Teaching the Immune System to Let Medicines Do Their Job
August 5, 2022
While biologics and gene therapies have altered what it means to have a rare disease for many people, one problem with these treatments is that they can trigger an immune response that can make a patient ineligible for gene therapies or render a medicine ineffective. Selecta Biosciences is developing a platform technology called ImmTOR that trains the immune system with precision not to react to specific antigens and can restore balance to the immune system. We spoke to Carsten Brunn, president and CEO of Selecta Biosciences, about the problem of immunogenicity to biologics, the company’s ImmTOR platform, and how its leveraging that platform with a growing pipeline of biologics and gene therapies.
Daniel Levine: Carson. Thanks for joining us.
Carsten Brunn: Thanks for having me.
Daniel Levine: We’re going to talk about Selecta, its ImmTOR platform technology, and its strategy for building a pipeline across various therapeutic modalities. Biologics ranging from enzyme replacement therapies to gene therapies hold great promise for treating rare diseases. One of the challenges though, is that these therapies can trigger unwanted immune responses. How big a problem does this represent and does it ever prevent a promising therapy from reaching the market?
Carsten Brunn: Great question and the answer is yes it is a big problem. Everything you give as a drug, as a biologic, usually elicits an immune response and which oftentimes renders the biologic ineffective or less effective. So, it does have an impact [that] obviously depends on how immunogenic the biologic is. Some are humanized, there’s less of an issue, but in general, it’s a large issue that also the FDA is always looking at immunogenicity. It is a big challenge. And specifically, if you look at some of the modalities that we are pursuing, one obviously is enzymes that are immunogenic. They are of either bacterial or fungal origin so they’re foreign to the body and you can only give them one time because the body has a strong immune response and that’s where our technology comes in. It enables the re-dosing. So, it makes it tolerable for the body. Another good example is gene therapy. Obviously these are viral vectors that are immunogenic [and] only given as one dose, which is challenging because it’s not as durable as we initially thought. So, the answer is yes, it’s a big problem for all those modalities. Then of course there’s the ultimate modality, which is autoimmune disease, which is a growing problem in the United States where the antigen actually is an auto antigen. That’s a big problem that we are focusing on more and more as a company, I’m sure we’ll have a chance to talk about this.
Daniel Levine: What happens within the immune system to cause this type of response to a biologic therapy?
Carsten Brunn: It’s a natural response that’s actually good and keeps us alive. That means if you have a pathogen entering your bloodstream, the immune system is responding, producing antibodies so the next time you’re exposed to it, it doesn’t affect you as much. So, it’s a natural defense mechanism, but obviously in the case of drugs or biologics, it renders them ineffective. That’s really the challenge and that’s what we’re trying to prevent with our technology.
Daniel Levine: It’s not unusual for a patient being infused with a biologic to be pretreated with something like Benadryl. You mentioned the immune response renders the therapies ineffective, how much of a concern is that? Do they completely render them ineffective? And is there a risk to the long term health of the patient? Can they get a severe enough response that it becomes life threatening?
Carsten Brunn: Yeah, you’re right, they’re numerous. And there are numerous antihistamines like Benadryl and antihistamine or steroids being used and they’re usually being used to prevent or reduce infusion related reactions—initial allergic reaction to the product. Of course, you don’t want to give steroids long term. They do have a negative impact on your body. You don’t want to immune suppress patients long-term, which is really the challenge. The current modalities are immune suppression, which means you’re prone to infections, prone to certain cancers now, especially with COVID, even more relevant on an artificially suppressed the immune system. So, there’s a lot of limitations around that. And I think where we come in is that we’re trying to address specifically the antigen, to really have antigen specific immune tolerance that gets around the issues associated with broad immune suppression.
Daniel Levine: Rapamycin is a drug that seems to generate excitement at doing everything from treating cancer to preventing aging. It’s history though, is as an immune suppressant used to prevent organ rejection in transplantation. What does rapamycin do at a biologic level?
Carsten Brunn: Yeah, rapamycin is a super interesting compound and has an interesting history. It was discovered about 50 years ago on the Easter Islands, which are called Rapanui. There were initially [used] as an antimicrobial and as an immune suppressant. What it does, it plays a central role in regulation of cell growth and that’s why the various applications, as an immune suppressant, but also used in certain cancers. It’s been used in anti-aging research. It extends life in various organisms. So, it’s definitely a very colorful compound with a long history. And we’re trying to harness that with our technology, and the exciting findings that came out of Harvard Medical School Ulrich von Andrian’s lab that basically showed that rapamycin in high doses in certain cells actually induces immune tolerance.
Daniel Levine: Well, how does rapamycin figure into your mTOR technology?
Carsten Brunn: Yeah, it’s a great question. So, ImmTOR is a biodegradable nanoparticle that encapsulates rapamycin. If you give rapamycin orally, it’s an immune suppressant. What von Andrian found, who’s an immunologist at Harvard, is if you target specific cells, antigen presenting cells called dendritic cells, you actually get a tolerogenic response instead of an immune suppressive. The challenge is how do you get this now into the body without triggering immune suppression and really the trickier [thing] was to encapsulate nanoparticle. The nanoparticle is the size of a viral particle basically, and the body thinks, okay, this is a foreign object, and we’re going to excrete this, and in the liver and the spleen it’s taken up by those potent management cells. And then in those cells, rapamycin is released and induces a tolerogenic message. So, it’s kind of cloaked if you like, until you get to the site of action and then it’s released there in high concentration. So, in a sense, rapamycin is the active ingredient in mTOR, but has a very different pharmacology than if you give it orally, chronically daily.
Daniel Levine: And it’s telling the immune system to be tolerant, but how does it have to be associated with the particular biologic agent you’re delivering?
Carsten Brunn: Yeah, the way we do this is there is a therapeutic window, a time window where we give we give mTOR first and then immediately after we give the antigen as an infusion. This can be an enzyme, it can be gene therapy, and they basically kind of co-localize. There’s a window of about 24 hours where you have this tolerogenic window where they both have to be present. That’s also the reason why we have never seen really any increase in infection rates because it’s a time limited window where you have that tolerogenic window where you produce so-called T-regulatory cells, which tell the body that the antigen actually is not foreign and induce tolerance. It’s a very elegant way of harnessing the immune system.
Daniel Levine: In delivering therapies with this technology though, are they conjugated or combined in any way, or is it just both delivered individually?
Carsten Brunn: Yeah, that makes it elegant as well. It doesn’t require any reformulation. We have now human data in combining mTOR with an enzyme, a highly energetic enzyme for the treatment of chronic refractory gout. You basically give an infusion of mTOR followed immediately by the actual enzyme, but it’s not reformulated in any way. Then the same for gene therapy, you infuse into first and then it’s followed by the actual AAV gene therapy. So, there’s no reformulation needed.
Daniel Levine: At the same time though. You have to test it with each individual therapy as opposed to seeking an approval for a universal pre-treatment.
Carsten Brunn: Yeah, that’s a good question. For now, we see it on an indication by indication basis because you always have to run toxicology studies as well in each disease model. Down the line, we might be able to get more of a blanket approval for gene therapy if we have a couple approved, but for now, we run basically studies from scratch, where we’re testing the toxicology first in various disease models. At this point, we don’t see it as a blanket approval. It has very broad applicability, but from a regulatory path perspective and a patient safety perspective, we want to make sure that we do this on a case by case basis.
Daniel Levine: One of the concerns about the use of viral vectors you mentioned with regard to gene therapies, is that it prevents them from being reusable. That’s raised a lot of concern about the durability of these therapies. How does mTOR potentially change that?
Carsten Brunn: Yeah, I think that’s a very exciting application of ImmTOR and really has the potential to unlock the potential of gene therapy. And there was initially a lot of excitement around gene therapy is once and done, but it looks like that’s not the case. AAV viral vectors, don’t self-replicate. That means over time, the cells get diluted down and you see a loss of expression, and there’s plenty of examples now out there where we clearly see that over time expression goes down, efficacy goes down and because it’s a viral vector, it’s highly immunogenic, the body develops neutralizing antibodies and you can’t give a second dose. What we’re trying to do with ImmTOR is we give ImmTOR with the first dose of AAV gene therapy to prevent the formation of neutralizing antibodies. And we’re actually able to demonstrate this in a healthy volunteer study with an, with an MTA AAV capsid, so no transgene. We’re able to prevent the formation of neutralizing antibodies in a certain timeframe, which is very exciting and really opens up pretty broad applicability across at least liver-directed AAV gene therapy.
Daniel Levine: Selecta is pursuing its own therapeutic pipeline, but it’s also engaged with a growing list of collaborations to leverage the platform around enzyme replacement therapies, gene therapies, and therapies for autoimmune diseases. What role does partnering play in your business model?
Carsten Brunn: Yeah, as a platform company, partnering is critically important. As a small company, there’s only so many indications you can pursue, only so many capabilities you can build in certain therapeutic areas. So, we obviously identified areas that we are focused on ourselves with our own proprietary pipeline, but partnerships are a very important way for us to get the technology into as many patients as possible, help as many patients as possible. It’s a way for us to finance the company as well. I’ll give you a couple of examples. We’ve done a large partnership with Sobi for our lead asset, which is currently in phase 3, which gave us a significant upfront of a $100 million and really allowed us to invest in the company. And we’re also to receive milestones and royalties down the line. It was an important validation for us. We have partnerships in the gene therapy space most notably with Takeda, for example, where we licensed mTOR for two of their lysosomal storage disorders, AAV gene therapy programs. That’s an important way where we can finance the company with, but we also have partnerships where we are leveraging other companies to develop our own products. For example, we’re working with Ginkgo Bioworks, a synthetic biology player, to develop a novel IGA pro, so where they’re developing something for us, which we then take into the clinic. But in general partnerships are quite important for our business model.
Daniel Levine: How do these partnerships generally work and ultimately, would your partner be selling mTOR as part of their product, or would you just both be selling your own product simultaneously?
Carsten Brunn: Yeah, so in the case of Sobi, for example, we basically licensed them both ImmTOR and the enzyme for a specific use in chronic refractory gout. So, they would be selling both. We would be manufacturing it for them, but they would be selling both products. In the case of Takeda where they’re planning to combine ImmTOR with a gene therapy product, we would provide ImmTOR to them. And then they would sell both as a combination product. We also have a partnership with Sarepta very similar for two of their lead indications where we provide ImmTOR and they would sell this in combination with their gene therapy product.
Daniel Levine: Given the broad applications of the technology in building your own pipeline, how are you prioritizing your indications?
Carsten Brunn: Yeah, it’s a real challenge and it’s a real strategic objective for us to figure out where is it that we spend our dollars. We’ve gone through a couple of iterations of the company and where we are right now is to focus on the use of ImmTOR and an iteration of ImmTOR, which is ImmTOR-IL. It’s a combination with an engineered IL-2 molecule for use in autoimmune disorders. So if you look at our pipeline right now, we’re really focusing mainly on auto autoimmune disorders. We have a program in gene therapy as well. But we really see this rather as a strategic regulatory blueprint for our partners. So, we kind of have a clear path into the clinic from a regulatory perspective in gene therapy. But our wholly owned programs are really focused on autoimmune disorders in the liver and kidney. And we think that’s the sweet spot for us. ImmTOR naturally accumulates in the liver. Our CMO is a well-known hepatologist. So, I think it’s a natural fit for us where we want to focus our own efforts.
Daniel Levine: I understand how ImmTOR works with regards to a biologic you’re infusing or a gene therapy. In the case of an autoimmune disease though, how does the body know what antigen you’re presenting?
Carsten Brunn: That’s a great question. The concept here in autoimmune diseases is slightly different than what I described earlier. In autoimmune disorders, you would also administer an auto antigen and you would encapsulate this in a nanoparticle as well, because you don’t make the disease worse, but you would, co-administer the auto antigen nanoparticle with ImmTOR. So, it gets delivered to those antigen presenting cells together with ImmTOR. So that would be the therapy, the auto antigen plus the tolergenic agent, which would be ImmTOR.
Daniel Levine: Is there a potential for this approach in something like a peanut allergy?
Carsten Brunn: Theoretically, yes, but there’s other approaches that are being tested already. And usually, those patients are fairly healthy otherwise, until they meet a peanut, but obviously rapamycin is not benign. And so, we haven’t focused on allergies per se. Another one is celiac disease, for example. We have identified as a lead indication now primary biliary cholangitis, which is liver-directed disease. Theoretically it would also likely work in peanut allergy and others, but in terms of mechanism of action, we believe liver and kidney based diseases are a better strategic fit and higher likelihood of technical success
Daniel Levine: Selected raised $38.7 million in April. How far will existing funding take you?
Carsten Brunn: Yeah, great question. We currently have cash into mid-2024, which in the current market environment, is a good cushion to have. We have an important readout of our lead asset in partnership with Sobi in chronic refractory gout in Q1 next year. That’s obviously an important milestone for us. We’re about to enter the clinic in gene therapy in Q4 this year. So we have some important catalysts, but we do have the cash to see all those through. And then, we are developing our PBC program. We have a program in IgA nephropathy. So, for now we’re well financed and we have important milestones that are additional potential value drivers for the company.
Daniel Levine: It’s a difficult time to be a public biotech today. How does being a public biotech complicate your job? And, and what’s the conversation like with investors?
Carsten Brunn: I think it’s a difficult time for biotech period. I think for both private companies and public companies it’s difficult to get time with investors. Many of them are licking their wounds from last year. At the same time there is capital to deploy. So we’re still very active in investor outreach. It’s just very targeted. I think what, what helps us, we actually have pretty good traction at the moment, is that we have a late stage asset with you know, an important readout in Q1 next year. So, it’s kind of a short term milestone, which is important at the same time, a pretty broad applicability with the pipeline as well, which many investors do like but it’s definitely a challenging time, but it’s also, a much needed correction as well. I think that the biotech market was overheated. I think too many companies went public too early, you know, preclinical. So, I think there’s also a bit of a mock correction happening as well at the moment.
Daniel Levine: Carsten Brun, president and CEO of Selecta Biosciences. Carsten, thanks so much for your time today.
Carsten Brunn: Thanks for having me, pleasure.
This transcript has been edited for clarity and readability.
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