Targeting Janus kinases in the treatment of autoimmune disease

靶向 Janus 激酶治疗自身免疫性疾病

• 批准号: 10712572
• 负责人: John O'Shea
• 金额: $ 24.48万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712572
• 关键词: Affect; Alopecia Areata; Ankylosing spondylitis; Apoptosis; Arthritis; Asthma; Atherosclerosis; Atopic Dermatitis; Autoantibodies; Autoimmune Diseases; BCL2 gene; Bacteria; Binding; Blood Vessels; Bone Marrow; COVID-19; Cardiometabolic Disease; Cell Cycle; Cells; Cholesterol; Chronic Childhood Arthritis; Clinical; Clinical Trials; Collaborations; Controlled Clinical Trials; Cooperative Research and Development Agreement; Cytokine Signaling; Dermatologic; Development; Differentiation and Growth; Disease; Double-Blind Method; Endothelium; Event; FDA Emergency Use Authorization; Family; Functional disorder; Generations; Genes; Goals; Growth and Development function; Hematopoiesis; High Density Lipoproteins; Homeostasis; Host Defense; Human; Hypersensitivity; IL7 gene; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunomodulators; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Interferon Type I; Interferons; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-9; Janus kinase; Laboratories; Legal patent; Link; Liver; Longitudinal Studies; Lupus; Lymphoid; Lymphoid Cell; Mediating; Metabolism; Molecular; Mus; Mutation; Myeloproliferative disease; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Natural Immunity; Natural Killer Cells; Nephritis; Opportunistic Infections; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phosphatidylcholine-Sterol O-Acyltransferase; Phosphorylation; Phosphotransferases; Placebo Control; Placebos; Pre-Clinical Model; Production; Proteins; Psoriasis; Psoriatic Arthritis; Randomized; Receptor Activation; Rheumatoid Arthritis; STAT4 gene; Serum; Severe Combined Immunodeficiency; Skin; Spleen; Systemic Lupus Erythematosus; Testing; Tissues; United States National Institutes of Health; Virus; Vitiligo; Withdrawal; adaptive immune response; adaptive immunity; antagonist; arterial stiffness; autoimmune pathogenesis; base; cardiovascular risk factor; cell growth; cell type; clinical center; clinically relevant; congenital immunodeficiency; cytokine; density; endothelial dysfunction; extracellular; fungus; genetic signature; graft vs host disease; granulocyte; improved; inhibitor; insight; liver function; mouse model; neutrophil; new therapeutic target; particle; placebo group; pre-clinical; premature; risk variant; skin disorder; tissue repair; transcriptome; treatment group

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 clinically relevance. Clinical trials with newer jakinibs are being planned in other diseases in the NIAMS portfolio.

细胞因子包含一大类分泌蛋白，调节细胞生长和多种类型细胞的分化。这些因子对于调节免疫和炎症反应以及调节淋巴系统的发育和分化尤其重要。毫不奇怪，细胞因子在许多自身免疫性疾病（如类风湿性关节炎、系统性红斑狼疮、炎症性肠病和牛皮癣）的发病机制中至关重要。了解细胞因子作用的分子基础为了解免疫介导疾病的发病机制提供了重要的见解，并提供了新的治疗靶点。 我们发现了人 Jak3，这是一种对结合常见 γ 链 gc（IL-2、IL-4、IL-7、IL-9、IL-15 和 IL-21）的细胞因子信号传导至关重要的激酶。我们发现 Jak3 突变会导致原发性免疫缺陷疾病，称为严重联合免疫缺陷 (SCID)。我们已获得两项与以 Jak3 为基础的新型免疫调节药物相关的专利，并与辉瑞公司建立了合作研究与开发协议 (CRADA)，以生产第一代 Jak 拮抗剂。托法替尼是辉瑞公司开发的一种化合物，被发现在临床前模型中有效。托法替尼和其他 JAK 抑制剂 (jakinibs) 被批准用于治疗类风湿性关节炎、银屑病关节炎、幼年关节炎、特应性皮炎和炎症性肠病。 Jakinibs 还在强直性脊柱炎和许多皮肤病（包括牛皮癣、斑秃和其他疾病）中进行研究。 Jakinibs 已获得 Covid-19 的紧急使用授权。 与辉瑞更新了 CRADA，旨在更好地了解托法替布和相关抑制剂的作用机制。在考虑 Jakinibs 可能有用的其他临床情况时，我们认为 SLE 可能是此类药物的合适候选者。许多影响先天免疫和适应性免疫的细胞因子被认为有助于 SLE 的免疫发病机制，包括干扰素 IL-6、IL-21 和其他干扰素。此外，SLE 中的免疫细胞失调也与过早的血管损伤有关。迄今为止，尚无药物被证明可以同时针对 SLE 的疾病活动性和心血管风险增加。在临床前模型中，我们发现托法替布治疗可改善肾炎、皮肤炎症和自身抗体的产生。此外，托法替布治疗显着降低了相关细胞因子的血清水平。托法替尼还调节中性粒细胞功能障碍和内皮异常。因此，我们得出结论，托法替布可以调节小鼠狼疮的先天性和适应性免疫反应并改善血管功能。基于这些临床前发现，NIH 临床中心与 Kaplan 实验室和 NIAMS 狼疮临床试验合作，启动了针对轻中度 SLE 的临床试验。这项 1b/2a 期随机、双盲、安慰剂对照临床试验在 30 名 SLE 受试者中使用托法替尼（药物与安慰剂比例为 2:1），根据 STAT4 风险等位基因的存在或不存在进行分层。这项研究显示，与安慰剂组相比，到第 56 天，托法替布治疗组的 I 型干扰素基因特征、低密度粒细胞和中性粒细胞胞外陷阱的循环水平显着降低，同时不同免疫细胞的 pSTAT 磷酸化也显着降低。使用托法替布导致接受托法替布治疗的患者的 HDL-C 和 HDL 颗粒数显着增加，同时卵磷脂：胆固醇酰基转移酶 (LCAT) 浓度和胆固醇流出能力显着改善。与安慰剂组相比，治疗组的动脉僵硬度和内皮功能障碍有所改善。在研究结束时，即停用托法替布 4 周后，大多数变化恢复到基线值。 其中一些变化与 STAT4 风险等位基因的存在或缺失有关。此外，托法替布的耐受性良好，没有出现 SLE 疾病活动性恶化、没有严重 AE、机会性感染、血栓栓塞事件或肝功能异常。因此，在一项短期试验中，托法替布的使用显着改善了与 SLE 动脉粥样硬化加速相关的心脏代谢和免疫疾病参数。需要长期研究来确定托法替布对 SLE 各种表现（包括心血管风险）的疗效。 为了更好地了解使用第一代和第二代 jakinibs 的影响，特别是在炎症性肠病中，还研究了这些药物对小鼠模型中适应性和先天淋巴细胞稳态的影响。 我们发现，在接受 jakinibs 治疗的小鼠中，与肝脏、脾脏和骨髓中存在的 NK 细胞池相比，肝脏 ILC1 稳态池受到的影响较小。 JAK 抑制对两个亚群的转录组有重叠的影响，主要影响调节细胞周期和凋亡的基因。然而，JAK 抑制的不同影响与 ILC1 表达的抗凋亡基因 Bcl2 的高水平有关。我们的研究结果为 JAK 抑制剂对 NK 细胞和 ILC1 的影响提供了机制解释，这可能具有临床意义。 NIAMS 正在计划针对其他疾病进行新型 jakinib 的临床试验。