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Accelerated dissociation of IgE receptor complexes

IgE 受体复合物加速解离

基本信息

批准号：
10736917
负责人：
Theodore S Jardetzky
金额：
$ 46.34万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736917
关键词：
Acceleration Address Affinity Allergens Allergic Alpaca Ankyrin Repeat Antibodies Antigens B-Lymphocytes Basophils Binding Biological Biological Process Cell Degranulation Cell surface Cells Chronic Complement 3d Receptors Complex Coupled Critical Thinking Cryoelectron Microscopy Directed Molecular Evolution Disease Dissociation Dose Effector Cell Engineering Epithelial Cells Epitope Mapping Epitopes Equilibrium Excision Fc Receptor Hybrids IgE IgE Receptors Immune Immune response Immunity Immunization Immunoglobulin G Kinetics Lead Libraries Ligands Link Llama Low affinity IgE receptor Lysosomes Mediating Mediator Molecular Conformation Monoclonal Antibodies Patients Play Positioning Attribute Production Proteins Protocols documentation Reagent Receptor Signaling Regulation Research Resolution Role Route Signal Pathway Structure Surface Therapeutic Urticaria Variant Visualization Yeasts allergic response anti-IgE antibody engineering arm autoreactivity clinical application desensitization design design and construction inhibitor insight mast cell nanobodies neoplasm immunotherapy novel novel strategies receptor receptor binding reconstruction tool

项目摘要

Project Summary IgE antibodies and receptors are important mediators of the allergic cascade, but may also provide distinct functions in anti-tumor immunotherapy. IgE engages its high affinity IgE Fc receptor (FceRI) on mast cells and basophils as well as a low affinity receptor (FceRII/CD23) expressed on B cells and epithelial cells. IgE binding to FceRI sensitizes allergic effector cells to allergens and is very stable, with the complexes persisting for months even in the presence of potent anti-IgE antibodies. We have developed approaches to rapidly destabilizing IgE:FceRI complexes and desensitizing allergic effector cells using hybrid, bispecific IgG/DARPin molecules that recognize two distinct epitopes on the IgE-Fc. Here in Aim 1 we will explore alternative approaches to target and remove IgE:FceRI complexes from cell surfaces using novel bispecific anti-IgE antibodies. In addition, we will use two anti-IgE antibodies that we have produced to gain greater insights into the structure and dynamics of intact IgE. The IgE interaction with CD23 also mediates important biological effects in B cells, together with CD21. Here, in Aim 2, we will use yeast display to evolve higher affinity variants of CD23 for its ligands to enable structural studies of these complexes and to probe CD23-dependent regulation of IgE production by B cells. Finally, in Aim 3, we seek to isolate and study new anti-FceRIa antibodies using yeast display, to develop novel reagents for the FceRI-directed modulation of allergic effector cell activities.

项目概要 IgE 抗体和受体是过敏级联反应的重要介质，但也可能提供独特的作用在抗肿瘤免疫治疗中发挥作用。 IgE 与肥大细胞上的高亲和力 IgE Fc 受体 (FceRI) 结合，嗜碱性粒细胞以及 B 细胞和上皮细胞上表达的低亲和力受体 (FceRII/CD23)。 IgE 结合 FceRI 使过敏效应细胞对过敏原敏感，并且非常稳定，复合物持续存在即使存在有效的抗 IgE 抗体，也能维持数月的时间。我们已经开发出快速的方法使用混合双特异性 IgG/DARPin 破坏 IgE:FceRI 复合物的稳定性并使过敏效应细胞脱敏识别 IgE-Fc 上两个不同表位的分子。在目标 1 中，我们将探索替代方案使用新型双特异性抗 IgE 靶向并去除细胞表面 IgE:FceRI 复合物的方法抗体。此外，我们将使用我们生产的两种抗 IgE 抗体来更深入地了解完整 IgE 的结构和动力学。 IgE 与 CD23 的相互作用也介导重要的生物学功能与 CD21 一起对 B 细胞产生影响。在目标 2 中，我们将使用酵母展示来进化更高亲和力的变体 CD23 的配体，以便能够研究这些复合物的结构并探测 CD23 依赖性 B 细胞 IgE 产生的调节。最后，在目标 3 中，我们寻求分离和研究新的抗 FceRIa 使用酵母展示的抗体，开发用于 FceRI 定向调节过敏效应子的新型试剂细胞活动。