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

• 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
• 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; 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

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，该抗体使过敏效应敏化 肥大细胞和嗜碱性细胞等细胞。与IgG抗体相反，IgE与亚纳摩尔亲和力结合 高亲和力IgE受体（FCERI），并在过敏性效应细胞上以受体结合形式持续数月 即使存在高亲和力抗IgE抗体抑制剂，例如omalizumab。我们已经表明 两种抗体和设计的氨基氨酸重复蛋白（DARPINS）都能够在动力学上加速 通过两种机制将IgE从FCERI解离：一种促进的解离机制，允许 受体抑制剂促进受体解离和变构机制，将IgE限制为A 与受体结合不相容的构象。我们已经开发了一种选择酵母显示方法 能够破坏受体复合物并证明我们选择更有效的能力的抗IgE抑制剂 omalizumab的抗IgE变体。此外，我们展示了工程更有效的途径 由颠覆性抗IgE域和非竞争性IgE锚定的二价破坏性抑制剂 领域。在这里，我们建议采用这些方法来询问抗神经免疫库，以隔离更多 有效的破坏性抑制剂，探索破坏性抑制剂的机械多样性并发展 超能力二价抗IgE抑制剂与未来的临床发育兼容。