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得到满足的需求是一种有效的治疗策略，它侧重于疾病的根本原因，而不仅仅是治疗或管理其症状。至少一个公认的哮喘病理生理表达的潜在贡献者是过度表达和失调的辅助性T细胞2型(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在调节这种以Th2为主的呼吸道反应以维持适当的Th1/Th2免疫平衡方面发挥着重要作用。这些研究表明，C5a以一种下调Th2反应的方式与C5a受体(C5aR)的呼吸道树突状细胞(DC)结合，显然允许表达和维持有益的Th1/Th2平衡。因此，一种潜在的治疗哮喘的方法是使用一种C5a模拟物，能够通过选择性地接触携带C5aR的气道DC来上调Th1细胞因子，作为重建和维持这一有益的Th1/Th2平衡的一种方式，但不接触携带C5aR的气道浸润性炎症细胞。为此，一种名为EP67的C5a反应选择性激动剂已经开发出来。EP67可激活含C5aR的DC释放Th1细胞因子，但缺乏激活含C5aR的炎性中性粒细胞的能力。该项目的长期目标是将EP67推向商业化的道路，使其成为治疗人类哮喘的安全有效的方法。这项第一阶段研究是追求这一目标的关键一步，其主要目标是在已建立的与人类相关的哮喘小鼠模型中证明EP67在体内的潜在保护作用。这一目标将通过以下具体目标来实现：1)利用急性过敏原攻击模型，证明EP67在预防Th2偏向的气道炎症和AHR方面的治疗效果；以及2)利用慢性过敏原暴露模型，证明EP67在逆转已建立的小鼠呼吸道炎症和AHR方面的治疗效果。EP67的这种使用意义重大，因为它有助于建立对免疫有益的Th1/Th2环境，因此可以通过提供一种安全有效的方法来解决疾病的根本原因，从而对哮喘的治疗产生积极影响，方法是选择性地增强C5a的有益作用，而不是不加区别地阻止其有害作用。支持EP67作为治疗哮喘的商业候选药物的创新用途的其他特点包括：1)大批量和高纯度生产的经济和易用性；2)它在室温下的长期(数年)稳定性；3)它在水中的高溶解性；4)它易于鼻腔给药；以及5)它的无毒性。

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.