Novel Anti-allergic Single-domain Antibody Against IgE

描述（由申请人提供）：阻断IgE活化的蛋白质治疗剂有望用作治疗哮喘的下一代药物。事实上，奥马珠单抗，一种抑制IgE-Fc与高亲和力IgE受体Fc 5 RI结合的人源化单克隆抗体，在治疗症状未得到充分控制的中度至重度过敏性哮喘患者中具有有益作用。尽管奥马珠单抗有效，但其治疗仅限于患有非常严重疾病的患者，可能是由于这种单克隆抗体药物的成本非常高。 该项目旨在开发IgE-Fc结合单域抗体（SDA），用于哮喘的经济有效治疗。具体而言，我们将使用称为mRNA展示的定向蛋白质进化方法来开发新一代的IgE-Fc结合SDA，其基于新鉴定的单体人VH结构域（hVH）。我们将首先通过基于扩增的迭代轮体外选择，从含有超过1013个独特序列的mRNA展示的hVH结构域文库中产生与人IgE-Fc上的Fc 5 RI结合区紧密且特异性结合的SDA。将通过特殊程序的组合来优化所选序列以获得高靶标结合亲和力和特异性。将使用各种体外和体内方法详细表征所得SDA的靶标结合特性。优化的SDA将被二聚化以增加其与IgE-Fc的结合强度。基于hVH结构域的所得IgE-Fc结合SDA将具有许多优点，包括高靶结合亲和力和特异性、低免疫原性，以及由于其在细菌中的高表达水平而显著降低的制造成本。这样的SDA可以在哮喘的治疗中具有重要的应用。 公共卫生相关性：哮喘是一个主要的全球性健康问题，在过去几十年中患病率大幅增加。仅在美国，就有大约2000万人患有哮喘，其中包括近900万儿童。尽管有效且相对便宜的治疗方法使大多数哮喘患者受益，但约5%的重度哮喘患者仍然控制不佳。该研究旨在开发一类新型抗哮喘人单域抗体，其具有独特的功能，包括高功效，低免疫原性和显着降低的制造成本。这种生物药物的可用性可以大大有利于许多严重症状性哮喘患者。

DESCRIPTION (provided by applicant): Protein therapeutics that blocks the activation of IgE hold the promise of being used as the next generation of drugs in the treatment of asthma. Indeed, omalizumab, a humanized monoclonal antibody that inhibits the binding of IgE-Fc to the high-affinity IgE receptor Fc5RI, has beneficial effects in the treatment of moderate to severe allergic asthma in patients whose symptoms are inadequately controlled. Despite its effectiveness, omalizumab treatment is only limited in patients with very severe disease, presumably due to the very high cost of this monoclonal antibody drug. This project is directed at developing IgE-Fc-binding single domain antibodies (SDAs) for cost-effective treatment of asthma. Specifically, we will use a directed protein evolution method called mRNA-display to develop a new generation of IgE-Fc-binding SDAs that are based on a newly identified monomeric human VH domain (hVH). We will first generate SDAs that tightly and specifically bind to the Fc5RI-binding region on human IgE-Fc from an mRNA-displayed hVH domain library containing more than 1013 unique sequences through amplification-based, iterative rounds of in vitro selection. The selected sequences will be optimized to acquire high target-binding affinity and specificity through a combination of special procedures. The resulting SDAs will be characterized in detail for their target-binding properties using various in vitro and in vivo approaches. The optimized SDA will be dimerized to increase its binding strength with IgE-Fc. The resulting IgE-Fc-binding SDAs based on hVH domain would have a number of advantages, including high target-binding affinity and specificity, low immunogenicity, and significantly reduced manufacturing costs due to their high expression levels in bacteria. Such SDAs could have significant applications in the treatment of asthma. PUBLIC HEALTH RELEVANCE: Asthma is a major global health problem with an enormous increase in prevalence during the past few decades. In the United States alone, about 20 million people, including nearly 9 million children, have asthma. Despite the availability of effective and relatively cheap treatments that benefit the majority of asthma patients, approximately 5% of severe asthmatic patients remain poorly controlled. The proposed research aims at developing a novel class of anti-asthma human single domain antibodies that possess unique features, including high efficacy, low immunogenicity, and significantly reduced manufacturing cost. The availability of such biopharmaceuticals could greatly benefit many patients with severe-symptomatic asthma.