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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：
9311611
负责人：
Theodore S Jardetzky
金额：
$ 39.09万
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 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311611
关键词：
Affect Affinity Allergens Animals Ankyrin Repeat Antibodies Basophils Binding Biological Biological Response Modifier Therapy Biophysics Cells Complex Development Disease Dissociation Engineering Equilibrium Exhibits Extrinsic asthma Fc Receptor Food Hypersensitivity Foundations Glean Human Hypersensitivity IgE IgE Receptors Immune response Inflammatory Libraries Ligands Macromolecular Complexes Mediating Methods Modeling Molecular Conformation Mus Passive Cutaneous Anaphylaxis Peripheral Proteins Reaction Research Surface Therapeutic Therapeutic antibodies Tissues Treatment Efficacy Tumor Necrosis Factor Receptor Work Yeasts allergic response anti-IgE antibody engineering base crosslink design improved inhibitor/antagonist insight macromolecule mast cell novel novel strategies novel therapeutics omalizumab receptor receptor binding small molecule synthetic protein therapeutic development tool

项目摘要

Project Summary IgE antibodies bind the high affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Potent inhibitors of IgE:FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. Omalizumab is also being used experimentally for the treatment of food allergies. However, improved therapeutics are needed for the treatment of allergies. With current anti-IgE therapy, IgE remains bound to receptors on mast cells in peripheral tissues for months, maintaining these cells in a sensitized state and highlighting the high affinity and low turnover of the preformed IgE receptor complexes. Our studies of anti-IgE DARPin inhibitors have revealed that these inhibitors can rapidly dissociate IgE:FcεRI complexes, with the potential for greater therapeutic efficacy than the current anti-IgE therapy. We refer to these inhibitors as “disruptive” since they are able to accelerate the dissociation of preformed receptor complexes. Our results with the DARPins demonstrate that macromolecular inhibitors can accelerate the dissociation of receptor complexes and raises the possibility that other macromolecules, such as antibodies, can be found that have similar activity. The ability to disrupt preformed receptor complexes represents a previously unappreciated potential function for macromolecular inhibitors in general and raises the possibility of developing novel research tools and biological therapeutics. In this proposal, we are exploring multiple approaches to better understanding the mechanism of the disruptive DARPin inhibitors and how to improve their activities further. Since these synthetic proteins are not likely to replace current anti-IgE therapy, as they may induce immune responses in humans, we also propose to indentify an anti-IgE antibody that exhibits similar disruptive inhibitor activity as the DARPins. The potential overall impact of this proposal is high, given the possibility of improving anti-IgE antibody therapeutics and also by providing foundational approaches for developing disruptive macromolecular inhibitors for other receptor-ligand complexes.

项目概要 IgE 抗体结合高亲和力 IgE Fc 受体 (FcεRI)，主要存在于肥大细胞和嗜碱性粒细胞上，并且引发过敏反应的炎症级联反应。 IgE:FcεRI 结合的有效抑制剂已被证实鉴定出抗 IgE 治疗抗体（奥马珠单抗）用于治疗严重过敏性哮喘。奥马珠单抗也正在实验性地用于治疗食物过敏。不过，改进了需要治疗来治疗过敏。在目前的抗 IgE 治疗中，IgE 仍然与外周组织肥大细胞上的受体持续数月，使这些细胞保持敏化状态强调了预先形成的 IgE 受体复合物的高亲和力和低周转率。我们的抗 IgE 研究 DARPin 抑制剂表明，这些抑制剂可以快速解离 IgE:FcεRI 复合物，与目前的抗 IgE 疗法相比，具有更大的治疗效果的潜力。我们将这些抑制剂称为 “破坏性”是因为它们能够加速预先形成的受体复合物的解离。我们的成果与DARPins的结合证明大分子抑制剂可以加速受体的解离复合物并增加了发现其他大分子（例如抗体）的可能性类似的活动。破坏预先形成的受体复合物的能力代表了一种以前未被重视的能力一般而言，大分子抑制剂的潜在功能并提出了开发新型药物的可能性研究工具和生物疗法。在本提案中，我们正在探索多种方法来更好地了解破坏性 DARPin 抑制剂的机制以及如何进一步提高其活性。由于这些合成蛋白不太可能取代当前的抗 IgE 疗法，因为它们可能会诱导免疫为了研究人类的反应，我们还建议鉴定一种具有类似破坏性抑制剂的抗 IgE 抗体 DARPins 的活动。考虑到改进的可能性，该提案的潜在总体影响很大抗 IgE 抗体疗法，并提供开发破坏性药物的基础方法其他受体-配体复合物的大分子抑制剂。