Novel Anti-allergic Single-domain Antibody Against IgE

新型抗过敏单域IgE抗体

基本信息

批准号：
8197410
负责人：
Rihe Liu
金额：
$ 18.23万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197410
关键词：
Address Adrenal Cortex Hormones Affinity Age Anti-Allergic Agents Antibodies Asthma Bacteria Binding Biological Products Cells Child Development Disadvantaged Disease Dose Effectiveness Evolution Extrinsic asthma Generations Human IgE IgE Receptors Immunoglobulin G In Vitro Length Libraries Mediating Mediator of activation protein Messenger RNA Methods Monoclonal Antibodies Patients Penetration Phage Display Pharmaceutical Preparations Post-Translational Protein Processing Prevalence Procedures Property Proteins Randomized Research Scaffolding Protein Specificity Symptoms System Techniques Tissues United States allergic response asthmatic patient base cost cost effective effective therapy global health high throughput screening humanized monoclonal antibodies immunogenicity in vivo mast cell next generation novel omalizumab public health relevance receptor scaffold small molecule therapeutic protein

项目摘要

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.

描述（由申请人提供）：阻断 IgE 激活的蛋白质疗法有望成为治疗哮喘的下一代药物。事实上，奥马珠单抗（omalizumab）是一种人源化单克隆抗体，可抑制 IgE-Fc 与高亲和力 IgE 受体 Fc5RI 的结合，对治疗症状未得到充分控制的中度至重度过敏性哮喘患者具有有益作用。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，这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 (SDAs)，用于经济有效的哮喘治疗。具体来说，我们将使用一种称为 mRNA 展示的定向蛋白质进化方法来开发新一代 IgE-Fc 结合 SDA，该 SDA 基于新鉴定的单体人类 VH 结构域 (hVH)。我们将首先通过基于扩增的迭代体外选择，从包含超过 1013 个独特序列的 mRNA 展示的 hVH 结构域文库中生成与人 IgE-Fc 上的 Fc5RI 结合区紧密且特异性结合的 SDA。选定的序列将通过特殊程序的组合进行优化，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。优化后的 SDA 将被二聚化，以增加其与 IgE-Fc 的结合强度。由此产生的基于 hVH 结构域的 IgE-Fc 结合 SDA 将具有许多优点，包括高靶点结合亲和力和特异性、低免疫原性，并且由于其在细菌中的高表达水平而显着降低制造成本。此类 SDA 在哮喘治疗中具有重要应用。公共卫生相关性：哮喘是一个主要的全球健康问题，在过去几十年中患病率急剧上升。仅在美国，就有约 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% 的严重哮喘患者仍控制不佳。拟议的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，包括高效、低免疫原性和显着降低的制造成本。此类生物药物的出现可以使许多患有严重症状哮喘的患者受益匪浅。