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

PI - Andrew Saxon医学博士 翻译后摘要：这个SBIRI应用程序的目标是实现关键的“长期”安全性和有效性的时间过程 设计用于预防性治疗所有重度/IgE介导的食物过敏的新型生物制剂的研究 反应和肥大细胞增多症。过敏性疾病和特别严重的食物过敏已经增加到 成为一个主要的全球公共卫生问题，特别是在美国和其他发达国家， 国家目前，针对此类过敏症的有效的新型治疗选择仍然是一个主要的未满足的需求; 对多种严重食物过敏（例如花生、鸡蛋、牛奶等过敏）的有效治疗是可行的。 我们的方法独特地采用了低亲和力过敏反应抑制（LARI）的形式， 设计的单克隆抗体（LARI E59），靶向人嗜碱性粒细胞和肥大细胞上的Fcε RI结合IgE。 LARI E59的结合和释放在功能上阻断了三种不同的过敏反应的诱导。 方面的影响. LARI治疗被设计为泛过敏原有效，并适用于所有IgE驱动的食物过敏。 此外，LARI由于其独特的作用机制，已被授予孤儿药资格，用于 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LARI 通过快速抑制关键的速发型超敏反应的活性， 过敏效应细胞：嗜碱性粒细胞和肥大细胞，而更高剂量的LARI不能触发过敏反应 脱颗粒然而，仍然存在两个关键问题（1）LARI重复给药是否安全？(2)什么 LARI的治疗效果的时间过程是什么？本提案旨在具体回答这些问题 利用目前可用的用人CD 34+干细胞重建的复合免疫缺陷小鼠的问题 产生IgE的细胞为了确定重复注射LARI重建的NSG-SMS小鼠的安全性， 表达人IgE将在一个时间过程中用LARI注射四次，该时间过程代表在一个月内的治疗。 在人类中大约6个月的时间过程。在每个时间点，将仔细评估小鼠的证据 过敏性反应。为了确定LARI功效的时间过程，重构的NSG-SMS小鼠， 通过管饲法对花生致敏的小鼠，将用LARI处理，然后在第+7、+14或 治疗后+21这将测试LARI在人类中大约一个月、两个月和三个月后的功效。 完成这些研究后，我们将回答两个关键的遗留问题， LARIs可能是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.