Validation of a Negative Regulator as a Novel Therapy for Autoimmune Disease

负调节剂作为自身免疫性疾病新疗法的验证

基本信息

批准号：
8461514
负责人：
RANDOLPH J. NOELLE
金额：
$ 30万
依托单位：
IMMUNEXT, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461514
关键词：
Action Potentials Address Agonist Area Autoimmune Diseases Autoimmunity Binding Biological Response Modifiers CD8B1 gene Cancer Model Cell Differentiation process Cells Cloning Development Differentiation and Growth Disease Engineering Equilibrium Evaluation Experimental Autoimmune Encephalomyelitis Extracellular Domain Family Family member Foundations Future Goals Human Immune Immune response Immune system Immunity Immunoglobulins Immunosuppression Immunosuppressive Agents In Vitro Investigation Lead Leukocytes Ligands Lymphocyte Modeling Multiple Sclerosis Mus Myelogenous Onset of illness Outcome Pathway interactions Pharmaceutical Preparations Phase Population Production Proteins Proteomics Regulation Relapse Severities Signal Transduction Small Business Technology Transfer Research System Systemic Lupus Erythematosus T cell response T-Cell Activation T-Cell Activation Pathway T-Cell Proliferation T-Lymphocyte Testing Therapeutic Therapeutic Agents Treatment Cost Tumor Immunity Ursidae Family Validation cytokine design drug development effective therapy experience expression cloning human disease immune function in vivo insight meetings mouse model novel novel therapeutics programs receptor response scaffold success

项目摘要

DESCRIPTION (provided by applicant): The immune system depends upon an exquisite balance between positive and negative signals to maintain proper function. However, disruptions of this balance can lead to inappropriate responses: for example loss of negative regulation can result in autoimmunity. VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation), is a recently identified negative checkpoint regulator of immune function. Studies in multiple cancer models have shown that blockade of VISTA dependent signals leads to enhanced tumor immunity. Additionally, in a model of experimental allergic encephalomyelitis (EAE), blockade of VISTA resulted in early disease onset and enhanced severity. These findings suggest that VISTA expression is an important regulator of immunity and modulation of this pathway could lead to the development of novel therapeutics for the treatment of autoimmunity. With nearly 50 million people suffering from autoimmune diseases in the US alone, and with treatment costs projected to be over $100B/yr, development of safe, effective therapies is an utmost priority. VISTA has been validated as a negative regulator in the murine system. The goal of this proposal is to confirm that VISTA also functions as negative regulator of human immunity. Studies will determine VISTA expression on both lymphocyte and myeloid populations. Functional studies will determine the effects of VISTA dependent signals on T cell proliferation, effector function and differentiation. The studies also will evaluate whether VISTA may regulate the function of other immune cells providing valuable insights on where therapies modulating the VISTA pathway may have the greatest therapeutic potential. Insoluble forms of VISTA-Ig have been shown to inhibit T cell responses in vivo. These results demonstrate that engagement of the currently undefined receptor leads to modulation of immunity. We will develop multimeric soluble forms of VISTA-Ig as potential therapeutic agents. We will test them in vitro for the ability to modulate T cell responses. Agonists targeted to the VISTA pathway could be used to treat a variety of human autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. Because of the compelling unmet need, the documented activity of VISTA in EAE, and our experience in the development of drugs in MS, we chose MS as the first indication to develop. After meeting the success criteria for this Phase 1 STTR, the Phase 2 STTR program will develop the lead VISTA agonist as an immunosuppressive drug to treat relapsing/remitting MS.

描述（由申请人提供）：免疫系统依赖于正信号和负信号之间的微妙平衡来维持正常的功能。然而，这种平衡的破坏可能导致不适当的反应：例如，负调节的丧失可能导致自身免疫。 VISTA（含 V 区免疫球蛋白的 T 细胞激活抑制剂）是最近发现的免疫功能负检查点调节剂。对多种癌症模型的研究表明，阻断 VISTA 依赖性信号可增强肿瘤免疫力。此外，在实验性过敏性脑脊髓炎 (EAE) 模型中，阻断 VISTA 会导致疾病提前发作并加剧严重程度。这些发现表明 VISTA 表达是免疫的重要调节因子，调节该途径可能会导致治疗自身免疫的新疗法的开发。仅在美国就有近 5000 万人患有自身免疫性疾病，治疗费用预计将超过每年 100B 美元，开发安全、有效的疗法是当务之急。 VISTA 已被验证为小鼠系统中的负调节剂。该提案的目的是确认 VISTA 也能起到人体免疫力负调节剂的作用。研究将确定淋巴细胞和骨髓细胞群上的 VISTA 表达。功能研究将确定 VISTA 依赖性信号对 T 细胞增殖、效应功能和分化的影响。这些研究还将评估 VISTA 是否可以调节其他免疫细胞的功能，为调节 VISTA 通路的疗法可能具有最大治疗潜力提供有价值的见解。不溶性形式的 VISTA-Ig 已被证明可以抑制体内 T 细胞反应。这些结果表明，当前未定义的受体的参与会导致免疫调节。我们将开发多聚体可溶形式的 VISTA-Ig 作为潜在的治疗剂。我们将在体外测试它们调节 T 细胞反应的能力。针对 VISTA 通路的激动剂可用于治疗多种人类自身免疫性疾病，包括系统性红斑狼疮和多发性硬化症。由于迫切的未满足需求、VISTA 在 EAE 中的活性记录以及我们在 MS 药物开发方面的经验，我们选择 MS 作为第一个开发的适应症。在满足第一阶段 STTR 的成功标准后，第二阶段 STTR 计划将开发主要的 VISTA 激动剂作为治疗复发/缓解型多发性硬化症的免疫抑制药物。