Discovery and engineering of novel anti-IgE disruptive inhibitors

新型抗 IgE 破坏性抑制剂的发现和工程设计

基本信息

批准号：
10353982
负责人：
Theodore S Jardetzky
金额：
$ 23.61万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353982
关键词：
Acute Affinity Allergens Allergic Allergic Disease Allergic Reaction Anaphylaxis Ankyrin Repeat Anti-Allergic Agents Antibodies Antigen Presentation Antigens Asthma B-Lymphocytes Basophils Binding Biochemical Cells Clinical Pathways Clinical Research Complex Data Diagnosis Dissociation Drug Hypersensitivity Effector Cell Eligibility Determination Engineering Epithelial Cells Exhibits Fc Immunoglobulins Food Food Hypersensitivity Foundations Future Health Human Hypersensitivity IgE IgE Receptors Immune Immune response Immune system Immunization Immunoglobulin G Incidence Individual Inflammatory Inflammatory Response Kinetics Libraries Ligands Llama Mediating Mediator of activation protein Methods Molecular Conformation Nuts Pathway interactions Peripheral Pollen Population Process Production Proteins Protocols documentation Publishing Shellfish Stains Structure Sudden Death Testing Therapeutic Tissues Translating United States Urticaria Variant Yeasts allergic response anti-IgE antibody inhibitor base chronic rhinosinusitis clinical development desensitization design experimental study flexibility human disease human morbidity improved inhibitor/antagonist mast cell nanobodies novel novel strategies omalizumab receptor receptor binding screening therapeutic development therapeutic target

项目摘要

Project Summary The majority of allergic reactions are caused by anti-allergen IgE antibodies, which sensitize allergic effector cells such as mast cells and basophils. In contrast to IgG antibodies, IgE binds with subnanomolar affinity to the high affinity IgE receptor (FceRI) and persists in a receptor-bound form on allergic effector cells for months even in the presence of high affinity anti-IgE antibody inhibitors, such as omalizumab. We have shown that both antibodies and Designed Ankyrin Repeat Proteins (DARPins) are able to kinetically accelerate the dissociation of IgE from FceRI through two mechanisms: a facilitated dissociation mechanism that allows receptor-adjacent inhibitors to promote receptor dissociation and an allosteric mechanism that restricts IgE to a conformation incompatible with receptor binding. We have developed a yeast display approach to selecting anti-IgE inhibitors capable of disrupting receptor complexes and demonstrated our ability to select more potent anti-IgE variants of omalizumab. In addition, we have demonstrated pathways to engineering more potent bivalent disruptive inhibitors consisting of a disruptive anti-IgE domain and a non-competitive IgE anchoring domain. Here we propose to apply these approaches to interrogate an anti-IgE immune library, to isolate more potent disruptive inhibitors, to explore the mechanistic diversity of disruptive inhibitors and to develop ultrapotent bivalent anti-IgE inhibitors compatible with future clinical development.

项目概要大多数过敏反应是由抗过敏原 IgE 抗体引起的，它使过敏效应器敏感细胞，例如肥大细胞和嗜碱性粒细胞。与 IgG 抗体相比，IgE 以亚纳摩尔亲和力结合高亲和力 IgE 受体 (FceRI) 并以受体结合形式在过敏效应细胞上持续数月即使存在高亲和力抗 IgE 抗体抑制剂（例如奥马珠单抗）。我们已经证明抗体和设计锚蛋白重复蛋白 (DARPins) 都能够在动力学上加速 IgE 通过两种机制从 FceRI 解离：促进解离机制，允许受体邻近抑制剂促进受体解离和变构机制将 IgE 限制在构象与受体结合不相容。我们开发了一种酵母展示方法来选择抗 IgE 抑制剂能够破坏受体复合物，并证明我们有能力选择更有效的抑制剂奥马珠单抗的抗 IgE 变体。此外，我们还展示了设计更有效的途径由破坏性抗 IgE 结构域和非竞争性 IgE 锚定结构组成的二价破坏性抑制剂领域。在这里，我们建议应用这些方法来询问抗 IgE 免疫库，以分离更多有效的破坏性抑制剂，探索破坏性抑制剂的机制多样性并开发与未来临床开发兼容的超强二价抗 IgE 抑制剂。