Therapeutic Vaccine for Asthma

哮喘治疗疫苗

基本信息

批准号：
7538915
负责人：
Peter Blackburn
金额：
$ 30万
依托单位：
MERCIA PHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-22 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7538915
关键词：
Active Immunization Address Adjuvant Adult Adverse effects Affect Allergens Allergic Allergic rhinitis American Animal Model Antibodies Antibody Formation Antigens Applications Grants Asthma Attenuated Autoimmunity Biological Biological Assay Bronchial Hyperreactivity CCL11 gene CCL24 gene Cell-Mediated Cytolysis Cells Characteristics Child Childhood Chronic Chronic Disease Chronic lung disease Class Clinical Clinical Management Clinical Trials Colorectal Cancer Conjugate Vaccines Data Development Diphtheria Toxoid Disease Disease Progression Dose Eotaxin Epitopes Extrinsic asthma Family Functional disorder Gastrins Goals Healthcare Hormones Hyperplasia Immune system Immunotherapeutic agent In Vitro Individual Inflammatory Interleukin-13 Interleukin-5 Legal patent Lung Lung diseases Malignant neoplasm of prostate Mediator of activation protein Methodology Mucous body substance Mus Pancreas Patients Peptides Phase Phenotype Play Prevalence Public Health Recombinants Resolution Role Safety Screening procedure Secondary Immunization Small Business Technology Transfer Research Small inducible cytokine A24 Stomach System Technology Testing Therapeutic Therapeutic Effect Thinking Tissues Toxicology Vaccinated Vaccination Vaccines airway inflammation airway remodeling base beta-Chemokines chemokine concept cost crosslink cytokine design design and construction eosinophil immune self tolerance immunogenic in vivo mortality mouse model neutralizing antibody novel novel strategies novel vaccines pre-clinical prevent response success therapeutic vaccine vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic lung disease affecting some 150 million people worldwide. An estimated 20.3 million Americans have asthma, of which 6.3 million are children. The current therapeutic approaches for the treatment of asthma, whose prevalence and mortality are increasing, have had limited impact on clinical management and resolution of the disorder. The eotaxin family of CC chemokines and the pro- inflammatory cytokines, IL-5 and IL-13, have been shown to specifically direct and orchestrate many of the characteristic features of the disease, namely airway inflammation, bronchial hyper-reactivity and airway remodeling. The study is designed to provide proof-of-concept for the development of an immunotherapeutic vaccine for the treatment of asthma and other allergic diseases. Our novel vaccination strategy of active immunization with a multi-epitope construct formulated in Mercia's proprietary adjuvant/delivery system, MAS-1, aims to induce the host's own immune system to generate endogenous antibodies to simultaneously neutralize the asthma targets eotaxins, IL-5 and IL-13. Mercia's preliminary data have shown the efficacy and safety of this proprietary vaccine approach to neutralize secreted hormones. Significantly, preliminary data obtained from clinical trials show that this strategy does not induce autoimmunity to endogenous soluble mediators, and that the antibody titers wane when booster immunizations are discontinued. Our strategy to select the optimal immunogenic constructs involves the active immunization of mice with the peptide conjugates in MAS-1 adjuvant followed by in vivo and in vitro functional assays to show that neutralizing antibodies are induced and capable of inhibiting the biological activity of the respective recombinant murine chemokines/cytokines. Selected conjugated vaccine constructs are evaluated for therapeutic potential in a mouse model of asthma. Mice are first sensitized and challenged with an allergen, then vaccinated with the immunogenic constructs in MAS-1, followed by challenge with allergen. This proof of concept study aims to test the hypothesis that therapeutic vaccination will produce neutralizing antibodies that concertedly reduce the bioactivity of eotaxins, IL-5 and IL-13 attenuating the allergen-induced asthma phenotype, namely bronchial hyper-responsiveness, airways inflammation and mucus secretion. PUBLIC HEALTH RELEVANCE: Asthma constitutes a significant healthcare problem in the U.S with about one in twenty Americans, or nearly 20 million people, suffering from this chronic inflammatory disorder of the airways, estimated to cost the US $27.6 billion annually. A therapy that addresses the underlying cause of the disease and prevents disease progression would provide a significant benefit to the patient. The proposed therapeutic vaccine targeting key mediators, shown to be important in the disease, could help fulfil this need.

描述（由申请人提供）：哮喘是一种慢性肺部疾病，影响了全球约1.5亿人。估计有2030万美国人患有哮喘，其中630万是儿童。当前的治疗哮喘治疗方法的患病率和死亡率正在增加，对疾病的临床管理和解决方案的影响有限。 CC趋化因子的eotaxin家族以及促炎性细胞因子IL-5和IL-13已被证明可以特异性直接和策划该疾病的许多特征，即气道炎症，支气管炎症，支气管高反应性和气道重塑。该研究旨在为开发免疫治疗疫苗的概念证明，以治疗哮喘和其他过敏性疾病。我们在Mercia专有的辅助/递送系统MAS-1中使用多种蛋白质构建体进行主动免疫的新型疫苗接种策略，旨在诱导宿主自己的免疫系统，以产生内源性抗体，同时中和哮喘靶标Eotaxinss eotaxinss eotaxinss EL-5和IL-13。 Mercia的初步数据表明，这种专有疫苗方法的功效和安全性可以中和分泌的激素。值得注意的是，从临床试验获得的初步数据表明，该策略不会引起内源性可溶性介质的自身免疫性，并且当停止增强免疫接种时，抗体滴度会减弱。我们选择最佳免疫原性构建体的策略涉及小鼠与MAS-1辅助物中的肽结合物的主动免疫接种，然后进行体内和体内功能测定，以表明中和抗体是诱导并能够抑制相应重组鼠类趋化因子/细胞因子的生物学活性的能力。在小鼠哮喘模型中评估选定的共轭疫苗构建体的治疗潜力。首先用过敏原对小鼠进行敏感和挑战，然后用MAS-1中的免疫原性接种，然后对过敏原进行挑战。这项概念研究旨在检验以下假设：治疗性疫苗接种将产生中和抗体，从而协同降低eotaxins，IL-5和IL-13的生物活性，从而减轻过敏原诱导的哮喘表型，即支气管炎症性过高，炎症和mucus serigams和mcus。公共卫生相关性：在美国，哮喘构成了一个重大的医疗保健问题，大约有二十个美国人，即近2000万人，患有这种慢性炎症性疾病，估计每年耗资276亿美元。一种解决疾病根本原因并防止疾病进展的疗法将为患者带来重大好处。拟议的治疗性疫苗靶向主要介质在疾病中很重要，可以帮助满足这一需求。