Accelerated dissociation of IgE receptor complexes

项目摘要 IgE抗体结合主要在肥大细胞和嗜碱性粒细胞上发现的高亲和力IgE Fc受体（FcεRI）， 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 已鉴定出抗IgE治疗性抗体（奥马珠单抗），用于治疗严重过敏性哮喘。 奥马珠单抗也被实验性地用于治疗食物过敏。然而，改善 需要治疗剂来治疗变态反应。在目前的抗IgE治疗中，IgE仍然结合于 受体在外周组织中的肥大细胞上数月，维持这些细胞处于致敏状态， 突出了预先形成的IgE受体复合物的高亲和力和低转换。我们的抗IgE研究 DARPin抑制剂已经揭示，这些抑制剂可以快速解离IgE：FcεRI复合物， 具有比目前的抗IgE疗法更高的治疗功效的潜力。我们将这些抑制剂称为 它们是“破坏性的”，因为它们能够加速预先形成的受体复合物的解离。我们的结果 DARPins的研究表明，大分子抑制剂可以加速受体的解离， 复合物，并提出了其他大分子的可能性，如抗体，可以发现， 类似的活动。破坏预先形成的受体复合物的能力代表了以前未被认识到的 潜在的功能，一般的大分子抑制剂，并提出了可能性，开发新的 研究工具和生物疗法。在本提案中，我们正在探索多种方法，以更好地 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目前的抗IgE治疗，因为它们可能诱导免疫应答， 反应，我们还建议确定一个抗IgE抗体，表现出类似的破坏性抑制剂 就像DARPins一样。鉴于有可能改善这一状况，这项建议的潜在总体影响很大。 抗IgE抗体治疗，并提供基础方法， 其他受体-配体复合物的大分子抑制剂。

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.