Plasmacytoid dendritic cells or pDCs are immune cells that help the body fight infections but in certain chronic autoimmune condition these cells can become continuously activated and cause the body to attack itself. Horizon Therapeutics is developing an experimental monoclonal antibody known as daxdilimab that can get certain immune cells to deplete the pDC and shut down chronic inflammation in these conditions. We spoke to Jodi Karnell, senior director of Research at Horizon Therapeutics, about the role of pDCs in certain autoimmune conditions, how daxdilimab works, and why it may offer a way to address a range of rare autoimmune condition for which there are no approved therapies or that are poorly addressed by existing treatment options.
Daniel Levine: Jodi, thanks for joining us.
Jodi Karnell: Thanks for having me. It’s a pleasure to be here.
Daniel Levine: We’re going to talk about rare autoimmune conditions, Horizon Therapeutics, and it’s experimental therapy daxdilimab, which takes a novel approach to addressing these conditions. There is endless complexity to the immune system, and it seems like we continually learn about new targets to modulate it. I thought we could begin with plasmacytoid dendritic cells or PDCs. What are these and what role do they play in an immune response?
Jodi Karnell: I think of PDCs as a rare and mighty cell of the immune system. PDCs make up less than 1 percent of circulating white blood cells, so they’re pretty rare. But they’re specialized to sense and respond to nucleic acids—DNA and RNA. So, in the context, let’s say, of a viral infection, PDCs sense viral DNA, and then they can orchestrate the immune response in a number of different ways. First they’re good at producing a bunch of different pro-inflammatory mediators, but what they’re well known for is their ability to produce robust quantities of a family of proteins called type 1 interferon. Type 1 interferons are important for viral defense, but we also know that they’re dysregulated in a number of different autoimmune settings. So, PDCs produce a lot of type 1 interferon. They also produce proteins that recruit other immune cells to sites of inflammation so they can call in and activate other immune cells, such as B cells and T cells. So, we really think of PDCs as playing a role both through the production of type 1 interferons, but also by unleashing additional arms of the immune response.
Daniel Levine: These cells are typically activated by pathogens, such as a virus. In the case of certain immune conditions though, what activates these cells and what role do they play in those conditions?
Jodi Karnell: Yeah. I mentioned in the case of viruses, it’s viral DNA that can activate PDCs. It’s also nucleic acids that we think are activating PDCs in settings of autoimmunity, but in this case, it’s self- derived DNA or RNA. For example, in the case of systemic lupus, a common feature of the disease is the presence of these anti-DNA autoantibodies. So, patients have floating around in their blood these anti-DNA antibodies, they’re bound to their own DNA, and we know PDCs can take up these complexes and it’s your own self-DNA that can trigger activation of the PDC. As I described before, when it sees self- DNA these PDCs start producing type 1 interferons and can directly promote inflammation, and also call in other immune cells to the inflamed tissue to really perpetuate the inflammatory response.
Daniel Levine: You seem to be targeting diseases that involve either the skin or kidney. Are these cells unique to particular tissue?
Jodi Karnell: That’s a great question. If we take a step back and we think a little bit about what we know about tissue, which is an important question, because we think the PDCs are really acting locally. We think it’s really in the tissue that the important action of the PDC is happening. And if we look in healthy tissue, let’s take skin for example. As you mentioned, you don’t see any PDCs in healthy skin, but when you look in some settings of skin inflammation, if you think about something like a cutaneous lupus, you start to see that the PDCs start leaving the blood and migrating into the tissue. And we don’t just see this in the skin. We see these in a number of different autoimmune conditions in a number of different tissue settings. So, you highlighted the kidney where we see PDCs accumulate in diseases like lupus nephritis, but we also see PDCs in muscle tissue in myositis patients and in salivary glands in patients with Sjogren’s syndrome. So, it’s not a tissue-specific cell type.
Daniel Levine: How did Horizon come to look at these cells as potential targets to treat certain autoimmune conditions?
Jodi Karnell: We’ve known for a long time that there are a number of autoimmune diseases that are characterized by very high levels of these type 1 interferons. We call these diseases interferonopathies and while virtually all cell types in the body have the capacity to produce type 1 interferons, PDCs are generally considered to be really the professional type 1 interferon producers. They are just exquisitely designed to rapidly produce high quantities of type 1 interferon. So, the hypothesis behind targeting PDCs is that you can really specifically remove a key cellular source of type 1 interferon in autoimmunity without globally impairing all type 1 interferon responses. We’re just taking out the population we think is responsible for driving a lot of the interferon production in autoimmunity.
Daniel Levine: Well, walk me through how you move from looking at this as a potential target to validating it and finding a means of exploiting it.
Jodi Karnell: There was really a lot of preclinical evidence that supported or validated targeting PDCs. First we have some mouse studies, some animal models that showed that when you target and deplete PDCs, you can improve disease manifestations in, let’s say, a mouse model of lupus. So, there’s animal data that supports removing PDCs in settings of inflammation can be beneficial. And then there’s a whole wealth of well-validated literature that really demonstrates that PDCs are really enriched in target tissues in a number of different autoimmune diseases that are associated with this dysregulated type 1 interferon. So, we really have evidence in human disease that PDCs are migrating into damaged tissues; that there’s a really robust type 1 interferon response in these tissues; and then animal models that show us that removing those PDCs can be beneficial. So, it was really the basis of these observations that we generated an antibody that could specifically target and deplete human PDCs. And that’s the molecule we call daxdilimab.
Daniel Levine: Well, daxdilimab is your experimental clinical candidate in development for a number of rare autoimmune conditions. What conditions are you targeting and why?
Jodi Karnell: We’re targeting a number, as you’ve said. Daxdilimab is currently in a phase 2 clinical trial for systemic lupus erythematous, so SLE, and that trial is underway, but we’re also exploring daxdilimab in four other disease areas. We’re looking at it in alapecia areata, which is an autoimmune disorder that’s characterized by non-scarring hair loss, and we just announced that the first patient was dosed with daxdilimab in our phase 2 alopecia study. So, that’s an exciting milestone for the program. We’re also looking at daxdilimab in dermatomyositis, which is a rare autoimmune disorder characterized by rashes, debilitating muscle weakness, and interstitial lung disease. And then in other forms of lupus as well. So, we’re looking at daxdilimab in discoid lupus, which is a rare chronic inflammatory skin condition characterized by lesions that result in scarring, and lupus nephritis as well, which we’ve touched on a bit earlier, which is a rare autoimmune and inflammatory condition of the kidney.
Daniel Levine: How does lupus manifest itself and progress?
Jodi Karnell: Again, there’s different forms of lupus and systemic lupus can manifest in different ways in different individuals. It’s systemic, it can impact joints, it can impact skin, it can impact kidney. So it really is a systemic disease that impacts different people in different ways. Then there’s really these subsets of lupus that we’re also exploring where we’re looking specifically at patients who just have skin manifestations or predominantly have kidney disease. So, lupus can present in a very different way in different patients. So, it makes it a very challenging disease to study. But we’re excited to see how daxdilimab can benefit these patients.
Daniel Levine: There’s a fairly large arsenal today to modulate immune activity, certainly within autoimmune disease. How well addressed are these conditions by existing therapies?
Jodi Karnell: For most of the indications that we’re pursuing, for alopecia, for dermatitis, for discoid lupus, there are no approved therapies for these patients. In the case of lupus, current treatments are really mainly steroids or immunosuppressants, which aren’t uniformly effective for patients and can have some very serious side effects. So, really we think of all of these indications as ones where there’s significant need for more treatment options for the patients.
Daniel Levine: What is daxdilimab and how does it work?
Jodi Karnell: Daxdilimab is a monoclonal antibody that is designed to deplete these PDCs that we’ve been talking about. So, daxdilimab binds to a protein that’s called ILT7, that is uniquely expressed on the cell surface of PDCs. Only PDCs express ILP7 so daxdilimab will only bind to PDCs. One end of the molecule binds to PDCs. The other end of daxdilimab can bind to an effector cell like a natural killer cell. And when both ends of this antibody are engaged, it triggers release of cytolytic granules, which cause the destruction of the PDC. So, basically daxdilimab is specifically designed with precision to deplete human PDCs.
Daniel Levine: Interleukin 1 plays an important role within the immune system to protect against pathogens. How specific is daxdilimab to the areas that are involved in the autoimmune disease?
Jodi Karnell: That’s really an important question. So, daxdilimab specifically, as I just described, depletes PDCs, which we really think in various settings of autoimmunity are a key cellular source of type 1 interferon. So, we really think of the PDC in these autoimmune settings as being the chief producer of type 1 interferon. That’s our hypothesis, but nearly all cells in the body are capable of producing type 1 interferon. So, even when we deplete PDCs, there’s still many sources of type 1 interferon available to respond in the context of pathogens like a virus. So, while we think we’re removing a key cellular source that’s really driving some of these autoimmune manifestations, we aren’t globally impairing the type 1 interferon response, and there’s still that machinery and many cells that can produce type 1 interferons to respond to some of these pathogen threats.
Daniel Levine: Autoimmune conditions are characterized by periods of remission and flares. Is the therapy expected to be used to treat flares or would it be a chronic therapy?
Jodi Karnell: We’re still in the early days of studying daxdilimab and really understanding how it should be used to deliver the greatest efficacy, but the question you’re asking is very important. Questions around timing and frequency of treatment and all that will be evaluated in our ongoing and upcoming clinical studies.
Daniel Levine: Well, what’s known about the safety and efficacy of daxdilimab from studies that have been done to date.
Jodi Karnell: We have data from some phase 1 studies with daxdilimab, including a phase 1b study in patients with cutaneous lupus. Again, these are patients that have skin manifestations of lupus, and from that study, what we know is that the safety profile of daxdilimab was similar to placebo, but obviously, further trials are really needed to establish the safety profile of the molecule. But we got a lot of interesting information out of that phase 1b study in CLE. What we saw was that treatment with daxdilimab potently depleted PDCs, both in the blood as well as locally in the cutaneous lupus skin lesion. So, we were effectively able to deplete the PDCs in the blood and in the tissue. Again, an important observation for us from this study was that if we depleted PDCs with daxdilimab, we saw a robust reduction in type 1 interferon activity, both in circulation and in the skin, suggesting that removal of PDCs was associated with a reduction in this type 1 interferon activity.
Daniel Levine: And what’s the development path forward?
Jodi Karnell: Yeah. There’s just a lot of activity around daxdilimab right now. We’re going to be studying the molecule in five different diseases so there’ll be additional trials initiated, and we’ll be looking forward to seeing the data read out from those studies to inform the best path forward for the molecule.
Daniel Levine: As you think about the future development of daxdilimab, are you looking beyond the current indications you’re pursuing? Is there potential to target other conditions as well?
Jodi Karnell: Absolutely. I think one of the things that gets me so excited about this molecule is its broad potential across diseases characterized by this dysregulated type 1 interferon response. So, there’s significant need for more treatment options in lupus and other autoimmune diseases that really target specific drivers of disease such as type 1 interferon and we’re just going to continue to identify diseases where there’s strong rationale that this particular mechanism could be beneficial for patients.
Daniel Levine: Jodi Carnell, senior director of research at Horizon Therapeutics. Jodi, thanks so much for your time today.
Jodi Karnell: It’s been a pleasure. Thanks so much.
This transcript has been edited for clarity and readability.
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