IL-24

The study is the first to identify a damage response pathway that is distinct from but parallel to the classical pathway triggered by pathogens. It's a dangerous world out there. From bacteria and viruses to accidents and injuries, threats surround us all the time. And nothing protects us more steadfastly than our skin. The barrier between inside and out, the body's largest organ is also its most seamless defense. And yet the skin is not invincible. It suffers daily the slings and arrows of outrageous fortune, and it tries to keep us safe by sensing and responding to these harms. A primary method is the detection of a pathogen, which kicks the immune system into action. But new research from the lab of Rockefeller's Elaine Fuchs, published in Cell, reveals an alternative protective mechanism that responds to injury signals in wounded tissue -- including low oxygen levels from blood vessel disruption and scab formation -- and it doesn't need an infection to get into gear. The study is the first to identify a damage response pathway that is distinct from but parallel to the classical pathway triggered by pathogens. At the helm of the response is interleukin-24 (IL24), whose gene is induced in skin epithelial stem cells at the wound edge. Once unleashed, this secreted protein begins to marshal a variety of different cells to begin the complex process of healing. "IL24 is predominately made by the wound-edge epidermal stem cells, but many cells of the skin -- the epithelial cells, the fibroblasts, and the endothelial cells -- express the IL24 receptor and respond to the signal. IL24 becomes an orchestrator that coordinates tissue repair," says Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. Hints from pathogen-induced signaling Scientists have long understood how the host responses protect our body from pathogen-induced threats: somatic cells recognize invading bacteria or viruses as foreign entities and induce a number of defense mechanisms with the help of signaling proteins such as type 1 interferons. But how does the body respond to an injury that may or may not involve foreign invader? If we cut a finger while slicing a cucumber, for example, we know it instantly -- there's blood and pain. And yet how the detection of injury leads to healing is poorly understood on a molecular basis. While type 1 interferons rely on the signaling factors STAT1 and STAT2 to regulate the defense against pathogens, previous research by the Fuchs lab had shown that a similar transcription factor known as STAT3 makes its appearance during wound repair. Siqi Liu, co-first author in both studies, wanted to trace STAT3's pathway back to its origin. IL24 stood out as a major upstream cytokine that induces STAT3 activation in the wounds. Microbe-independent action In collaboration with Daniel Mucida's lab at Rockefeller, the researchers worked with mice under germ-free conditions and found that the wound-induced IL24 signaling cascade is independent of germs. But what injury signals induced the cascade? Wounds often extend into the skin dermis, where capillaries and blood vessels are located. "We learned that the epidermal stem cells sense the hypoxic environment of the wound," says Yun Ha Hur, a research fellow in the lab and a co-first author on the paper. When the blood vessels are severed and a scab forms, epidermal stem cells at the edge of the wound are starved of oxygen. This state of hypoxia is an alarm bell for cell health, and induced a positive feedback loop involving transcription factors HIF1a and STAT3 to amplify IL24 production at the wound edge. The result was a coordinated effort by a variety of cell types expressing the IL24 receptor to repair the wound by replacing damaged epithelial cells, healing broken capillaries, and generating fibroblasts for new skin cells. Collaborating with Craig Thompson's group at Memorial Sloan Kettering Cancer Center, the researchers showed that they could regulate Il24 gene expression by changing oxygen levels. Once the researchers pinpointed the origin of the tissue-repair pathway in epidermal stem cells, they studied the wound repair process in mice that had been genetically modified to lack IL24 functionality. Without this key protein, the healing process was sluggish and delayed, taking days longer than in normal mice to completely restore the skin. They speculate that IL24 might be involved in the injury response in other body organs featuring epithelial layers, which act as a protective sheath. In recent studies, elevated IL24 activity has been spotted in epithelial lung tissue of patients with severe COVID-19 and in colonic tissue in patients with ulcerative colitis, a chronic inflammatory bowel disease. "IL24 could be working as a cue to signal the need for injury repair in many organs," Hur says. Linked by function and evolution "Our findings provide insights into an important tissue damage sensing and repair signaling pathway that is independent of infections," explains Fuchs. An analysis with evolutionary biologist Qian Cong at UT Southwestern Medical Center revealed that IL24 and its receptors share close sequence and structure homology with the interferon family. Though they may not always be working in coordination at every moment, IL24 and interferons are evolutionarily related and bind to receptors sitting near each other on the surface of cells. The researchers suspect that these signaling molecules derive from a common molecular pathway dating far back in our past. "We think that hundreds of millions of years ago, this ancestor might have diverged into two pathways -- one being pathogen defense and the other being tissue injury," Liu says. Perhaps the split occurred to cope with an explosion of pathogens and injuries that caused a sea of troubles for life on Earth.

BALLERUP, Denmark I March 18, 2023 I LEO Pharma A/S, a global leader in medical dermatology, today announced that a Phase 2a trial evaluating the efficacy and safety of investigational agent LEO 138559 in adults with moderate-to-severe atopic dermatitis met its primary endpoint. Results were shared as one of two LEO Pharma late breaker oral presentations at the 2023 American Academy of Dermatology (AAD) Annual Meeting. 1 LEO 138559 is an investigational agent and its efficacy and safety are subject to further larger trials. LEO 138559 is an investigational monoclonal antibody currently in Phase 2 development for the treatment of moderate-to-severe atopic dermatitis, which blocks the IL-22RA1 receptor subunit thereby inhibiting the effect of the interleukin-22 (IL-22) cytokine – known to be elevated in patients with atopic dermatitis. 1–3 LEO 138559 potentially also inhibits to some extent the effects of cytokines IL-20 and IL-24; however, this remains to be fully understood. 1 “We know that atopic dermatitis is a complex immunological condition and LEO Pharma is committed to supporting patients and clinicians in dermatology by finding new ways to treat this chronic disease,” said Jörg Möller, Executive Vice President, Global Research and Development, LEO Pharma. “We are encouraged by these Phase 2a results, in moderate-to-severe atopic dermatitis and plans are underway for a Phase 2b trial.” The results from the Phase 2a trial in 58 adult patients showed that LEO 138559 dosed at 450 mg every other week (Q2W) via subcutaneous injections for 16 weeks had a favourable safety profile. 1 LEO 138559 demonstrated significant improvement compared with placebo in the primary endpoint of change in EASI score from baseline (-15.3 vs. -3.5) and across a range of endpoints including EASI-75 (41.6% vs.13.7%), EASI-90 (30.8% vs. 3.5%), EASI-100 (20.9% vs. 0%) and vIGA-AD 0/1 (27.3% vs. 7.0%). 1 The most frequently reported AEs in the LEO 138559 versus placebo arms were COVID-19 (13.8% vs 6.9%), dermatitis atopic (13.8% vs 13.8%), and upper respiratory tract infection (3.4% vs 10.3%). 1 “These results are promising, as they demonstrate for the first time the potential benefits of targeting the IL-22 receptor which is a new mode of action”, said Professor Diamant Thaci, MD, Head of Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany and the international coordinating investigator for the Phase 2a trial. “Patients with moderate-to-severe atopic dermatitis still face numerous unmet needs and we welcome any new advances that could provide us with additional options to help them.” LEO Pharma and argenx BV formed a strategic alliance in 2015 to develop innovative antibody-based solutions for the treatment of chronic inflammation that underlies many skin conditions. LEO Pharma and argenx BV jointly developed LEO 138559 under an exclusive option and research agreement. LEO Pharma obtained the license to LEO 138559 in 2022 and now assumes the responsibility to develop and commercialize LEO 138559 for inflammatory skin disorders, such as atopic dermatitis. The collaboration between LEO Pharma and argenx BV stands as a strong example of an external innovation sourcing model, which is a key pillar in LEO Pharma’s new Research and Development strategy. About the Phase 2a trial The LEO 138559 Phase 2a trial (NCT04922021) was a randomized, double-blind, placebo-controlled, multi-site, trial to evaluate the efficacy and safety of LEO 138559 in adult patients with moderate-to-severe atopic dermatitis. Patients were randomized 1:1 (n=29 per arm) to receive either LEO 138559 dosed at 450 mg Q2W or placebo, for 16 weeks. The primary endpoint was change in EASI score from baseline to Week 16. 1 Other endpoints included EASI-75, EASI-90, EASI-100 (which represent a 75, 90 and 100 percent improvement in atopic dermatitis area and severity) and vIGA-AD 0/1 (proportion of patients who achieved ‘clear’ or ‘almost clear’ skin). 1 About atopic dermatitis Atopic dermatitis is a chronic, inflammatory skin disease characterized by intense itch and eczematous lesions. 4 Atopic dermatitis is the result of skin barrier dysfunction and immune dysregulation, leading to chronic inflammation. 5 About investigational LEO 138559 LEO 138559 is an investigational monoclonal antibody that targets the IL-22RA1 receptor subunit, currently in Phase 2 development for the potential treatment of moderate-to-severe atopic dermatitis. 1 It blocks the IL-22RA1 subunit and thereby inhibits the effects of the IL-22 cytokine, and potentially also to some extent the effects of IL-20 and IL-24. 1 LEO 138559 does not bind to the IL-22 cytokine itself. 1 LEO Pharma has obtained a worldwide exclusive license to develop and commercialize LEO 138559 from argenx BV. About LEO Pharma LEO Pharma is a global company dedicated to advancing the standard of care for the benefit of people with skin conditions, their families and society. Founded in 1908 and majority owned by the LEO Foundation, LEO Pharma has devoted decades of research and development to advance the science of dermatology, and today, the company offers a wide range of therapies for all disease severities. LEO Pharma is headquartered in Denmark with a global team of 4,700 people, serving millions of patients across the world. In 2022, the company generated net sales of DKK 10.6 billion. Learn more at www.leo-pharma.com . About argenx BV argenx BV is a global immunology company committed to improving the lives of people suffering from severe autoimmune diseases. For more information, visit www.argenx.com References SOURCE: LEO Pharma