Targeting surface-bound IgE as a novel allergy therapeutic

描述（由申请人提供）：本次SBIR申请的总体目标是开发和商业化下一代过敏生物疗法。这是一种新的抗IgE单克隆半抗体，靶向表面结合的IgE在过敏效应细胞上，并在功能上阻断过敏反应。过敏性疾病已经增加到一个地步，他们现在已经成为一个主要的全球公共卫生问题，特别是在美国等发达国家。新的有效的过敏治疗方案仍然是一个主要的未满足的需求；严重的食物过敏如花生过敏没有有效的治疗方法，自2003年以Xolair(r)为基础的抗ige治疗以来，没有新的吸入性过敏治疗平台获得许可。在这个应用中，我们提出了一种新的方法，其中基因工程抗？单抗半分子[AEHM] E-3.56用于阻断过敏反应。这种治疗的基本原理

DESCRIPTION (provided by applicant): The overall goal of this SBIR application is to develop and commercialize a next generation allergy biologic therapy. This novel therapeutic, an anti-IgE monoclonal half antibody, targets the surface-bound IgE on allergic effector cells and functionally blocks allergic reactivity. Allergic disorders have increased to the point where they have now become 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. In this application we propose a new approach where a genetically engineered anti-? mAb half molecule [AEHM] E-3.56 is used to block allergic reactivity. The rationale of this therapeutic approach is based on our preliminary finding that binding of this AEHM to the Fc?RI bound IgE on allergic effector cells is incapable of mediating the cross-linking and triggering the cells due to its monovalent nature while at the same time, its binding inhibits subsequent allergen-induced reactivity. Thus the primary objective of this application is to produce a genetically engineered prototype AEHM E-3.56 and experimentally show that E-3.56 binding to surface-bound IgE on the allergic effector cells functions as a novel therapeutic against allergic reactivity. In Aim 1,we will engineer and express a prototypic IgG1 anti-epsilon (IgE) half antibody molecule E-3.56 composed of the mouse VH and VL regions linked to the human ?1 heavy chain and ? light chain constant regions respectively, with the two key cysteines in the C?1 hinge region mutated to preventing dimerization of the two CH chains. Co-expression of the chimeric H and L chains either by transient transfection or via established stable cell lines will result in the productionof E-3.56 that is monovalent for human IgE binding. In Aim 2, we will test the safety profile and therapeutic efficacy of E-3.56 for its ability to inhibit allergic responses in in vitro and in viv established allergy models. We will use a systemic allergic anaphylaxis model, passive cutaneous anaphylaxis model and human basophil stimulation to test an E-3.56's safety and therapeutic efficacy. In Aim 3 we will define by which of the following mechanisms E-3.56 suppresses allergic reactivity: 1) Steric hindrance preventing access to the allergen binding sites; 2) Triggering negative signaling in effector mast cells and basophils; 3) Promoting clearance of cell surface IgE- Fc?RI complexes; 4) Triggering conformational change of IgE's allergen-binding sites leading to loss of allergen binding; and/or 5) Interfering with the IgE cros-linking necessary for allergic signaling. This application is directed at the development of a nove allergy therapeutic that is relevant to the public health.