Response-Selective C5a Agonist for the Treatment of Asthma

用于治疗哮喘的反应选择性 C5a 激动剂

• 批准号: 8121318
• 负责人: Jill A Poole
• 金额: $ 28.15万
• 依托单位: PROMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121318
• 关键词: Acute; Address; Agonist; Allergens; Allergic; Anaphylatoxins; Antigens; Asthma; Basophils; Bronchoconstriction; C5a anaphylatoxin receptor; Cells; Chronic; Complement; Complement 5a; Complex; Data; Dendritic Cells; Development; Disease; Environment; Equilibrium; Extrinsic asthma; Fibrosis; Goals; Human; IgE; Immune; Immune response; Immunologics; Inflammatory; Inflammatory Infiltrate; Intranasal Administration; Investigational New Drug Application; Lung; Lung Inflammation; Lys-Asp; Maintenance; Mediating; Mediator of activation protein; Methods; Mission; Modeling; Mus; Parents; Pathway interactions; Phase; Physiological; Play; Production; Public Health; Publications; Research; Role; Solubility; Staging; Stimulus; Symptoms; Technology; Temperature; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Water; Work; airway hyperresponsiveness; airway inflammation; airway remodeling; commercialization; cytokine; eosinophil; expectation; in vivo; innovation; meetings; mimetics; neutrophil; novel; novel strategies; phase 1 study; prevent; protective effect; protective efficacy; research study; response; success; therapeutic development; treatment strategy

DESCRIPTION (provided by applicant): An unmet need in the treatment of allergic asthma is an effective therapeutic strategy that focuses on an underlying cause of the disease rather than merely treating or managing its symptoms. At least one well- accepted underlying contributor to the pathophysiologic expression of asthma is an over-expressed and dysregulated T helper type 2 (Th2)-mediated immune response to various environmental antigens. Recent studies have shown that the pro-inflammatory, complement-derived component C5a plays an important role in regulating this Th2-dominated response in the airway in order to maintain a proper Th1/Th2 immune balance. These studies showed that C5a engages C5a receptor (C5aR)-bearing airway dendritic cells (DC) in such a way as to downregulate this Th2 response and, apparently, allow for the expression and maintenance of a beneficial Th1/Th2 balance. Thus, a potential treatment approach for asthma would be the use of a C5a mimetic capable of upregulating Th1 cytokines via selective engagement of C5aR-bearing airway DCs as a way to re-establish and maintain this beneficial Th1/Th2 balance, but without engagement of C5aR-bearing airway-infiltrating inflammatory cells. Toward this end, a response-selective agonist of C5a known as EP67 has been developed. EP67 activates C5aR-bearing DCs to release Th1 cytokines yet lacks any ability to activate C5aR-bearing inflammatory neutrophils. The long-term goal of this project is to move EP67 along a commercialization pathway toward its use as a safe and effective method for treating asthma in humans. The main objective of this Phase I study, which is a crucial step in pursuit of this goal, is to demonstrate the potential protective effects of EP67 in vivo in well-established and human-relevant murine models of asthma. This objective will be approached by the following specific aims: 1) To demonstrate therapeutic efficacy of EP67 in preventing the induction of the Th2-biased airway inflammation and AHR utilizing acute allergen challenge models in mice; and 2) to demonstrate therapeutic efficacy of EP67 in reversing established airway inflammation and AHR utilizing chronic allergen exposure models in mice. This use of EP67 is significant, because it mediates the establishment of an immunologically beneficial Th1/Th2 environment and, consequently, could have a positive impact on the treatment of asthma by providing a safe and effective method of addressing an underlying cause of the disease by selectively enhancing the beneficial effects of C5a rather than indiscriminately blocking its deleterious effects. Other features of EP67 that support its innovative use as a commercial candidate for the treatment of asthma include: 1) the economy and ease of its production in large and highly purified quantities; 2) its long-term (years) stability at room temperature; 3) its high solubility in water; 4) its ease of administration intranasally; and 5) its lack of toxicity. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will make available a convenient, effective, and unique way of treating allergic asthma - a disease that is on the rise worldwide. This disease target and treatment approach is relevant to the mission of the NIH that pertains to understanding the immunologic mechanisms responsible for allergic disorders and the development of therapeutics that could help treat these disorders.

描述（由申请人提供）：过敏性哮喘治疗中未满足的需求是一种有效的治疗策略，该策略侧重于疾病的根本原因，而不仅仅是治疗或控制其症状。哮喘病理生理学表达的至少一个被广泛接受的潜在因素是过度表达和失调的 2 型辅助 T (Th2) 介导的对各种环境抗原的免疫反应。最近的研究表明，补体衍生的促炎成分 C5a 在调节气道中以 Th2 为主的反应以维持适当的 Th1/Th2 免疫平衡方面发挥着重要作用。这些研究表明，C5a 以下调 Th2 反应的方式与携带 C5a 受体 (C5aR) 的气道树突细胞 (DC) 结合，显然允许表达和维持有益的 Th1/Th2 平衡。因此，哮喘的一种潜在治疗方法是使用能够通过选择性参与携带 C5aR 的气道 DC 来上调 Th1 细胞因子的 C5a 模拟物，作为重建和维持这种有益的 Th1/Th2 平衡的一种方式，但不参与携带 C5aR 的气道浸润炎症细胞。为此，开发了一种称为 EP67 的 C5a 反应选择性激动剂。 EP67 激活携带 C5aR 的 DC 释放 Th1 细胞因子，但缺乏激活携带 C5aR 的炎症中性粒细胞的能力。该项目的长期目标是推动 EP67 沿着商业化道路发展，成为治疗人类哮喘的安全有效的方法。这项 I 期研究的主要目的是在成熟的人类相关哮喘小鼠模型中证明 EP67 的潜在保护作用，这是实现这一目标的关键一步。该目标将通过以下具体目标来实现：1）利用小鼠急性过敏原激发模型，证明 EP67 在预防 Th2 偏向性气道炎症和 AHR 诱导方面的治疗功效； 2) 利用小鼠慢性过敏原暴露模型证明 EP67 在逆转已建立的气道炎症和 AHR 方面的治疗功效。 EP67 的这种用途意义重大，因为它介导了免疫学上有益的 Th1/Th2 环境的建立，因此，通过提供一种安全有效的方法来解决疾病的根本原因，通过选择性增强 C5a 的有益作用而不是不加选择地阻断其有害作用，可以对哮喘的治疗产生积极影响。 EP67 支持其作为治疗哮喘的商业候选药物的创新用途的其他特征包括：1) 经济且易于大批量、高纯度生产； 2）其在室温下的长期（年）稳定性； 3）其在水中的溶解度高； 4) 易于鼻内给药； 5）其无毒性。 公共健康相关性：拟议的研究与公共健康相关，因为它将提供一种方便、有效且独特的方法来治疗过敏性哮喘（一种在全球范围内呈上升趋势的疾病）。这种疾病目标和治疗方法与 NIH 的使命相关，该使命涉及了解过敏性疾病的免疫机制以及开发有助于治疗这些疾病的疗法。