Response-Selective C5a Agonist for the Treatment of Asthma

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，其重点是疾病的潜在原因，而不仅仅是治疗或控制其症状。至少一个被广泛接受的哮喘病理生理表达的潜在因素是对各种环境抗原的过度表达和失调的辅助性T型2 （Th2）介导的免疫反应。最近的研究表明，促炎补体衍生成分C5a在调节气道中Th2主导的反应中发挥重要作用，以维持适当的Th1/Th2免疫平衡。这些研究表明，C5a与携带C5a受体（C5aR）的气道树突状细胞（DC）结合，从而下调这种Th2反应，显然，允许表达和维持有益的Th1/Th2平衡。因此，一种潜在的哮喘治疗方法是使用C5a模拟物，通过选择性地参与携带c5ar的气道dc来上调Th1细胞因子，以此来重建和维持这种有益的Th1/Th2平衡，但不参与携带c5ar的气道浸润性炎症细胞。为此，一种被称为EP67的C5a反应选择性激动剂已经被开发出来。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将EP67推向商业化的道路，使其成为一种安全有效的治疗人类哮喘的方法。该I期研究的主要目标是在已建立的哮喘小鼠模型中证明EP67在体内的潜在保护作用，这是实现这一目标的关键一步。这一目标将通过以下具体目标来实现：1)利用小鼠急性过敏原攻击模型，证明EP67在预防th2偏置气道炎症和AHR诱导方面的治疗效果；2)利用小鼠慢性过敏原暴露模型，验证EP67在逆转气道炎症和AHR方面的治疗效果。EP67的使用是重要的，因为它介导了免疫有益Th1/Th2环境的建立，因此，通过选择性地增强C5a的有益作用而不是不加选择地阻断其有害作用，提供了一种安全有效的方法来解决疾病的根本原因，从而可能对哮喘的治疗产生积极影响。EP67的其他特性支持其作为哮喘治疗的商业候选药物的创新用途，包括：1)经济且易于大量和高纯度生产；2)常温下的长期（年）稳定性；3)在水中的高溶解度；4)鼻内给药的便利性；5)它没有毒性。

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.