the disease and, therefore, get a much better effect. And you sidestep the systemic exposure you get with injected antibodies. In other words, not only can you make a more effective drug for highly prevalent diseases, such as C. difficile infection, but it is also a safer drug.”
The challenge though is manufacturing huge quantities of antibodies – metric tons - for oral delivery at a miniscule cost. “You are never going to get there with sterile fermentation.”
So how does spirulina come into play?
"Well, it is the only microbe that is farmed at commercial scale for human consumption. Most importantly, it grows under unusual conditions, very high temperature, very high salinity, and very high pH. It is very nutritious, that facet is very well established, as is its safety profile. That makes it possible for us to make extraordinarily inexpensive, and very large volumes of therapeutic protein, in a system that is safe enough to eat, and that means we can bypass all of the purification steps necessary for a traditional approach. It allows us to finally realize the long-held Gates Foundation’s goal of orally delivering antibody drugs or protein therapeutics,” said Finrow.
The process
The entire manufacturing process is done indoors at Lumen’s integrated Seattle lab and cGMP plant, which has been operational since 2018.
A gene encoding the therapeutic molecule - an antibody, for example - is introduced into the spirulina chromosome. When that strain of spirulina is grown, the cell manufactures the therapeutic protein and stores it away inside the cell.
The production system requires only water, salt, CO2, and light, thereby making it rapid and scalable, said the company.
Harvesting is done by spray-drying the biomass into a powder comprised of spirulina cells, each one filled with a therapeutic protein ‘payload’. This powder can be packed into dose-specific capsules, which don't require refrigeration and are shelf-stable at room temperature, it explained.
While the cells do not survive the drying process, the cell membrane protects the therapeutic proteins during transit through the stomach when orally delivered and releases them in the small intestine where they can bind to and neutralize their disease targets, said the firm.
Prophylaxis using the spirulina platform could be affordable, even in the developing world. The fact that the antigen-binding domains and other biologics in dry spirulina powder are shelf stable without refrigeration could facilitate distribution, especially into regions lacking high-quality infrastructure and is another reason why the Gates Foundation is interested in Lumen’s technology, said the CEO.
Disease programs
Lumen is currently applying the technology to a growing list of highly prevalent diseases.
Its oldest program is Gates Foundation led – it is a single antibody directed at preventing infection by the most common strain of C. jejuni, which is a major cause of traveler’s diarrhea in Southeast Asia. It is currently undergoing a Phase 2 clinical trial in Baltimore.
BARDA’s CARB-X program is funding the development of a second-generation version of that product, to create a low-cost, edible antibody drug cocktail that blocks infection by two of the main causes of travelers’ diarrhea: enterotoxigenic E. coli and campylobacter.
In terms of additional programs, LMN-201, a complex biologic cocktail for prevention of C. difficile infection, is being run in collaboration with the US National Institute of Allergy and Infectious Diseases (NIAID) and Rockefeller University. It has completed Phase 1 and is set to enter Phase 2 studies in the summer. “We have cleared the IND.”
LMN-301 is an antibody cocktail designed for topical delivery. The initial program is directed at the GI manifestations of Covid-19 and is funded by the US Defense Health Agency. It is moving into Phase 2 clinical trials in Brazil this summer. “We have also funding from the Gates Foundation to reformulate that for airway delivery, to prevent or nip infection in the bud after exposure.”
Another complex biologic cocktail is targeted at treatment of inflammatory bowel disease. And, in collaboration with Novo Nordisk, Lumen is developing orally delivered biologics against GI targets relevant to cardiometabolic disease.