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: 9360989
• 负责人: John O'Shea
• 金额: $ 27.48万
• 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/9360989
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Ankylosing spondylitis; Arthritis; Autoantibodies; Autoimmune Diseases; BCL2 gene; Binding; Blood Vessels; Cell Differentiation process; Cells; Chronic; Chronic Childhood Arthritis; Clinical; Clinical Trials; Cooperative Research and Development Agreement; Cytokine Signaling; Development; Disease; Disease model; Drug Combinations; Enhancers; Family; Generations; Genes; Goals; Homeostasis; Human; Human T-lymphotropic virus 1; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Interferons; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-7; Interleukin-9; Janus kinase; Laboratories; Legal patent; Lupus; Lymphoid; Malignant Neoplasms; Mediating; Memory; Molecular; Mus; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Immunity; Nephritis; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Pre-Clinical Model; Production; Proteins; Psoriasis; Psoriatic Arthritis; Receptor Activation; Research Personnel; Rheumatoid Arthritis; Serum; Severe Combined Immunodeficiency; Signal Transduction; Skin; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic Agents; Therapeutic Trials; Trans-Activators; Tumor Burden; United States National Institutes of Health; Vascular Diseases; Work; adaptive immunity; autocrine; base; cardiovascular risk factor; cell growth; cell type; congenital immunodeficiency; curative treatments; cytokine; endothelial dysfunction; improved; inhibitor/antagonist; insight; mouse model; neutrophil; new therapeutic target; paracrine; premature; tax Gene Products

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 immunosuppressant/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. The drug was tested in rheumatoid arthritis, and has now been approved for this indication. Tofacitinib is also being studied in psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile arthritis, IBD and various dermatological conditions. Several other Jakinibs have been developed and are also in clinical trials, including late phase pivotal trials. The CRADA with Pfizer was renewed and is 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 appropriatecandidate 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. The action of these cytokines are all blocked by first generation Jakinibs like tofacitinib. 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. We therefore set out to assess whether tofacitinib might have utility in SLE in terms of both immune cell dysfunction and vascular damage. 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. These results indicate that JAKinibs have the potential to be beneficial in treating SLE and its associated vascular damage in humans. Based on these favorable findings, we have begun a clinical trial of tofacitinib in mild-moderate SLE at the NIH Clinical Center. In related work in cancer, we collaborated on work with a Jakinib in Adult T-cell leukemia (ATL), a disease caused by infection with HTLV1 associated with constitutive activation of the Jak/STAT pathway. This is an important unmet need as presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) activates autocrine/paracrine interleukin-2 (IL-2), IL-9, and IL-15 production, resulting in amplified JAK/STAT signaling. The selective Jakininb ruxolitinib was examined in a high-throughput matrix screen combined with greater than 450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL. In related studies, devoted to better understanding the mechanism of action of tofacitinib, we examined its effect on the evolving enhancer landscapes of activated T cells. We found that tofacitinib has a selective effect on super-enhancers compared to typical enhancers. Finally, we collaborated with external investigators to identify new potential targets that affect Th17 cells.

细胞因子包括一个大型分泌的蛋白质家族，这些蛋白质调节了许多类型的细胞的细胞生长和分化。这些因素在调节免疫和炎症反应以及调节淋巴发育和分化方面尤为重要。毫不奇怪，细胞因子对于许多自身免疫性疾病（例如类风湿关节炎，SLE，IBD和牛皮癣）的发病机理至关重要。了解细胞因子作用的分子基础为免疫介导疾病的发病机理提供了重要的见解，并提供了新的治疗靶标。 我们发现了人类JAK3，这是一种通过结合共同伽马链（IL-2，IL-4，IL-7，IL-7，IL-9，IL-9，IL-15和IL-21）的细胞因子信号传导所必需的激酶。我们发现JAK3的突变导致原发性免疫缺陷障碍称为严重的免疫缺陷（SCID）。我们已经获得了针对JAK3作为新的一类免疫抑制剂/免疫调节药物的基础的两项专利，并与辉瑞建立了合作研究与发展协议（CRADA），以生成第一代JAK拮抗剂。一种化合物，tofacitinib是由辉瑞开发的，发现在临床前模型中有效。该药物在类风湿关节炎中进行了测试，现在已批准用于这种迹象。牛皮替尼还在牛皮癣，银屑病关节炎，强直性脊柱炎，青少年关节炎，IBD和各种皮肤病学疾病中进行了研究。已经开发了其他几种jakinib，并且还在临床试验中，包括晚期关键试验。 与辉瑞的Crada进行了更新，并指向更好地理解tofacitinib和相关抑制剂的作用机理。在考虑其他可能有用的jakinibs的临床情况下，我们认为SLE可能是这类药物的适当顾问。已经提出了许多影响先天和适应性免疫的细胞因子，以有助于SLE的免疫发病发生，包括干扰素IL-6，IL-21和其他干扰素。这些细胞因子的作用都被诸如tofacitinib这样的第一代jakinib所阻断。另外，SLE中的免疫细胞失调也与早产血管损伤有关。迄今为止，尚无证明针对疾病活动和SLE中心血管风险增强的药物。因此，我们着手评估tofacitinib在免疫细胞功能障碍和血管损伤方面是否可能具有SLE的实用性。我们发现用tofacitinib治疗导致肾炎，皮肤炎症和自身抗体的产生改善。此外，tofacitinib治疗显着降低了相关细胞因子的血清水平。 Tofacitinib还调节中性粒细胞功能障碍和内皮异常。因此，我们得出的结论是，tofacitinib可以调节鼠狼疮中的先天和适应性免疫反应并改善血管功能。这些结果表明，jakinibs有可能有益于治疗SLE及其相关的血管损伤。根据这些有利的发现，我们已经开始了在NIH临床中心轻度中度SLE中Tofacitinib的临床试验。 在癌症的相关工作中，我们与jakinib合作在成人T细胞白血病（ATL）中进行了合作，这是一种与HTLV1感染有关的疾病，与JAK/STAT途径的组成型激活有关。这是一个重要的未满足需求，因为目前没有ATL治疗疗法。 HTLV-1编码的蛋白质税（来自X-Gene区域的反式激活器）激活自分泌/旁分泌白介素-2（IL-2），IL-2），IL-9和IL-15产生，从而导致放大的JAK/STAT信号传导。在高通量基质筛选中检查了选择性jakininb ruxolitinib，结合了450个潜在的治疗剂，Bcl-2/bcl-XL抑制剂navitoclax被鉴定为多药治疗的有力候选者。 ruxolitinib和navitoclax独立表现出适度的抗肿瘤功效，而组合大大降低了肿瘤负担，并在ATL鼠模型中延长了生存率。这些研究提供了使用抑制JAK信号传导和抗凋亡蛋白BCL-XL的药物组合对患有闷热/慢性ATL患者的治疗试验的支持。 在相关研究中，致力于更好地了解tofacitinib的作用机理，我们检查了其对活化T细胞不断发展的增强子景观的影响。我们发现，与典型的增强剂相比，Tofacitinib对超增强剂具有选择性影响。 最后，我们与外部研究人员合作，确定影响Th17细胞的新潜在靶标。