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

• 批准号: 8314301
• 负责人: RANDOLPH J. NOELLE
• 金额: $ 30万
• 依托单位: IMMUNEXT, INC.
• 依托单位国家: 美国
• 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/8314301
• 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

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. PUBLIC HEALTH RELEVANCE: VISTA is a recently identified negative checkpoint regulator of immune function. Studies in murine models have demonstrated that blockade of VISTA dependent signals can enhance autoimmunity. This project will characterize VISTA expression and function in the human immune system and test soluble mutlimeric forms of VISTA-Ig as agonistic agents. We believe engagement of the VISTA pathway has the potential to be harnessed as a novel treatment for a wide range of autoimmune diseases, including Multiple Sclerosis.

描述（由申请人提供）：免疫系统依赖于正负信号之间的微妙平衡来维持正常功能。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（V-region Immunoglobulin-containing Suppressor of T cell Activation）是最近发现的一种免疫功能负检查点调节剂。在多种癌症模型中的研究已显示阻断VISTA依赖性信号导致增强的肿瘤免疫。此外，在实验性过敏性脑脊髓炎（EAE）的模型中，VISTA的阻断导致早期疾病发作和严重程度增加。这些发现表明VISTA表达是免疫的重要调节剂，并且调节该途径可导致开发用于治疗自身免疫的新型疗法。仅在美国就有近5000万人患有自身免疫性疾病，治疗费用预计超过1000亿美元/年，开发安全有效的治疗方法是当务之急。 VISTA已被验证为鼠系统中的负调节剂。该提案的目的是确认VISTA也作为人体免疫的负调节剂发挥作用。研究将确定淋巴细胞和骨髓细胞群体上的VISTA表达。功能研究将确定VISTA依赖性信号对T细胞增殖、效应子功能和分化的影响。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的治疗潜力提供有价值的见解。 已显示VISTA-Ig的不溶性形式在体内抑制T细胞应答。这些结果表明，目前未定义的受体的参与导致免疫调节。我们将开发VISTA-Ig的多聚体可溶形式作为潜在的治疗剂。我们将在体外测试它们调节T细胞反应的能力。 靶向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中的记录活性以及我们在MS药物开发方面的经验，我们选择MS作为开发的第一个适应症。 在满足该I期STTR的成功标准后，II期STTR项目将开发领先的VISTA激动剂作为治疗复发/缓解型MS的免疫抑制药物。 公共卫生相关性：VISTA是最近发现的免疫功能负检查点调节剂。在鼠模型中的研究已证明阻断VISTA依赖性信号可增强自身免疫。该项目将表征VISTA在人类免疫系统中的表达和功能，并测试可溶性多聚体形式的VISTA-Ig作为激动剂。我们相信，VISTA通路的参与有可能被利用作为一种新的治疗广泛的自身免疫性疾病，包括多发性硬化症。