Dario Gutierrez, PhD, was shocked by the lack of medical treatment for a family member suffering from immune thrombocytopenic purpura (ITP), an autoimmune disease in which T cells identify a receptor on platelets and target them for destruction.
“I saw how she went to treatment, and it was high-dose steroids for a while—pretty much, many people don’t respond to it, and then they remove the spleen, which is where they think a lot of the degradation of the platelets is happening,” Gutierrez told Inside Precision Medicine. “As I saw the treatment, I thought that this has got to be a joke—is this really the standard care?”
Building off the atomic-level understanding of how autoantibodies bind to target receptors (revealed by cryoEM and other structural tools) to drive the pathogenesis of autoimmune diseases, Gutierrez began to explore the idea of a precision immunology company to develop a new generation of immunotherapies as an Entrepreneur-in-Residence at Third Rock Ventures. The result was Merida Biosciences, where Gutierrez and a team had been working in stealth since 2022 on biotherapeutics using the fragment crystallizable (Fc) region of antibodies located at the base of the Y-shaped structure to neutralize pathogenic autoantibodies.
Merida Biosciences has now decloaked and has revealed a lead program based on pioneering a novel approach to treating Graves’ disease, a rare disease that affects about 3% of women and 0.5% of men. Their approach began with an in-depth exploration of how diverse autoantibodies interact with the thyroid-stimulating hormone receptor (TSHR) at the atomic level. Leveraging advanced techniques like structural characterization, polyclonal mapping, and computational protein design, the team is developing a biotherapeutic capable of selectively neutralizing these harmful autoantibodies. Crucially, their approach seeks to leave normal thyroid hormone signaling and protective immunoglobulin levels untouched, offering a highly targeted solution to this autoimmune disorder.
In preparation for the launch, the company recently brought on CEO Adam Townsend, COO Dodzie Sogah, PhD, and chief medical officer Matthew Leoni, MD. “This is week six for me, and we became a public company a couple of days ago,” Townsaid told Inside Precision Medicine. “Chasing after the root cause of some of these debilitating autoimmune disorders is precisely the type of thing I think we all want to do. We’re going to go and chase big diseases with a small, lean team, and the word that seems to resonate now is a scrappy team. It’s Dario’s brainchild that we are all responsible for driving forward.”
What about all the CAR-T hype?
In 2020, Georg Schett, MD, treated a patient with severe lupus with CAR-T cells, which sent shockwaves through the autoimmune disease community as a bedridden, treatment-resistant patient made a hasty full recovery in a matter of weeks. Since then, pharma giants and startups have been racing to be the first to get FDA approvals for CAR-T cell therapies in several major autoimmune diseases.
While CAR-T cell therapy results in autoimmune diseases (and oncology) have been remarkable—indeed, I remember being shocked a year and a half ago seeing a presentation from Kyverna Therapeutics with a video of a myasthenia gravis patient going from incapacitated in a hospital bed to riding a bicycle in a few months—there are some significant drawbacks. The complicated manufacturing logistics, slow turnaround time, and high costs are substantial concerns. As Gutierrez put it, “You always want to find the simplest solution to any problem—you don’t need to build a rocket ship to go from Boston to New York.” Sogah added, “It’s hard for me to see how CAR-T cell therapy would have a path toward having a reasonable product profile indication like Graves’ disease versus a subcutaneous therapeutic that could be used once every couple of years.”
While manufacturing, logistics, and costs can be cut with time, the significant risk imbued by using CAR-T therapy that targets B cells remains: taking down the entire B-cell population and not just a specific subset. “With CAR-T cell therapy for autoimmune diseases, you’re basically burning an entire field just to kill a couple of weeds,” Leoni told Inside Precision Medicine. “You’re wiping out the entire B cell population when all you want to get at is the autoantibodies that are there and the cells producing them.”
Wiping out B-cell populations leaves a patient utterly vulnerable to infection. To this end, the first adult patient treated with CAR-T cell therapy was William Ludwig. He was treated at the University of Pennsylvania’s Abramson Cancer Center and remained cancer-free for 11 years before dying from COVID-19 complications in early 2021. “If you get infected with COVID-19 tomorrow or if you’re going to get vaccinated for tetanus again, you’d wish you had those cells because they are protective,” said Gutierrez. “Most of your B cells are there for a reason—they’re very protective.”
In this regard, CAR-T cell therapy is in some ways not very different mechanistically from the preceding generation of treatments like rituximab or another anti-CD20. “You’re still wiping stuff out,” said Leoni. “For autoimmune diseases, such as ITP, broad-spectrum steroids are used to wipe out all the B cell components, and steroids can have an effect on every cell in your body, which is why they can cause so much damage.”
A clever protein engineering design
Merida’s Fc biotherapeutics were designed (with the help of AI) to enable two key mechanisms of action. First, the engineered proteins completely remove the autoantibodies that cause symptomatic clinical outcomes, reducing their levels to zero. Second, the Fc biotherapeutics also target a specific B-cell population, which is the bad actor.
The dual action of Merida’s biotherapeutic lies in targeting an Fc receptor subtype, FcγRIIB. Upon capturing the autoantibody, the biotherapeutic is soaked by liver sinusoidal endothelial cells (LSECs), which express FcγRIIB and degrade the complex. FcγRIIB is also found on memory B cells that produce the autoantibody, and when agonized, it shuts this subset of B cells down and, ultimately, the production of the pathogenic antibody.
“You’re pulling the weeds out and not actually burning the field,” said Leoni. “The elegance is not only the specificity in targeting but also being able to remove it silently without lighting up any other parts of the immune system or causing any effect—cell activity or formation of immune complexes—that your body would recognize. It’s basically only being recognized by the exact cells we want to recognize; it is the LSECs that are going to suck it up, destroy it, and remove it. We also target the bad B cell that identifies and shuts down the target. You can’t get a level of precision beyond that.”
Finally, Merida’s Fc fusions are also being designed with specific pharmacokinetic properties in mind. Specifically, the biotherapeutics have a half-life typical of IgG1, so patients can easily follow a therapeutic dosing regimen for a lifelong illness.
While there isn’t much safety data on Fc biotherapeutics, they should be safe given their mechanism of action and design. “If it’s not binding to the autoantibody, it’s not really doing anything else, so we’re not expecting off-target toxic effects because it’s not targeting broad-spectrum B cells or other parts of the immune system,” said Leoni. “That’s the beauty of these things—it’s very hard to get off-target toxicity and that’s why it has a unique safety profile.”
Beyond autoimmune disease
In addition to having specificity and safety advantages, the Fc biotherapeutics approach is a pretty straightforward strategy that can be adapted to other autoantibodies and autoimmune indications.
“You can essentially switch the Fc to a new binding domain and capture a different set of pathogenic antibodies,” said Gutierrez. “As long as you’re very good at doing that first thing, it’s a modular platform, and we’re very excited about that. We thought about that promise when we started working on it over three years ago and what it could do, such as eliminating the eye disease associated with Graves’ disease, which can be addressed using our first molecule. We have to prove this in the clinic, and then we will have programs like really close behind to go and do it again.”
Townsend added, “We have this optionality for us as we grow, where we can look at new molecules in new indications—there are over two dozen autoimmune disorders that we can target, if not more, and we want to make sure that we’re having a really good shot on goal with all of them. Graves’ disease is our first lead indication. The plan is to open the IND and get into the big clinic as quickly as we can. We’ll definitely open the IND this year.”
Beyond autoimmune diseases, the company is also working on an IgE platform for allergies, starting with food allergies. “As long as it works in food allergy and all of the sites are pointing in the right direction, we can move into a broader allergic disorders space,” said Townsend. “That’s a pure platform opportunity, whereas our lead asset in Graves’ disease is a one-drug opportunity that can shut down Graves at the root of the disease. Then we have another drug for primary membranous nephropathy, a rare kidney indication, which is also really exciting, not only internally but also for many external strategic partners that like our programs.”
Merida’s aspirations are mirrored by a Board of Directors comprised of industry leaders with extensive expertise in drug discovery and development, including Reid Huber, PhD, partner, Third Rock Ventures and Board Chair; Abbie Celniker, PhD, partner, Third Rock Ventures; Andrew Hack, MD, PhD, partner, Bain Capital Life Sciences; Rich Levy, MD, former chief drug development and medical officer at Incyte; John Maraganore, PhD, former founding CEO of Alnylam Pharmaceuticals; Amol Punjabi, director, BVF Partners; and Adam Townsend, president and CEO of Merida.
