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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：
10495213
负责人：
Theodore S Jardetzky
金额：
$ 19.68万
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/10495213
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 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.

项目摘要大多数过敏反应是由抗过敏原IgE抗体引起的，它能使过敏效应器致敏。肥大细胞和嗜碱性粒细胞等细胞。与免疫球蛋白抗体不同，免疫球蛋白E以亚纳摩尔亲和力结合高亲和力IgE受体(FceRI)在变态反应效应细胞上以受体结合的形式存在数月即使在存在高亲和力的抗IgE抗体抑制剂的情况下，如奥马珠单抗。我们已经证明了抗体和设计的Ankyrin重复蛋白(DARPins)都能够动力学地加速 IgE通过两种机制从FceRI解离：促进解离机制，允许受体相邻抑制剂促进受体解离和变构机制将IgE限制为构象与受体结合不相容。我们已经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体，并表明我们有能力选择更有效的奥马珠单抗的抗IgE变异体。此外，我们还展示了工程设计更有效的途径由干扰性抗IgE结构域和非竞争性IgE锚定组成的双价干扰性抑制剂域。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理多样性并开发与未来临床发展相适应的超强双价抗IgE抑制剂。