The history of the biotechnology industry pivots off breakthroughs in genetic engineering. The first major leap was in the 1970s with E. coli, which laid the groundwork for the creation of Genentech and is still a workhorse of biotech today. Then, in the 1980s, mammalian cell engineering was cracked, enabling the manufacturing of monoclonal antibodies, which set the stage for enormously successful companies like Amgen. More recently, in the 1990s, an equally valuable set of patents came out with the ability to engineer yeast, which is now being used to generate all sorts of industrial biologics, like laundry detergent enzymes.
Researchers worldwide have long suspected that spirulina (Arthrospira platensis)—a type of cyanobacteria (blue-green algae) that is used as a dietary supplement and has made its way into many smoothie recipes—would be a valuable tool for making biologic drugs. Being extraordinarily high in soluble protein, spirulina cells can express far higher amounts of therapeutic proteins than any other food crop (>60%). And the production system requires only water, salt, carbon dioxide, and light, so it is cheap and rapidly scalable. But efforts to hack spirulina for therapeutic molecule production and delivery failed for decades.
Lumen Bioscience was the first to reach this milestone and is already on the path to commercializing orally administered biologics. The company’s patented spirulina technology is designed to enable the manufacturing of biologic drugs at a cost that according to the company is orders of magnitude lower than traditional biotech manufacturing systems—cheap enough even for oral delivery.
Lumen believes that biologic medications are the quickest, safest, and most effective approach to treating various disorders that traditional biopharmaceutical techniques have failed to address. These therapies are particularly well adapted to resolving antibiotics’ unintended consequences and the developing world, where a lack of infrastructure makes traditional medications unavailable to millions of vulnerable children and adults.
The Seattle-based company has made clinical development progress on its lead candidate, LMN-201, an orally delivered biologic cocktail to treat and prevent a form of colitis called C. difficile infection (CDI). Lumen achieved FDA clearance for a planned Phase II study and successfully completed a Phase I first-in-human study, which validated drug delivery of enteric capsules into the gut.
LMN-201 combines four therapeutic proteins—manufactured and orally delivered in the edible microorganism spirulina—that work synergistically to neutralize both the C. difficile bacterium and the toxin that causes its virulence. LMN-201 is the world’s first complex biologic cocktail to enter human clinical trials and represents a significant advance in polypharmacology.
GEN Edge sat down with co-founders CEO Brian Finrow, JD, and CSO Jim Roberts, MD, PhD, who was previously the Director of the Fred Hutch Cancer Research Center’s Basic Sciences Division and an HHMI investigator. They shared how an initial conversation at a Thai restaurant has led them on a path to creating a clinical-stage biopharmaceutical that develops drugs for a range of gastrointestinal (GI) autoimmune and metabolic diseases via spirulina.
GEN Edge: Why did Lumen zero in on Spirulina as a biologics production platform?
Finrow: You could do many things with therapeutic proteins if only you could make them at metric ton or kiloton scales, rather than at gram and kilogram scales. People had been circling around various alternative expression platforms for a while. Many groups tried engineering plants and eukaryotic algae for this, but for technical reasons having to do with plant biology, those efforts never really went anywhere. Many well-funded groups even tried and failed to engineer spirulina. We weren’t the first to appreciate the organism’s potential, but none of those groups found a way to do it.
Orally delivered biologics are a holy grail in our industry. All biologic drugs approved until now have been injected. You might bet the trend will continue if you’re a betting man. We do have that technology, but it’s been talked about so longingly that people are a little bit skeptical. But this technology’s real. What would you do differently if you could make biologic drugs at the scale and low cost typically associated with small-molecule drugs? That is a kind of a reformulation of the question we started the company with.
Roberts: Spirulina is very stable once genetically engineered. Once we had a way of doing engineering, we could augment that technology to put in different kinds of gene cassettes and multigene pathways. There are no limits to what we can do in that regard. We’ve made everything from peptides to large proteins, multi-protein complexes, vaccine antigens enzymes, cytokines, and antibodies. Expression levels are high enough that we can deliver high concentrations of biologics to the GI tract as often as necessary, with reasonable dose sizes.
Another key difference between what others are doing and what we’re talking about is that our platform is easily scalable enough to make affordable products for disease prevention, not just treatment. Prevention requires a very large scale because you’re treating many people who won’t get sick. In addition, the patient populations for all our initial programs are much larger than is typical nowadays for our industry, so it requires a platform like this to crack into the prevention market with biologics. Consequently, we measure everything in log scale, or orders of magnitude, not just small improvements like 10% or 20%. We want the scale to be a couple of logs larger and the price or the cost to be a couple of logs cheaper than traditional approaches.
One of the advantages of spirulina from the genetic engineering perspective is that it can make a lot of the therapeutic protein. We can get up to 20% of biomass being the therapeutic protein. This not only makes the dose size manageable, it also makes everything cheaper. It’s also important that it is done in a continuous production system, not one where you grow, induce, harvest, and then regrow in a series of batches. It’s a stable constitutive expression where we continuously grow spirulina, then harvest part of the culture, and regrow the rest to keep it going continuously. That makes manufacturing easy. It’s photosynthetic: all you have to do is feed them sulfur, nitrogen, phosphorous, and water—that’s all it takes! The upstream growth is cheap, and the downstream processing is almost nonexistent. So, it’s massively scalable and extremely low cost.
Spirulina is also a safe package for delivering the therapeutic—it’s safe and good for you to eat. You can eat a lot of it, much more than we would ever deliver as a therapeutic. One consequence is that, at least for oral delivery, you don’t have to purify anything. That’s part of what makes it so darn cheap and scalable. You just grow the therapeutic protein in spirulina and dry it with a spray dryer. These were originally used by the powdered milk industry, and we adapted them to make powdered spirulina.
GEN Edge: What were the key problems that Lumen had to solve to crack open spirulina for drug development?
Roberts: In addition to solving the cell-engineering problem, we also had to invent the manufacturing platform. While spirulina has been grown commercially for decades, it’s all been outdoor growth in ponds that are unsuitable for pharmaceutical manufacturing. We had to build an entire system for indoor cultivation. Craig Behnke, our EVP, Production and Development, came to us from Sapphire Energy—one of the biggest U.S. algae biofuel developers. Craig understands more about photosynthetic organism cultivation than probably anyone in the world. He built an incredible indoor cultivation platform for spirulina; it’s the world’s only cGMP spirulina plant!
Finrow: Once you have the technology, the first big challenge is figuring out everything we could do with that. We had the core technology, but with something as broadly applicable as this, the big challenge has been to figure out what are the very best things to do with it first. That is what we’re still working through now. The cost profile and the scalability of it are cheap and abundant, like making aspirin rather than conventional antibody drugs. It has taken a lot of work to wrap our heads around the profound implications of that, particularly since in this industry, we all carry battle scars from just how arduous and expensive it is to first develop and later, after approval, manufacture and distribute conventional biologics. That immensely powerful technology was developed in the eighties, and we view ourselves as carrying that torch forward into this new field with oral delivery. Our job is to figure out what it is most useful for and how we can most quickly deploy the technology into those areas and help patients left behind by the traditional drug development tools—that is an interesting way to look at our pipeline.
A key conceptual breakthrough was entirely serendipitous. Unbeknownst to us, as we were starting the company, the Gates Foundation was finishing an 18-month global search for a way to manufacture and deliver orally delivered therapeutic antibodies for one of their global health programs. They found their way to us. Among all the therapeutic protein classes, they introduced us to the easiest, fastest, and probably the lowest hanging fruit to go after with our platform first: making therapeutic antibodies in spirulina and just feeding them to people to prevent these horrible diarrheal diseases that kill millions of infants and newborns in the developing world.
Our other programs build on this core insight. If you think about prevention of C. difficile infection, for example, it beautifully encapsulates these themes. Despite all the recent decades of research and biotechnology, we still have a $5–8 billion cash drain on the US hospital system every year because of C. difficile infection. The vaccines have all failed to date. People continue to try to develop new, narrower-spectrum antibiotics, but it’s still a major problem. There’s an injectable biologic on the market today for C. difficile infection. Still, it’s risky, inconvenient to administer, hard to distribute, and very expensive. It hasn’t seemed to be able to make a dent in that $5–8 billion problem.
We think that C. difficile infection prevention is an excellent showcase for what we can do. That’s not to say our platform will solve every human disease, of course. There are lots of things for which our tool will not be the best for the job. Still, we think there are prevalent disease areas that have been left behind, in some cases just completely abandoned, by drug developers. Diseases like C. difficile infection, which today has mostly been abandoned by the major biopharmaceutical companies. There will be many more opportunities like that, but the quickest path to get there, whether we’re doing it ourselves or partnering where appropriate, we will follow that path.
GEN Edge: Has Lumen developed into an end-to-end clinical-stage biopharmaceutical company?
Roberts: In just the 4.5 years we’ve been in existence, we now have three programs in phase II clinical trials. We were able to move that quickly because of the opportunities that were waiting for us and the platform’s simplicity. These are not simple mono-therapeutics where you just deliver one antibody or one biologic against a particular therapeutic target. We’re mostly manufacturing cocktail therapeutics: multiple antibodies packaged together into a single therapeutic pill, which has been inaccessible to conventional biotech manufacturing with rare exceptions. But is very easy to do on our simple platform.
GEN Edge: Given the breadth of opportunity, will Lumen be licensing out the spirulina platform?
Finrow: Yes—we have signed three commercial collaborations to date (Novo Nordisk, Kyorin Pharma, and Elanco) and we want to do more. There’s way more opportunity here than any one company could go after. There are many applications of the technology where it’s implausible to assume that we’re always going to have all the expertise we need internally. In our industry, there’s a shortage of great new targets—things that nobody else is going after. If you have a great new target that everybody can go after, every company does go after it in a stampede. There are, for example, seven PD-1 axis antibody drugs on the market in the U.S. alone and in 2021 there were more than 5,000 clinical programs going on with these antibodies. The same thing happened with CD-19-mediated cell therapies, and more recently with antibody drugs for COVID-19.
But what the biopharma industry lacks, we’ve got in spades here at Lumen: all kinds of underexplored biology and druggable targets that haven’t been tried before. This is probably what it felt like during the exciting early days of Genentech and Amgen in the early 1980s when, all of the sudden, they could go after all of these exciting biologic targets that were impossible to go after with the then-dominant drug development technology (small-molecule drugs). That’s the extensive excitement you see around Lumen now.
GEN Edge: Why did you decide to name the company Lumen?
Finrow: Lumen sounds nice, the website domain name was available, and it’s a double entendre! A lumen is an old measure of light fluency or brightness [lightbulb brightness is rated in lumens in the U.S.], which is fitting since we have a photosynthetic biomanufacturing system. The lumen is also the word for the interior space of a biological structure like the GI tract, where our initial clinical programs are directed.
Interestingly, if you talk to experts in different fields and ask them, “What kind of organ is the GI tract?” you get different answers. If you talk to an immunologist, they’ll say that the GI tract is the largest immune organ in the body. If you talk to the endocrinologist, they’ll say it’s the largest endocrine organ. The neuroscientist will point out that it’s the most heavily innervated organ in the body. Not surprisingly, it’s at the center of a lot of what’s going on in evolutionary biology, getting nutrients is pretty foundational. So it makes sense that all this would be true. All of these different “personalities” of the GI tract make for a wealth of potential new drug targets now that we have a way to scalably make and deliver biologic drugs to that area of the body.
Roberts: Going after GI targets is not easy. The GI tract is not like the bloodstream where you put in a biologic, and it can circulate for up to a month or more and maintain therapeutic levels for an extended period. To keep a therapeutic level, you’re going to have to at least dose once a day, if not 2–3 times a day. It’s the job of the GI tract to digest things. So, if you put a biologic into the GI tract, not only is it going to move along with the flow, it’s also going to be subjected to proteases and that’s going to diminish your therapeutic levels. This is one reason it was long considered infeasible to go after GI targets with biologics.
It reminds me of the days when everyone said that you couldn’t develop kinase inhibitors. Then they figured out the technology needed to go after these supposedly undruggable targets. Now there’s this even bigger class of undruggable targets, the GI tract targets. It spans everything from infectious diseases to metabolism and diet control to auto-immune disease. These were all considered undruggable; now we’ve proven that they are.
The platform is a simple solution where we’re just going to overwhelm those factors. We came up with a cGMP manufacturing platform in which you can make a whole lot of a thing pretty cheaply, so you can give the drug over and over again, and you give it an amount that you need to overcome technical issues like proteolytic stability and practical issues like scalability and COGS [cost of goods sold]. It’s as simple as that and opens the door to doing this. You can’t do it with a biologic that you have to make with a sterile fermentation system that costs thousands of dollars per dose. You just can’t scale up those conventional systems to deliver doses multiple times per day, for long periods of time, for all the patients who need it. That’s why until now these targets were just considered undruggable. Today, when we share our clinical, regulatory, and cGMP manufacturing data, people’s eyes open wide when they grasp the profound opportunities for human health that this new technology opens up.