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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.

项目摘要 Ige抗体和受体是过敏性级联反应的重要媒介，但也可能提供不同的在抗肿瘤免疫治疗中的作用。Ige与其高亲和力的Ig E Fc受体(FceRI)结合于肥大细胞并嗜碱性粒细胞和低亲和力受体(FceRII/CD23)表达于B细胞和上皮细胞。IGE绑定 TO FceRI使过敏效应细胞对变应原敏感，并且非常稳定，复合体持续时间为即使在存在强大的抗IgE抗体的情况下，也会持续数月。我们已经开发出方法来快速利用杂合双特异性Ig G/DARPin破坏IgE：FceRI复合体和脱敏变态反应细胞识别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新型双特异性抗IgE靶向和去除细胞表面IgE：FceRI复合体的研究抗体。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的IgE的结构和动力学。IgE与CD23的相互作用也介导了重要的生物学作用在B细胞中的作用，与CD21一起。在这里，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对其配体的CD23进行结构研究，并探索CD23依赖的 B细胞对免疫球蛋白E产生的调节。最后，在目标3中，我们试图分离和研究新的抗FceRIa 用酵母展示的抗体开发FceRI定向调节过敏效应器的新试剂细胞活动。