Depleting skin immune cells helps treat cutaneous lupus

A new antibody treatment reduced levels of type I interferon-producing cells in patients with cutaneous lupus, improving skin symptoms during phase 1 clinical trials.

Aug 13, 2021
Stephanie DeMarco, PhD
Depleting skin immune cells helps treat cutaneous lupus

People suffering from skin lesions due to lupus may soon feel some relief. Scientists developed a new compound called HZN-7734 that targets and depletes type I interferon-producing cells called plasmacytoid dendritic cells (pDCs), which are often present at high levels in cutaneous lupus skin lesions. In a new Science Translational Medicine study, the team reported that HZN-7734 safely reduced the level of pDCs and type 1 interferon activity in skin lesions and improved skin symptoms in patients with cutaneous lupus in phase 1 clinical trials, pointing to a potential new therapy for this difficult to treat autoimmune disease.

Patients living with cutaneous lupus and the related disease, systemic lupus, don’t have many treatment options. Symptoms vary drastically in type and severity from person to person, and currently available treatments can have serious and wide-ranging side effects. Physicians usually prescribe patients topical steroids to treat their skin lesions, but if those don’t work, they try the anti-malarial drug, hydroxychloroquine. There is currently no cure for either type of lupus.

“Once patients have failed topical steroids and anti-malarial therapy, then it's what I think of as dealer's choice,”  said J. Michelle Kahlenberg, a rheumatologist and physician scientist at the University of Michigan who was not involved in the study. “You basically try different meds to see if you can find something your patient responds to.” But, she said, “Not all of them work all that well.”

To find an effective treatment for lupus, Jodi Karnell, senior director at Horizon Therapeutics and senior author of the study, looked to a key driver of the disease: pDCs. These immune cells secrete large amounts of type I interferon, which helps clear viral infections, but too much type I interferon activity increases inflammatory responses and drives autoimmune disease. In fact, patients with autoimmune diseases like systemic sclerosis, Sjögren’s syndrome, and cutaneous lupus have increased levels of pDCs and type I interferon activity.

“We were interested in developing a therapeutic that would specifically take out these professional type I interferon-producing cells as a way to potentially target this broad range of interferon-associated diseases,” said Karnell.

In a phase 1a clinical trial, the researchers found that HZN-7734 was safe and reduced the levels of pDCs circulating in the blood of patients with autoimmune diseases characterized by dysregulated pDCs and high levels of type I interferon activity.

With those promising results, the team moved on to a phase 1b trial where they tested different doses of HZN-7734 in patients with autoimmune diseases. In addition to reducing levels of pDCs in patients’ blood, HZN-7734 also reduced pDCs and type I interferon activity in the skin. Patients with cutaneous lupus treated with a 150 mg dose of HZN-7734 also experienced a substantial clinical improvement in lupus disease activity.

Scientists found high levels of plasmacytoid dendritic cells (red staining) in the skin of a patient with cutaneous lupus, but 85 days after HZN-7734 treatment (inset photo), pDC levels significantly decreased.
Credit: Horizon Therapeutics

According to Kahlenberg, one of the real strengths of the work was that Karnell’s team specifically tested their compound’s effectiveness in patient skin.

“It's always very important to study the tissue immune response when you're using medications that are targeting a specific area of the body,” said Kahlenberg. “Too often, because blood is the easiest thing to get, we rely on that as a biomarker, but that does not always reflect what's happening in various organs of the disease.”

Getting those skin samples was no small feat for Karnell and her team.

“It can be very challenging to do studies in tissues because sometimes patients don't want biopsies from certain parts of their body, which is an understandable perspective,” said Karnell. “Making sure that we had consistent high-quality biopsies that really allowed us to understand and interpret the impact of the drug in the tissue was, for me personally, one of the biggest challenges of running this phase 1b study.”

While these trials were relatively small, Karnell and her team plan to test their compound in patients with systemic lupus in a clinical trial that will begin later this year. As it stands, the initial results look promising.

“In my clinical practice, I see a lot of patients whose skin hasn't responded to those usual things, so having something like this coming up the pipeline is very exciting,” said Kahlenberg.

Reference

  1. Karnell, J.L., et al. Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Sci. Transl. Med. 13, eabf8442 (2021).
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