Prevention of Allergic Rhinitis with Topical Immunomodulating Antibodies

描述(由申请人提供)：目前高达30%的美国人口受到鼻过敏的影响，导致每年的总成本(直接和间接)约为146亿美元。季节性过敏性鼻炎(AR)，由于暴露在空气中的花粉和霉菌，在美国和世界范围内是这个问题的主要组成部分。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使用它们相关的时间、精力和成本。这个第一阶段项目的目标是探索一种全新的预防季节性AR的范例，采用一种基于抗体的鼻腔预防药物，只有在患者知道他们将接触大量特定过敏原的情况下才使用。这个项目建立在我们由NIAID资助的山地雪松过敏实验模型系统的基础上。利用这个模型，我们发现约90%的患者抗雪松花粉的IgE与单一变应原Jun A 1的构象表位结合，而一个独特的单抗(E58)会导致Jun A 1上这些构象表位的广泛丢失。此外，E58的结合大大减少了用人IgE致敏并与Jun A 1挑战的肥大细胞释放过敏介质。因此，我们建立了一支由具有专业知识的临床和基础研究人员组成的多学科、学术-企业团队，以确定将E58开发为一种新的治疗方法的可行性，以造福季节性花粉症患者。该项目位于NIAID STTR感兴趣的区域内。这一阶段项目的目标是确定鼻腔滴注生物工程重组E58(RE58)是否可以预防急性鼻腔阻塞和其他过敏性炎症迹象。具体目的是：1)完成重组E58抗体(RE58)的优化，以提高亲和力、表达水平和下调Jun A1反应性的活性，并将rE58表达为单价、部分人源化的抗体。2)在我们的雪松花粉症小鼠模型中，测试鼻内滴注不同剂量的rE58抗体的有效性，以防止或显著减少随后经鼻暴露的雪松花粉的过敏反应。第一阶段的阳性结果将提供“概念证明”，即鼻腔注射优化的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，这些结果将为第二阶段研究奠定基础，在这些研究中，我们将：a)生产和测试潜在的商业制剂和rE58抗体的输送方法，以优化效果的快速起效和延长持续时间；b)在符合GLP标准的设施中验证有效性和安全性研究；以及c)启动FDA的讨论并提交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疗法来治疗季节性AR的其他原因。 公共卫生意义：变应性鼻炎(AR)已成为工业化国家最常见的慢性病之一，尽管每年在治疗上花费数十亿美元，但许多症状并未完全缓解。我们发现，一种特定的单抗rE58可以减少变应原-IgE的相互作用，并建议将这种抗体滴注到鼻黏膜可以防止季节性花粉症诱导的AR。该项目将测试这种治疗季节性鼻过敏的新范例的可行性，如果成功，可能会产生一种新的抗过敏抗体药物。

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.