Broadly neutralizing(BN) pan-IgE supersite vaccine for allergic asthma

用于过敏性哮喘的广泛中和 (BN) 泛 IgE 超级疫苗

• 批准号: 9341882
• 负责人: Swey-Shen Chen
• 金额: $ 81.35万
• 依托单位: IGE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341882
• 关键词: Active Immunization; Adult asthma; Affinity; Allergens; Allergic; Amino Acid Sequence; Anaphylaxis; Antibodies; Antigen-Antibody Complex; Asthma; B-Lymphocytes; Basophilic Cell; Binding; Blocking Antibodies; Blood Circulation; CD4 Positive T Lymphocytes; Cell Line; Cells; Child; Chronic; Collaborations; Competence; Complex; Dendritic Cells; Dictyoptera; Diffusion; Down-Regulation; Drug Industry; Ensure; Epithelial Cells; Epitopes; Excision; Exhibits; Extrinsic asthma; Half-Life; Household; Human; Hypersensitivity; Hypersensitivity skin testing; IgE; IgE Receptors; Imiquimod; Immunization; Immunoglobulin A; Immunoglobulin G; Inflammation; Inflammatory; Location; Lung; Macaca; Macaca mulatta; Mediating; Mediator of activation protein; Modality; Modeling; Molecular Conformation; Mus; Muscle Cells; Natural Immunity; Pathogenicity; Patients; Phase; Play; Product Approvals; Pyroglyphidae; Recovery; Reporting; Rest; Reticuloendothelial System; Risk; Rodent; Rodent Model; Route; Safety; Saline; Scaffolding Protein; Secretory Immunoglobulin A; Seminal; Serum; Source; Syndrome; Testing; Therapeutic; Time; Tissues; Translations; Ursidae Family; Urticaria; Vaccinated; Vaccination; Vaccines; Xolair; airway inflammation; asthmatic; asthmatic patient; base; cost; dander; eosinophil; immunogenic; immunogenicity; improved; inner city; innovation; mast cell; neutrophil; omalizumab; prevent; receptor binding; respiratory smooth muscle; response; subcutaneous; thermostability; vaccine efficacy; vaccine evaluation

ABSTRACT/SUMMARY Immunoglobulin E (IgE) in the lung plays a key role in allergic asthmatic inflammation. Asthmatic patients also exhibit elevated serum IgE levels, which may re-equilibrate with the lung IgE pool or enhance IgE-mediated allergic asthma. A seminal finding of IgE downregulation by active IgE immunization was first reported in our lab. This led to the product concept of the mAb omalizumab, and a subsequent collaboration with the pharmaceutical industry led to FDA approval of the XolairÒ. In the proposed project, the native conformation of receptor-binding IgE loops (e.g., the XolairÒ binding FG loop epitope) are conformationally constrained in a selected thermostable b-strand pair (dubbed super-b strands) and then fused to an immunogenic and thermostable protein scaffold as a bifunctional vaccine. The use of ImiquimodÔ(IMQ, 3M, Inc.) through a safe transcutaneous route of administration, followed by vaccine IN challenge in saline, ensures that mucosal IgA and IgG subclass anti-IgE antibodies target asthmogenic lung IgE as well as the removal of serum IgE by systemic anti-IgE antibodies. This specific targeting improves safety, and is unlikely to cause type 2 hypersensitivity or chronic urticaria. In the absence of a vaccine reboost, emerging anti-IgE producing B-cells are naturally tolerized by the endogenous self-IgE recovered during the rest period as another safety feature. A “just-in-time” vaccine reboost is required to break self-IgE tolerance to protect against allergen re-exposure. The lack of persistent IgE suppression preserves IgE competence for parasitic defenses. Our three aims are: Aim 1: Study immunogenicity of human FG supersite vaccine in rodents: location, duration, and efficacies. Aim 2: Evaluate therapeutic vaccination in alleviating IgE-mediated asthmatic inflammation and AHR in rodent models. Aim 3: Evaluate therapeutic vaccination in alleviating IgE-mediated asthmatic inflammation and AHR in rhesus macaques.

摘要/总结 肺中的免疫球蛋白E（IgE）在过敏性哮喘炎症中起关键作用。哮喘患者也 表现出升高的血清IgE水平，这可能与肺IgE库重新平衡或增强IgE介导的 过敏性哮喘主动IgE免疫导致IgE下调的开创性发现在我们的研究中首次报道。 实验室这导致了mAb奥马珠单抗的产品概念，以及随后与 制药行业导致FDA批准了Xolairiritol。 在拟议的项目中，受体结合IgE环的天然构象（例如，Xolairelavin结合FG 环表位）在构象上被限制在所选择的热稳定b链对（称为超级b 链），然后融合到免疫原性和热稳定的蛋白质支架上作为双功能疫苗。的 使用咪喹莫司汀（IMQ，3 M，Inc.）通过安全的经皮给药途径， IN盐水激发，确保粘膜伊加和IgG亚类抗IgE抗体靶向致喘性肺 IgE以及通过全身性抗IgE抗体清除血清IgE。这种针对性提高了 安全，不太可能引起2型超敏反应或慢性荨麻疹。在没有疫苗再加强的情况下， 新生的产生抗IgE的B细胞自然地被在免疫过程中恢复的内源性自身IgE耐受， 休息时间作为另一个安全功能。需要“及时”疫苗再加强以打破自身IgE耐受性， 防止过敏原再次暴露。缺乏持续的IgE抑制保留了IgE的能力， 寄生防御 我们的三个目标是： 目的1：研究人FG超级位点疫苗在啮齿动物中的免疫原性：位置、持续时间和免疫原性。 功效 目的2：评价治疗性疫苗接种在减轻IgE介导的哮喘炎症和AHR中的作用。 啮齿动物模型。 目的3：评价治疗性疫苗接种在减轻IgE介导的哮喘炎症和AHR中的作用。 恒河猴