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）：高达30%的美国人口现在受到鼻过敏的影响，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世界各地的主要组成部分。目前用于AR的药物和特异性免疫疗法的局限性包括其副作用以及与其使用相关的时间、精力和成本。该I期项目的目标是探索一种全新的预防季节性AR的模式，采用基于抗体的鼻腔预防剂，仅在患者知道他们将暴露于大量特定过敏原时使用。该项目建立在我们的NIAID资助的山雪松过敏实验模型系统。使用该模型，我们发现~90%的患者的抗山雪松花粉的IgE与单一过敏原Jun α 1的构象表位结合，并且独特的单克隆抗体（E58）导致Jun α 1上的这些构象表位的大量丢失。此外，E58的结合广泛地减少了过敏介质从用人IgE致敏并用Jun α 1激发的肥大细胞的释放。因此，我们开发了一个由临床和基础研究人员组成的多学科学术企业团队，他们具有专业知识，以确定开发E58作为一种新型治疗药物的可行性，以使季节性花粉症患者受益。该项目属于NIAID STTR感兴趣的领域。本1期项目的目标是确定经鼻滴注生物工程重组E58（rE 58）是否能预防急性鼻气道阻塞和其他过敏性炎症体征。具体目标是：1）完成重组E58抗体（rE 58）的优化，以增强亲合力和表达水平以及下调Jun al反应性的活性，并将rE 58表达为单价的部分人源化抗体。2)在我们的雪松花粉症小鼠模型中测试鼻内滴注不同剂量的rE 58抗体在预防或基本上减少对随后鼻暴露于山雪松花粉的过敏反应中的功效。阳性I期结果将提供“概念证明”，即经鼻滴注优化的抗体可以在吸入的过敏原和患者鼻粘膜中的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，在II期研究中，我们将：a）生产和测试rE 58抗体的潜在商业制剂和递送方法，以优化快速起效和延长作用持续时间; B）在GLP合规性设施中验证疗效和安全性研究;以及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导致类似的基于抗过敏原的治疗方法用于季节性AR的其他原因。 公共卫生相关性：过敏性鼻炎（AR）已成为工业化国家最常见的慢性疾病之一，尽管每年花费数十亿美元用于治疗，但许多症状并未完全缓解。我们已经发现，一种特异性单克隆抗体rE 58减少过敏原-IgE相互作用，并提出滴注这种抗体的鼻粘膜可能会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模式的可行性，如果成功，可能会导致一类新的抗过敏抗体药物。