Prevention of Allergic Rhinitis with Topical Immunomodulating Antibodies

使用外用免疫调节抗体预防过敏性鼻炎

• 批准号: 8201881
• 负责人: Randall M Goldblum
• 金额: $ 30万
• 依托单位: CHRYSALIS BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201881
• 关键词: Acute; Adverse effects; Affect; Allergens; Allergic; Allergic Disease; Allergic Reaction; Allergic inflammation; Allergic rhinitis; Anti-Allergic Agents; Antibodies; Area; Asthma; Avidity; Binding; Biological Models; Biomedical Engineering; Breathing; Businesses; Chronic Disease; Clinical; Clinical Trials; Costs and Benefits; Developed Countries; Development; Disease; Dose; Drug Formulations; Engineering; Enhancing Antibodies; Epitopes; Experimental Models; Exposure to; Facilities and Administrative Costs; Fermentation; Funding; Goals; Hay fever; Human; Hypersensitivity; IgE; Immune Targeting; Immune response; Immunotherapy; Intervention; Lead; Mediator of activation protein; Medical; Methods; Modeling; Molds; Molecular Conformation; Monoclonal Antibodies; National Institute of Allergy and Infectious Disease; Nose; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Poaceae; Pollen; Population; Prevalence; Prevention; Recombinants; Research; Research Personnel; Response Elements; Safety; Small Business Technology Transfer Research; Structure of mucous membrane of nose; Surface; Symptoms; System; Testing; Therapeutic; Time; Work; airborne allergen; airway obstruction; allergic response; base; clinical application; cost; humanized antibody; interest; mast cell; mouse model; multidisciplinary; novel; novel therapeutics; phase 2 study; prevent; prophylactic; research study; safety study; success; tree pollen

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.

描述（由申请人提供）：多达30％的美国人口受鼻过敏的影响，导致每年的总成本（直接和间接）约为146亿美元。由于暴露于空气传播的花粉和霉菌，季节性过敏性鼻炎（AR）是美国和全球该问题的主要组成部分。当前药物和特定免疫疗法对AR的局限性包括它们的副作用以及与使用相关的时间，精力和成本。该阶段I项目的目的是探索一种用于预防季节性AR的全新范式，仅当患者知道他们会暴露于大量特定的过敏原时，才使用基于抗体的鼻腔预防性。该项目建立在我们NIAID资助的山雪松过敏的实验模型系统上。使用该模型，我们发现约90％的患者对山雪松花粉的IgE与单个过敏原A 1的构象表位结合，而独特的单克隆抗体（E58）的独特的单克隆抗体（E58）会导致这些构象的广泛损失，从而导致a 1 a a 1的构型表位。此外，E58的季节均释放的媒体均具有较大的媒介剂量。因此，我们已经建立了一个具有专业知识的临床和基础研究人员的多学科，学术公司团队，以确定将E58作为一种新型治疗方法的可行性，以使季节性的粉丝症患者受益。该项目位于感兴趣的NIAID STTR领域。该第1阶段项目的目的是确定鼻腔滴注生物工程的重组E58（RE58）是否会防止急性鼻气道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，以增强自相形和表达水平以及对Jun A1反应性的调节活性，并表达RE58作为一种单价，部分人性化的抗体。 2）在我们的雪松花粉症的小鼠模型中测试了不同剂量的RE58抗体在预防或大大降低对随后鼻雪松花粉的鼻暴露的过敏反应方面的鼻内滴注的功效。积极的I阶段结果将提供“概念证明”，即鼻腔对优化抗体可以在鼻粘膜中吸入过敏原和患者的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工作。 a）生产和测试RE58抗体的潜在商业配方和递送的方法，以优化效果的快速发作和延长持续时间； b）在符合GLP的设施中验证功效和安全研究； 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的疗法，以实现其他季节性AR原因。 公共卫生相关性：过敏性鼻炎（AR）已成为工业化国家中最常见的慢性疾病之一，但是尽管每年花费了数十亿美元用于治疗疗法，但许多症状并未完全缓解。我们已经发现，特定的单克隆抗体RE58降低了过敏原相互作用，并提出将这种抗体滴入鼻粘膜可能会阻止季节性粉红细胞增多诱导的AR。该项目将测试这种新范式治疗季节性鼻过敏的可行性，如果成功的话，可能会导致一类新的抗过敏抗体药物。