Targeting surface-bound IgE as a novel allergy therapeutic

 描述（由申请人提供）：SBIR II期申请的总体目标是开发和商业化用于治疗过敏性疾病的下一代生物制剂。这种治疗性低亲和力抗IgE单克隆抗体靶向过敏效应细胞上的表面结合IgE，并通过一种新机制在功能上阻断过敏反应性。过敏性疾病已经增加到它们现在是一个主要的全球公共卫生问题的程度，特别是在发达国家如美国。过敏症的新型有效治疗选择仍然是一个主要的未满足的需求;没有有效的治疗方法可用于严重的食物过敏，如花生过敏，自2003年基于Xolair（r）的抗IgE治疗以来，没有新的吸入性过敏平台获得许可。在这里，我们提出了一种新的方法，即低亲和力的抗IgE单克隆抗体，p6.2，块过敏反应。这种治疗方法背后的基本原理是基于I期项目的结果，该项目显示p6.2与IgE结合，IgE与过敏效应细胞上的FceRI结合，驱动FceRI表达的快速下调和过敏反应性的丧失。通过以低亲和力结合IgE的构象表位，p6.2诱导非过敏性碎片脱颗粒，同时不能触发过敏性脱颗粒。此外，与循环IgE结合的p6.2保持活性，作为药物储库而不是药物去除的途径。本申请的目的是产生基因工程改造的人源化形式的鼠p6.2，更好地理解其治疗作用的机制以增强药物开发，设计/选择有限数量的最终临床候选物，并将这些转移到开发中（建立的细胞系、纯化方法和效价测定）以用于未来的IND使能研究。在目标1中，我们将从人源化p6.2 mAb变体中鉴定最终的临床候选物。这将通过确定人源化p6.2变体的过敏治疗指数（抑制与潜在释放的比率）并鉴定具有最佳指数的那些来实现。将使用我们建立的嗜碱性粒细胞活化、被动皮肤过敏反应和小鼠全身过敏反应模型确定治疗指数。在目标2中，我们将进一步探索人源化p6.2介导其抗过敏治疗作用的机制。更好地了解p6.2的新的治疗效果的基础将使我们能够使用合理的药物设计，以开发未来的改进/第二代治疗。在目标3中，我们将从目标1中定义的几个最佳人源化p6.2 mAb克隆中建立稳定的研究CHO细胞库。由这些细胞系生产的抗体将用于未来的IND前研究（例如毒理学、生产），该研究将确定主细胞库生产的最终临床候选物。我们将同时开发一组效价生物测定，用于分析药物的疗效和安全性。这一目标将使我们坚定地走上商业化的道路。

 DESCRIPTION (provided by applicant): The overall goal of this SBIR Phase II application is to develop and set for commercialization a next generation biologic for the treatment of allergic disease. This therapeutic, a low affinity anti-IgE monoclonal antibody targets surface-bound IgE on allergic effector cells and functionally blocks allergic reactivity by a novel mechanism(s). Allergic disorders have increased to the point where they are now a major worldwide public health issue and particularly so in developed countries such as the US. Novel effective treatment options for allergies remain a major unmet need; no effective therapy is available for severe food allergies such as peanut allergy and no new platforms for inhalant allergy have been licensed since Xolair(r)-based anti-IgE therapy in 2003. Herein we propose a new approach whereby a low affinity anti-IgE mAb, p6.2, blocks allergic reactivity. The rationale behind this therapeutic approach is based on results from the Phase I project that showed that p6.2 binding to IgE bound to FceRI on allergic effector cells drives rapid down-regulation of FceRI expression and loss of allergic reactivity. By binding with low affinity to a conformational epitope of IgE, p6.2 induces non- allergic piecemeal degranulation while failing to trigger anaphylactic degranulation. Additionally, p6.2 bound to circulating IgE remains active, functioning as a drug reservoir rather than a pathway for drug removal. The objectives of this application are to produce a genetically engineered humanized version of murine p6.2, better understand the mechanisms of its therapeutic effect to enhance drug development, design/select a limited number of final clinical candidates, and move these into development (established cell lines, purification methods and potency assays) for future IND enabling studies. In Aim 1, we will identify the final clinical candidates from the humanized p6.2 mAb variants. This will be accomplished by determining the allergic therapeutic index (ratio of inhibition to potential release) for the humanized p6.2 variants and identifying those with the best index. The therapeutic index will be determined using our established models of basophil activation, passive cutaneous anaphylaxis, and murine systemic anaphylaxis. In Aim 2, we will further explore the mechanisms by which humanized p6.2 mediates its anti-allergic therapeutic effects. Better understanding of the basis for p6.2s novel therapeutic effects will position us to use rational drug design to develop future improved/second generation therapeutics. In Aim 3, we will establish stable research CHO cell banks from several optimal humanized p6.2 mAb clones defined in Aim 1. The antibodies produced from these cell lines will be used in future pre-IND studies (e.g. toxicology, manufacturing), that will define the final clinical candidate for Master Cell Bank production. We will simultaneously develop a panel of potency bioassays for analysis of the drug's efficacy and safety profile. This aim will put us squarely on the road to commercialization.