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

摘要/摘要 肺内免疫球蛋白E(IgE)在过敏性哮喘炎症中起关键作用。哮喘患者也 表现为血清IgE水平升高，这可能与肺IgE池重新平衡或增强IgE介导的 过敏性哮喘。我们首次报道了一项由主动免疫引起的IgE下调的开创性发现。 实验室。这导致了单抗omalizumab的产品概念，并随后与 制药行业促使FDA批准了Xolair？ 在拟议的项目中，受体结合IgE环的天然构象(例如，Xolair结合FG 环表位)在选择的耐热b-链对(称为超b)中构象受限 链)，然后融合到免疫原性和耐热的蛋白质支架上，作为双功能疫苗。这个 Imiquimod‘(ImQ，3M，Inc.)的使用通过安全的经皮给药途径，然后是疫苗 在生理盐水中激发，确保粘膜中的IgA和IgG亚类抗IgE抗体靶向致喘性肺 免疫球蛋白E以及全身抗IgE抗体对血清IgE的清除作用。这一特定的目标改进了 安全性高，不太可能导致2型超敏反应或慢性荨麻疹。在没有疫苗补种的情况下， 新出现的产生抗IgE的B细胞自然地被内源性自身IgE耐受 休息期是另一个安全特征。需要“及时”重新接种疫苗，以打破自身对IgE的耐受性 防止过敏原再次暴露。缺乏持续性的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超位疫苗在啮齿动物体内的免疫原性：位置、持续时间和 药效。 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。

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.