Response-Selective C5a Agonist for the Treatment of Asthma

描述（由申请方提供）：过敏性哮喘治疗中未满足的需求是一种有效的治疗策略，其重点是疾病的根本原因，而不仅仅是治疗或管理其症状。哮喘的病理生理学表达的至少一个公认的潜在贡献者是对各种环境抗原的过度表达和失调的辅助性T细胞2型（Th 2）介导的免疫应答。最近的研究表明，促炎性补体衍生组分C5 a在调节气道中的这种Th 2主导的应答以维持适当的Th 1/Th 2免疫平衡中起重要作用。这些研究表明，C5 a以下调这种Th 2应答的方式与携带C5 a受体（C5 aR）的气道树突状细胞（DC）接合，并且显然允许有益的Th 1/Th 2平衡的表达和维持。因此，哮喘的潜在治疗方法是使用能够通过选择性接合携带C5 aR的气道DC而上调Th 1细胞因子的C5 a模拟物，作为重建和维持这种有益的Th 1/Th 2平衡的方式，但不接合携带C5 aR的气道浸润炎性细胞。为此，已经开发了称为EP 67的C5 a的反应选择性激动剂。EP 67激活携带C5 aR的DC以释放Th 1细胞因子，但缺乏任何激活携带C5 aR的炎性中性粒细胞的能力。该项目的长期目标是使EP 67沿着商业化途径发展，使其成为治疗人类哮喘的安全有效的方法。这项I期研究是实现这一目标的关键一步，其主要目的是证明EP 67在完善的人类相关小鼠哮喘模型中的体内潜在保护作用。该目的将通过以下具体目的来实现：1）利用小鼠中的急性过敏原攻击模型来证明EP 67在预防诱导Th 2偏向的气道炎症和AHR中的治疗功效;和2）利用小鼠中的慢性过敏原暴露模型来证明EP 67在逆转已建立的气道炎症和AHR中的治疗功效。EP 67的这种使用是重要的，因为它介导免疫学上有益的Th 1/Th 2环境的建立，并且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而对哮喘的治疗产生积极影响，该方法通过选择性地增强C5 a的有益作用而不是不加选择地阻断其有害作用来解决疾病的根本原因。支持其作为治疗哮喘的商业候选物的创新用途的EP 67的其他特征包括：1）其大量和高度纯化的量的经济性和容易性; 2）其在室温下的长期（年）稳定性; 3）其在水中的高溶解度; 4）其易于鼻内施用;和5）其无毒性。

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.