Targeting Jak3 in the treatment of autoimmune disease

靶向 Jak3 治疗自身免疫性疾病

基本信息

批准号：
7964897
负责人：
John O'Shea
金额：
$ 26.71万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/7964897
关键词：
Arthritis Attenuated Autoimmune Diseases Autoimmune Process Autoimmunity Binding Biochemical Pathway Boxing CD4 Positive T Lymphocytes Cell Differentiation process Cells Collaborations Cooperative Research and Development Agreement Cytokine Signaling Development Disease Drug effect disorder Family Generations Goals Graft Rejection Helper-Inducer T-Lymphocyte Homeostasis Human Immune Immunologic Deficiency Syndromes Immunosuppressive Agents In Vitro Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin 2 Receptor Gamma Interleukin-15 Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-7 Interleukin-9 Isomerism Janus kinase Joints Laboratories Legal patent Lymphoid MAP Kinase Gene Mediating Memory Modeling Molecular Multiple Sclerosis Mutation National Human Genome Research Institute National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Diabetes and Digestive and Kidney Diseases Pathogenesis Peripheral Pharmaceutical Preparations Phase Phase II Clinical Trials Phosphotransferases Pre-Clinical Model Proteins Proto-Oncogene Proteins c-akt Psoriasis Receptor Activation Rheumatoid Arthritis Severe Combined Immunodeficiency Signal Transduction Spondylarthropathies Systemic Lupus Erythematosus T-Cell Activation T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Th1/Th2 Differentiation Pathway Thymus Gland Transforming Growth Factor beta base cell growth cell type cytokine drug efficacy forkhead protein human disease in vivo Model inhibitor/antagonist insight interest mouse model new therapeutic target novel response stereochemistry

项目摘要

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, regulating lymphoid development and differentiation. Cytokines also regulate immune homeostasis, tolerance, and memory. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease 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 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 received a patent for targeting Jak3 as the basis for a new class of immunosuppressant drugs and established a CRADA with Pfizer to generate a the first generation Jak3 antagonists. One compound, CP 690,550, was produced by Pfizer and found to be effective in preclinical models. The drug is being tested presently in Phase II studies in rheumatoid arthritis, psoriasis and transplant rejection, where it appears to be efficacious. The CRADA with Pfizer was renewed this year and was directed at better understanding the mechanisms of action of this drug. We began by assessing the effect of CP 690,550 on biochemical pathways activated by IL-2. There has been debate over the years regarding Jak-dependent and independent aspects of cytokine signaling. However, to date, we have found that all substrates phosphorylated in response to IL-2 are abrogated by CP 690,550. These include MAPK and AKT activation, as well as STAT activation. We have also determined that CP 690,550 has dramatic effects on T cell proliferation and viability. We next assessed the effect of the Jak3 inhibitor on CD4+ helper cell differentiation. CD4+ T cells have a number of potential fates. In addition to the well-known helper T cell fates, T helper 1 and T helper 2 cells, other fates are now recognized. Regulatory T cells (Treg cells) are an essential subset that maintains peripheral tolerance. Tregs are generated in the thymus from CD4+ T cells (natural Treg cells or nTregs) and can be induced in the periphery (iTreg cells). Both nTreg and iTreg cells express a transcription factor, forkhead box protein 3 (Foxp3). Deficiency of Foxp3 results in lethal autoimmunity in mouse models and in humans; the disease in humans is termed IPEX. An even more recently recognized subset of CD4+ T cells is cells that preferentially produce the cytokine IL-17 (Th17 cells). IL-17 is a major inflammatory cytokine, which appears to contribute to the pathogenesis of many autoimmune and autoinflammatory disorders including rheumatoid arthritis, spondyloarthropathy, multiple sclerosis and inflammatory bowel disease. Of interest is that Th17 cells are thought to be developmentally related to regulatory T cells (Tregs) as both subsets can be induced from naive CD4+ T cells in the presence of transforming growth factor-beta (TGFb-1) in the context of different cytokines. We found that CP 690,550 blocked Th1 and Th2 differentiation. The latter can be explained by effects on IL-4 signaling, which is dependent upon gc/Jak3. We found that the former was also blocked and this was because CP 690,550 blocked IFNg signaling via effects on Jak1. The effects on CP 690,550 on in vivo models of autoimmunity where also examined We have found that CP 690,550 is very effective in attenuating disease in arthritis models. Importantly We have also found that CP 690,550 has actions beyond effects on gc cytokines. , we found reduced expression of IL-17 in arthritic joints. We believe that these effects are an important aspect of the efficacy of this drug. In a collaboration with NIDDK and NHGRI, we also investigated the stereochemistry of CP 690,550 and found that only the 3R, 4R isomer of CP 690,550 potently inhibited Jak3.

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、调节淋巴系统的发育和分化尤其重要。细胞因子还调节免疫稳态、耐受性和记忆。毫不奇怪，细胞因子在类风湿性关节炎、系统性红斑狼疮、炎症性肠病和牛皮癣等自身免疫性疾病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 Jak3，一种对结合共同伽马链 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)。我们获得了一项针对 Jak3 作为新型免疫抑制剂药物基础的专利，并与辉瑞建立了 CRADA 来生产第一代 Jak3 拮抗剂。辉瑞公司生产的一种化合物 CP 690,550 被发现在临床前模型中有效。该药物目前正在类风湿关节炎、牛皮癣和移植排斥的二期研究中进行测试，似乎是有效的。今年与辉瑞续签了 CRADA，旨在更好地了解该药物的作用机制。我们首先评估 CP 690,550 对 IL-2 激活的生化途径的影响。多年来，关于细胞因子信号转导的 Jak 依赖性和独立方面一直存在争议。然而，迄今为止，我们发现所有响应 IL-2 磷酸化的底物均被 CP 690,550 消除。其中包括 MAPK 和 AKT 激活，以及 STAT 激活。我们还确定 CP 690,550 对 T 细胞增殖和活力具有显着影响。接下来我们评估了 Jak3 抑制剂对 CD4+ 辅助细胞分化的影响。 CD4+ T 细胞有许多潜在的命运。除了众所周知的辅助 T 细胞命运、辅助 T 细胞 1 和辅助 T 细胞 2 之外，其他命运现已得到认可。调节性 T 细胞（Treg 细胞）是维持外周耐受的重要亚群。 Treg 是在胸腺中由 CD4+ T 细胞（天然 Treg 细胞或 nTreg）产生的，并且可以在外周（iTreg 细胞）中诱导。 nTreg 和 iTreg 细胞均表达转录因子叉头盒蛋白 3 (Foxp3)。 Foxp3 缺乏会导致小鼠模型和人类产生致命的自身免疫；这种人类疾病被称为 IPEX。最近认识到的 CD4+ T 细胞亚群是优先产生细胞因子 IL-17 的细胞（Th17 细胞）。 IL-17 是一种主要的炎症细胞因子，它似乎与许多自身免疫和自身炎症性疾病的发病机制有关，包括类风湿性关节炎、脊柱关节病、多发性硬化症和炎症性肠病。有趣的是，Th17 细胞被认为与调节性 T 细胞 (Treg) 发育相关，因为在不同细胞因子的背景下，在转化生长因子-β (TGFb-1) 存在的情况下，这两个亚群都可以由初始 CD4+ T 细胞诱导产生。我们发现 CP 690,550 阻断 Th1 和 Th2 分化。后者可以通过对 IL-4 信号传导的影响来解释，该信号依赖于 gc/Jak3。我们发现前者也被阻断，这是因为 CP 690,550 通过影响 Jak1 阻断 IFNg 信号传导。还检查了 CP 690,550 对自身免疫体内模型的影响我们发现 CP 690,550 在减轻关节炎模型中的疾病方面非常有效。重要的是，我们还发现 CP 690,550 的作用超出了 gc 细胞因子的作用。，我们发现关节炎关节中 IL-17 的表达减少。我们认为这些作用是该药物疗效的一个重要方面。在与 NIDDK 和 NHGRI 的合作中，我们还研究了 CP 690,550 的立体化学，发现只有 CP 690,550 的 3R、4R 异构体能有效抑制 Jak3。