Safety and efficacy of an allergy therapeutic targeting FcERI bound IgE in human immune reconstituted mice.

皮安德鲁·萨克森医学博士 摘要：SBIRI应用的目标是完成关键的“长期”安全性和有效性时间进程。 预防治疗ALS/IgE介导性食物过敏的新型生物制剂的研究 反应和肥大细胞增多症。过敏性疾病，特别是严重的食物过敏，已经增加到 成为一个主要的世界性公共卫生问题，特别是在美国和其他发达国家 国家。目前，针对这类过敏的有效的新治疗选择仍然是一个尚未得到满足的主要需求；没有 对于各种各样的严重食物过敏(如花生、鸡蛋、牛奶等过敏)，都有有效的治疗方法。 我们的方法独特地采用了低亲和力过敏反应抑制(LAI)，其形式是仔细的 设计了针对人嗜碱性粒细胞和肥大细胞上FcεRI结合的Ig E的单抗(LARI E59)。 LARI E59的结合和释放功能阻断了三种不同的致敏反应的诱导 效果。LARI治疗被设计为泛变应原有效，并对所有由IgE引起的食物过敏有效。 此外，拉瑞因其独特的作用机制已被授予治疗孤儿药物的称号 FDA的肥大细胞增多症。我们已经进行了广泛的概念验证研究，证明了Lari 通过快速抑制Key Immediate的活性，显示出对过敏反应的有效阻断作用 过敏效应细胞：嗜碱性粒细胞和肥大细胞，而大剂量的LARI不能触发过敏反应 脱颗粒。然而，两个关键问题仍然存在：(1)重复使用Lari是否安全？(2)什么 拉瑞的疗效是时程的吗？本提案旨在具体回答这些问题 利用现有的人CD34干细胞重组的复杂免疫缺陷小鼠提出的问题 制造IgE的细胞。为了确定重复注射LARI重组NSG-SMS小鼠的安全性， Express人免疫球蛋白E将在一段时间内注射四次LAI，这代表着在 在人类身上大约6个月的时间进程。在每个时间点，都会对老鼠进行仔细的证据评估 过敏反应。为了确定LARI，重组NSG-SMS小鼠的疗效的时间进程， 通过灌胃对花生敏感，将用Lari处理，然后在第7天、第14天或 治疗后21例。这将在大约一个月、两个月和三个月后在人类身上测试LARI的疗效。 在完成这些建议的研究后，我们将回答剩下的两个关键问题，因为 拉里斯有可能成为一种安全有效的治疗方法。

PI - Andrew Saxon MD Abstract: The goal of this SBIRI application is to accomplish key “long term” safety and efficacy time-course studies of a novel biologic designed for the preventive treatment of all severe/IgE mediated food allergic reactions and mastocytosis. Allergic diseases and specifically severe food allergies have increased to the point of becoming a major worldwide public health problem, particularly in the US and other developed countries. Currently, effective novel treatment options for such allergies remain a major unmet need; no effective therapy is available for the broad array of severe food allergies (e.g. peanut, egg, milk etc. allergy). Our approach uniquely employs Low-affinity Allergy Response Inhibition (LARI) in the form of a carefully designed monoclonal antibody (LARI E59) that targets FcεRI-bound IgE on human basophils and mast cells. The binding and release of LARI E59 functionally blocks the induction of allergic reactions by three distinct effects. LARI treatment is designed to be pan-allergen effective and work for all IgE driven food allergies. Additionally, LARI, because of its unique mechanism of action has been granted orphan drug designation for mastocytosis by the FDA. We have performed extensive proof-of-concept studies that demonstrate that LARI exhibits a potent blocking effect on allergic reactivity by rapidly inhibiting the activity of the key immediate allergic effector cells: basophils and mast cells while far higher doses of LARI fail to trigger anaphylactic degranulation. However, two key questions remain (1) Will repeated administration of LARI be safe? (2) What is the time course of the therapeutic effect of LARI? This proposal is designed to specifically answer these questions utilizing the now available complex immunodeficient mice reconstituted with human CD34+ stem cells that make IgE. To determine the safety of repeated injections of LARI reconstituted NSG-SMS mice that express human IgE will be injected four times with LARI over a time course that represents treatments over an approximate 6 month time course in humans. At each time point, mice will be carefully evaluated for evidence of allergic reactivity. To determine the time course for the efficacy of LARI, reconstituted NSG-SMS mice, sensitized to peanut by gavage, will be treated with LARI and then challenged with peanut at day +7, +14 or +21 after the treatment. This would test the efficacy of LARI after about one, two and three months in humans. Having accomplished these studies proposed, we will have answered two key remaining questions as the LARIs potential as a safe and effective therapeutic.