Jun 24, 2019
By Po Bronson
Beeline Therapeutics: Supercharging T-regs
Dimitre Simeonov, Michael Wyman, and Chris Chavez of Beeline Therapeutics

Beeline takes engineered immune cell therapy in a new direction. They are unique in how they have engineered regulatory T cells (Tregs), which play a natural role in ramping down the immune system. This has wide applications for autoimmune diseases and organ transplantation.

We talked with company founders Dimitre Simeonov and Michael Wyman.

Since you’ve announced that you’ve successfully engineered Tregs, you’ve had a good number of pharma companies wanting to partner with you. How did you accomplish something they couldn’t do on their own?

A number of companies have learned how to edit the genome of effector T cells, such as killer T cells. The idea of doing similar genetic engineering of Tregs was beginning to be considered. But actually doing it was another story.

To start with, Tregs are just hard to cultivate and proliferate. Then, there were a lot of hurdles to overcome in terms of the genetic engineering. We weren’t just engineering a receptor into the Tregs to localize them to the spot of inflammation. We wanted to go beyond that — to enhance the natural immunosuppressive power of Tregs. This meant delivering a very large genetic payload to a precise spot, without interrupting the normal function of the gene we were targeting. We found unique ways to pull this off.

How do they work, and what’s the benefit of a “living drug”?

Tregs naturally quiet the immune system. They do this through a unique cellular programming that relies on transcription factors, cell surface receptors, and cytokines that help a Treg shutdown other immune cells. Sometimes this process fails as Tregs can be overwhelmed by the immune response. So we supercharge them and put them back into a patient’s bloodstream, so they can migrate to inflammation hotspots, where they can secrete therapeutic proteins to calm an immune response.

As a “living drug”, Tregs have unique advantages over standard molecular therapies. First, we can harness the cell’s ability to produce protein to continuously manufacture therapeutic proteins in the body. And not just anywhere — but precisely at the site that needs the therapy. No more biweekly injections — just a single shot of your own cells. Second, cells can “sense” their environment and respond accordingly by changing gene expression. By engineering our therapies into the “responder genes” our cells will make therapeutic proteins in response to the environment that those cells are in. For example, say we are trying to quell inflammation as in the case of Crohn’s disease — we might engineer our therapeutic so that its expression is increased in an inflammatory environment thereby allowing us to precisely control dose and ensure we are delivering the highest doses to the areas of the body that need them. Finally, cells are complex machines armed with a number of “tools” that allow them to accomplish their functions. This is fundamentally different from the medicines that have so far dominated the clinic — generally drugging a single target or pathway.

Our technique solves a problem that every drug company is challenged with. How to get the drug exactly where you need it, and maintain a dose potency that is appropriate to the severity of the disease.

It’s like having a drug factory in your body.

Yes, though we’re technically not secreting synthetic drugs. We can do that (as long as they are protein-based), but at this point, our cells secrete the natural signalling compounds the body already makes and uses on its own. We’re the first therapeutics company to publicly announce that we’ve made the proteins we’re making from Tregs; it’s very exciting.

Why did you use DNA-cutting enzymes instead of the more conventional viral vectors?

We actually are doing both approaches. With the viral approach, we do get a high expression rate, but it comes at a tradeoff. The virus lands randomly on a cell’s DNA. You can’t control where the virus integrates the payload. And when it integrates, it can disrupt gene function, which might be a pretty important gene. Also, every gene has a different expression level. So in one cell, you might randomly hit an area of the DNA that is highly acvtive, and in another cell, you could hit an inactive area. You end up with different levels of the therapeutic in each cell — or worse some of the cells may not express the therapeutic because the surrounding inactive DNA could spread to your therapeutic.

To get a much more controlled result, we are also using non-viral engineering approaches. This overcomes many of challenges we mentioned earlier and allows us to think about how to use a cell’s natural gene regulation to regulate our therapy.

In what critical indications is your cell therapy most needed?

Helping the transplantation of organs is where physicians are the most excited by what we’ve done. Today, to prevent rejection of a donated kidney, physicians have to give patients a lot of broad systemic immunosuppressants. These patients are already in a weakened state, and having no immune activity is dangerous. Also the drugs make the patient very vulnerable to cancer; one of the most common drugs is classified as a Group 1 carcinogen. There are a lot of patients who don’t even get put on the waiting list for a kidney, because they are too high risk.

By localizing the immune suppression, and helping patients’ immune system not reject a donor organ, we can open the door to new types of transplants that aren’t very feasible yet. One of those is pancreatic islet cells; they produce hormones. People with Type I diabetes could be alleviated with islet transplantation.

One of the exciting potentials of this therapy is long term tolerance — meaning patients could potentially come off of immunosuppressants all together. This is something we are actively working towards.

What’s the next year look like for Beeline Therapeutics?

We have the ability to engineer receptors to help the Tregs home to the right places in the body — over the next year we’re going to expand that platform with more receptors. A kidney donor has to match the patient’s HLA markers. We’ll use the patient’s HLA markers to design receptors to recruit Tregs into the donor tissue.

Also, proving our method works in mice presents an interesting challenge, because we engineer human T-regs, but a mouse’s immune system would attack human cells. The elegant way to solve this is to use a mouse model without any immune system, repopulate it with a human immune system, and then transplant the mouse with human tissue, to see if we can prevent rejection.

Watch CASPR Biotech pitch on IndieBio Demo Day, Tuesday June 25th in San Francisco or via LiveStream. Register here!