Targeting Janus kinases in the treatment of autoimmune disease

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

Cytokines comprise a large family of secreted proteins that regulate cell growth and differentiation of many types of cells. These factors are especially important in regulating immune and inflammatory responses, and regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of many autoimmune diseases such as rheumatoid arthritis, SLE, IBD and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have received two patents related to targeting Jak3 as the basis for a new class of immunomodulatory drugs and established a Cooperative Research and Development Agreement (CRADA) with Pfizer to generate the first-generation Jak antagonists. One compound, tofacitinib, was developed by Pfizer and found to be effective in preclinical models. Tofacitinib and other JAK inhibitors (jakinibs) are approved for rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, atopic dermatitis and inflammatory bowel disease. Jakinibs are also being studied in ankylosing spondylitis, and many dermatological conditions including psoriasis, alopecia areata and other disorders. Jakinibs have received emergency use authorization for Covid-19. The CRADA with Pfizer was renewed and was directed at better understanding the mechanisms of action of tofacitinib and related inhibitors. In considering other clinical circumstances in which Jakinibs might be useful, we considered that SLE might be an appropriate candidate for this class of drugs. A number of cytokines that impact both innate and adaptive immunity have been suggested to contribute to the immunopathogenesis of SLE, including interferons IL-6, IL-21, and other interferons. In addition, immune cell dysregulation in SLE is also associated with premature vascular damage. To date, no drug has proven to target both disease activity and enhanced cardiovascular risk in SLE. In a preclinical model, we found that treatment with tofacitinib led to improvement in nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment significantly reduced serum levels of relevant cytokines. Tofacitinib also modulated neutrophil dysfunction and endothelial abnormalities. Thus, we concluded that tofacitinib can modulate the innate and adaptive immune responses in murine lupus and improve vascular function. Based on these preclinical findings, in collaboration with the Kaplan lab and the NIAMS Lupus Clinical Trials clinical trial in mild-moderate SLE was launched at the NIH Clinical Center. This phase 1b/2a randomized, double-blind, placebo-controlled clinical trial of using tofacitinib in 30 SLE subjects (2:1 drug to placebo ratio) was stratified by the presence or absence of STAT4 risk allele. This study showed the type I Interferon gene signature, circulating levels of low-density granulocytes and neutrophil extracellular traps significantly decreased in the tofacitinib treated group compared to the placebo group by day 56, accompanied by significant decreases in pSTAT phosphorylation of different immune cells. The use of tofacitinib resulted in a significant increase in HDL-C and HDL particle number in tofacitinib-treated patients accompanied by significant improvements in lecithin: cholesterol acyltransferase (LCAT) concentration and cholesterol efflux capacity. Arterial stiffness and endothelial dysfunction improved in the treatment group as compared to the placebo group. Most of these changes reverted towards baseline values at the end of study, 4 weeks after withdrawal of tofacitinib. Some of these changes were associated to presence or absence of STAT4 risk allele. In addition, tofacitinib was well tolerated with no worsening of SLE disease activity, no severe AEs, opportunistic infections, thromboembolic events or liver function abnormalities. Thus, in a short-term trial, use of tofacitinib resulted in significant improvements in cardiometabolic and immunologic disease parameters associated with accelerated atherosclerosis in SLE. Long-term studies are needed to determine the efficacy of tofacitinib in the various manifestations of SLE including cardiovascular risk. To better understand the implications of the use of first and second generation jakinibs, especially in inflammatory bowel disease, the effects these agents on the homeostasis of adaptive and innate lymphoid cells in murine models was also investigated. We found that in mice treated with jakinibs, the homeostatic pool of liver ILC1 was less affected compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance. Clinical trials with newer jakinibs are being planned in other diseases in the NIAMS portfolio.