Prevention of Allergic Rhinitis with Topical Immunomodulating Antibodies

描述（由申请人提供）：高达30%的美国人口现在受到鼻腔过敏的影响，导致每年的总（直接和间接）成本约为146亿美元。季节性过敏性鼻炎（AR），由于暴露于空气中的花粉和霉菌是这个问题在美国和全世界的一个主要组成部分。目前治疗AR的药物和特异性免疫疗法的局限性包括它们的副作用以及与它们的使用相关的时间、精力和成本。这个I期项目的目标是探索一种预防季节性AR的全新范例，采用基于抗体的鼻腔预防性药物，只有当患者知道他们将暴露于大量特定过敏原时才使用。这个项目建立在我们niaid资助的山雪松过敏实验模型系统的基础上。使用该模型，我们发现约90%的患者针对雪松花粉的IgE与单一过敏原Jun a 1的构象表位结合，并且一种独特的单克隆抗体（E58）导致Jun a 1上这些构象表位的广泛丢失。此外，E58的结合广泛地减少了受人IgE致敏和受Jun a 1攻击的肥大细胞中过敏介质的释放。因此，我们建立了一个由临床和基础研究人员组成的多学科、学术和企业团队，他们具有专业知识，以确定开发E58作为一种新的治疗方法的可行性，以造福季节性花粉症患者。该项目属于NIAID str感兴趣的领域。本一期项目的目的是确定经鼻注入生物工程重组E58 （rE58）是否能预防急性鼻气道阻塞和其他过敏性炎症症状。具体目的是：1)优化重组E58抗体（rE58），提高其亲和度、表达水平和下调Jun a1反应活性，并将rE58表达为一价部分人源化抗体。2)在我们的雪松花粉症小鼠模型中测试鼻内注射不同剂量的rE58抗体对预防或显著减少随后鼻接触山雪松花粉的过敏反应的效果。I期阳性结果将提供“概念证明”，即经鼻腔滴注的优化抗体可以在吸入的过敏原和患者鼻黏膜中的IgE抗体之间提供有效的“屏障”。此外，这些结果将为II期研究奠定基础，我们将；a)生产和测试rE58抗体的潜在商业配方和递送方法，以优化快速起效和延长效果的持续时间；b)验证符合GLP的设施的有效性和安全性研究；c)启动FDA讨论并提交IND申请以启动临床试验。该产品的最终成功可能会导致类似的基于抗过敏原的治疗方法用于其他原因的季节性AR。

DESCRIPTION (provided by applicant): Up to 30% of the US population are now affected by nasal allergy, resulting in a total (direct and indirect) cost of approximately $14.6 billion per year. Seasonal allergic rhinitis (AR), due to exposure to airborne pollen and molds is a major component of this problem in the US and worldwide. The limitations of current pharmaceutical and specific immunotherapy for AR include their side-effects and the time, effort and cost associated with their use. The goal of this Phase I project is to explore an entirely new paradigm for preventing seasonal AR, employing an antibody-based, nasal prophylactic to be used only when patients know they will be exposed to large quantities of specific allergens. This project builds upon our NIAID-funded experimental model system of mountain cedar allergy. Using this model, we discovered that ~90% of patients' IgE against mountain cedar pollen binds to conformational epitopes of a single allergen Jun a 1 and that a unique monoclonal antibody (E58) causes extensive loss of these conformation epitopes on Jun a 1. Further, the binding of E58 extensively reduces of the release of allergic mediators from mast cells sensitized with human IgE and challenged with Jun a 1. We have therefore developed a multidisciplinary, academic-corporate team of clinical and basic investigators with expertise to determine the feasibility of developing E58 as a novel therapeutic to benefit seasonal pollinosis sufferers. This project is within an NIAID STTR Area of Interest. The goal of this Phase 1 Project is to determine whether nasal instillation of bioengineered, recombinant E58 (rE58) will prevent the acute nasal airway obstruction and other signs of allergic inflammation. The Specific Aims are to: 1) Complete the optimization of a recombinant E58 antibody (rE58) for enhanced avidity and expression level and down-modulatory activity on Jun a1 reactivity and express rE58 as a univalent, partially humanized antibody. 2) Test in our mouse model of cedar pollinosis the efficacy of intranasal instillations of varying doses of rE58 antibody in preventing or substantially reducing the allergic response to subsequent nasal exposure of mountain cedar pollen. Positive Phase I results will provide "proof of concept" that nasal instillation of optimized antibodies can provide an effective "barrier" between an inhaled allergen and patient's IgE antibodies in the nasal mucosa. Further, these results will lay the ground work for Phase II studies, in which we will; a) produce and test potential commercial formulations and methods of delivery of rE58 antibody to optimize rapid onset and prolonged duration of the effect; b) validate efficacy and safety studies in GLP compliant facilities; and c) initiate FDA discussions and submission of an IND application to initiate clinical trials. The ultimate success of this product may lead to similar anti-allergen based therapeutics for other causes of seasonal AR. PUBLIC HEALTH RELEVANCE: Allergic rhinitis (AR) has become one of the most common chronic diseases in industrialized countries, yet despite the billions of dollars spent each year on therapeutics, many symptoms are not fully relieved. We have discovered that a specific monoclonal antibody rE58 reduces allergen-IgE interactions and propose that instillation of this antibody to the nasal mucosa may prevent seasonal pollinosis-induced AR. This project will test the feasibility of this new paradigm for treating seasonal nasal allergy and if successful may lead to a new class of anti-allergy antibody drugs.