Blood transfusions have been on the medical radar since the 17th century, mainly used for various medical conditions to replace lost components of the blood. Today, blood transfusions remain one of the most commonly performed medical procedures, with approximately 85 million units of blood transfused worldwide each year.
Rubius Therapeutics, a clinical-stage biopharmaceutical company based in Boston, Massachusetts, is using this tried and true method to usher in a new era of cellular medicine with genetically engineered red blood cells aimed at treating a range of diseases.
Rubius Therapeutics is advancing its new class of cellular medicines called Red Cell Therapeutics (RCTs)—red blood cells engineered to express biotherapeutic proteins within or on their cell surface to create highly selective, potent, and allogeneic cellular therapies. They can potentially be used to kill tumors in cancer and regulate the immune system for the treatment of autoimmune diseases.
GEN Edge spoke to Pablo Cagnoni, MD, president and CEO of Rubius Therapeutics, to discuss a variety of topics, from how to nail down the problems therapeutic platforms aim to solve to the challenges companies face when dealing with cellular therapies and complex biologics.
GEN Edge: What was the company founded on?
Pablo Cagnoni: The company was founded by Harvey Lodish and Hidde Ploegh of the Whitehead Institute for Biomedical Research at MIT and the research and findings of Flagship Pioneering’s VentureLabs. They figured out how to make red cells at a small scale in dishes. We are the only company in the world that can engineer and manufacture red blood cells into medicines to treat cancer and autoimmune diseases. We create a completely novel and different class of allogeneic off-the-shelf cellular medicines to treat cancer and autoimmune diseases, at least those two for now.
GEN Edge: Why have you chosen to focus on cancer and autoimmune diseases?
Cagnoni: We looked at the platform, the properties of it, the problems out there, and then tried to figure out what problems can we solve with this platform.
When I joined in June 2018, we had a lot of preclinical data in oncology and auto-immunity. We thought there were a couple of problems in immuno-oncology that needed to be solved. When you think about immuno-oncology over the past ten years, checkpoint inhibitors, anti-PD-1 drugs, and CAR T-cell therapies have been the main stories. Checkpoint inhibitors remove the brakes for the immune system to attack the tumor. People have been trying to push the accelerator to come up with a good agonist for the past ten years. But those efforts have largely failed for several reasons. The main one is toxicity. When you give an antibody to try to stimulate the immune system that goes everywhere, you get a lot of normal tissue damage.
We thought that with the unique properties of engineered red blood cells expressing proteins on the surface that can activate the immune system and because of the limited distribution of red cells in the body, we would widen the therapeutic window of agonists. That’s our lead program. We then decided to build another platform within the platform. We asked if we could truly mimic what antigen presenting cells (APCs) do. When there’s a foreign target tumor cell, APCs process it, and then they show it to the T-cell to tell the T-cell what to kill. We have been able to build what we call artificial APCs.
In terms of tolerance induction, we destroy about 1% of our red cells every day, which happens in a tolerogenic way. We don’t have an immune reaction to that. The red cells are processed in a uniquely tolerogenic way. That’s an evolutionary concept. We believed— and we now have preclinical data to support it—that if we put certain antigens inside the red cell, the way the red cells are processed in a tolerogenic way could then trigger tolerance towards those antigens.
GEN Edge: Rubius Therapeutics works end-to-end, from R&D to manufacturing? Why have you taken that approach?
Cagnoni: For cellular therapy companies and companies that make complex biologics, it has become clear that controlling manufacturing is a critical part of the story. One of the reasons for going public in 2018 was because we wanted to build our own manufacturing facility. We used the proceeds of the IPO to purchase a manufacturing facility in Smithfield, Rhode Island, about 45–60 minutes from Boston. We gutted that facility and rebuilt it to manufacture red cell therapeutics.
That took us until about late 2019. At that time, we started doing engineering runs at that facility, then GMP runs, and then clinical runs. Every single patient that we’ve treated in our lead program—and every patient we’ll treat in the future—is treated with cells manufactured at the Rubius Therapeutics facility. From that perspective, we don’t have collaborators. We own and operate our manufacturing facility. A lot of reagents and parts of the process have required partnering with other people.
The real success for us at this point, which is not just making the cells and controlling that part of the process, is the ability to iterate. We have a team in Cambridge that is a process development team. We have a formulation development team as well. Those two teams iterate how to continue to optimize the process and improve productivity, yields, and formulations. They constantly interact with the manufacturing team in Rhode Island to work on things that can truly be translated to a better process on their manufacturing floor.
One of the things we’ve done recently is that we now have a new formulation. Our lead program is a liquid formulation, which is stable on the shelf for about 50 days — not ideal, but good enough to run a clinical trial. Our formulation development team started working a couple of years ago on a frozen drug substance formulation. We implemented that with our antigen-presenting cell, where we have a frozen drug substance that potentially has a shelf life of years. That greatly simplifies a supply chain. That’s the kind of thing you can do when you control every piece of the process.
GEN Edge: What kinds of challenges have you run into to reach your mission and vision goals?
Cagnoni: The hardest part of building a new company or a team inside a company is to find great people. The war for talent is super competitive! We’re also a capital-intensive company because we run our own manufacturing. I can’t pick up the phone and call someone to give me two metric tons of some molecule to run the next three trials.
We have a facility where the manufacturing floor alone is about 60 people. It’s a big team to make sure that we make these medicines and we make them right. We are a relatively more capital-intensive company at this stage than a small-molecule inhibitor company. Capital is always a challenge. We’ve recently had a big raise. It went very well. But we’re constantly thinking about when the next capital raise will be.
In addition to the normal challenges of a drug development company in oncology and auto-immunity, such as the execution of the clinical trials, the additional part of the story for us is to continue to improve manufacturing and to get it right. We need to continue to improve production yields, reduce the cost of manufacturing, or make something that nobody has ever made before. Nobody’s going to help us reduce the cost and improve the yields. It’s a great place to be when you think about the competitive landscape, but it’s hard. This is a company that welcomes people that are up to the challenge.
GEN Edge: How does being a publicly traded company affected the company, the culture, and the way things run?
Cagnoni: The level of scrutiny for a public company is completely different. A positive about being a private company is the fact that you can do a certain number of things, get to a certain point in your drug discovery and development process, without having to constantly face this extreme scrutiny of external investors. If you’re doing things right, the culture shouldn’t change.
I practiced medicine for seven years on bone marrow transplants before entering industry. I spent a lot of time with patients. I’ve always tried to emphasize in teams or companies that I run the importance of keeping patients front and center of everything we do. If we do that and embody that day in day out, the organization runs in a certain way that pushes market pressures aside. You continue to remember what your true mission is.
Of course, shareholders matter to me. I take very seriously the fact that people trust me with their money basically to spend it well and to generate returns over time for them. But for me, the critical piece of the story here is that we’re here to deliver new and better medicines for patients. If you keep that front and center in your culture, you should be fine, whether you’re private or public.
GEN Edge: Has there been any pushback to using genetically engineered cell therapies?
Cagnoni: No, we haven’t. We executed very well last year in the middle of COVID. We entered the clinic in May 2020, when COVID was at the worst time. We went through several doses and escalation cohorts for the lead program. We opened a second phase I study. The execution last year went very well in a very challenging environment. As you start generating good data and you get a lot of buzz, which is what’s happening now for us, you have no trouble enrolling participants for these studies. We entered the clinic relatively quickly after clearing the INDs.
You have to remember, we’ve been giving blood transfusions to patients for a hundred years. These are red cells. We engineer them, and we decorate them with proteins on the surface. But they’re red blood cells, at the end of the day. And it’s a very small volume. There’s not a big blood transfusion. The volume of cells we give is very, very small. I think the combination of the positive efficacy data we’ve seen with the very good safety that we’ve seen is making execution relatively easy.
The reason why I took this job, and many others have decided to join the company over the past couple of years, is because we truly try to do something that has never been done. Trying to create an entirely new therapeutic modality and a new way to treat patients with cancer and autoimmune diseases, that’s the mission we’re trying to build. We’re trying to build a company based on an entirely new way to treat patients. That’s an exciting part of the journey. We took an enormous first step early this year with the data we reported that proves that the platform can indeed modulate the immune system in cancer patients in a meaningful way. We think we’re going to have another very exciting year in 2021.