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Development of human monoclonal antibodies against infectious disease: SARS-associated coronavirus and avian influenza.

机译：抗传染病的人类单克隆抗体的开发：SARS相关冠状病毒和禽流感。

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摘要

In the 21st century, a number of novel infectious diseases emerged suddenly and spread rapidly, endangering the lives and well-being of people around the world. Severe acute respiratory syndrome (SARS) is a life threatening form of atypical pneumonia that ravaged Hong Kong, Taiwan, China, Canada and many cities in 2003. In the same year, novel avian influenza viruses infected human beings on two continents. Both of these diseases originated in animals and crossed over into the human population. These emerging diseases pose significant public health threats while providing a chilling reminder that another influenza pandemic could occur at any time. Thus, the development of effective therapeutics to control the disease is of paramount importance. Although several vaccines against SARS and avian influenza are available nowadays, the poor clinical performance and frequent mutation of viral strains may limit the practical use and value of the vaccines. Moreover, there are no promising antiviral drugs available for the treatment. Therefore, I aimed to develop an immunotherapy as an alternative treatment option against these diseases.;I utilized the phage system-based cloning method as an attractive approach to screen and identify virus-specific antibodies that can be encoded by the human genome. Once a useful phage clone is identified, unlimited amounts of human monoclonal virus-specific antibodies can be manufactured, and potentially applied clinically for prophylactic and therapeutic uses. The study focuses on two of these new infections, both of which cause severe respiratory disease: SARS and avian influenza.;I established the phage antibody library platform for the identification of specific antibodies. In the first part of my study, I tried to identify antibody against SARS-CoV. Two fragments on the spike protein, which is responsible for inducing viral entry, was chosen as target for the selection of antibody. An antibody was identified which can selectively recognize the SARS-CoV infected cells, but not non-infected cells. Although this antibody was found to retain no neutralizing ability, this specific antibody may have potential to develop for diagnostic purpose.;In the second part of my study, the extracellular domain of matrix protein of avian influenza virus was chosen as target for the selection of antibody. I successfully identified an antibody which can neutralize the avian influenza virus infection. This promising result indicated this antibody has potential to develop for therapeutic use and these antibodies can be easily manufactured in unlimited amounts for clinical application.;Identification of specific antibodies, either for diagnostic or therapeutic use, was successfully demonstrated in the two infectious disease models. The phage antibody platform offers a fast and cost-effective method to identify phage antibodies, which can easily be converted to human viral specific monoclonal antibodies for clinical use.
机译：在21世纪，许多新型传染病突然出现并迅速传播，危及世界各地人民的生活和福祉。严重急性呼吸系统综合症（SARS）是一种非典型肺炎的危及生命的形式，在2003年席卷了香港，台湾，中国，加拿大和许多城市。同年，新型禽流感病毒感染了两大洲的人类。这两种疾病均起源于动物，并传入人类。这些新出现的疾病构成了重大的公共卫生威胁，同时令人不寒而栗地提醒人们，随时可能发生另一种流感大流行。因此，开发控制该疾病的有效疗法至关重要。尽管如今有几种抗SARS和禽流感的疫苗可供使用，但不良的临床表现和病毒株的频繁突变可能会限制疫苗的实际使用和价值。而且，没有可用于治疗的有希望的抗病毒药。因此，我旨在开发一种免疫疗法作为针对这些疾病的替代疗法。我利用基于噬菌体的克隆方法作为一种有吸引力的方法来筛选和鉴定可被人类基因组编码的病毒特异性抗体。一旦鉴定出有用的噬菌体克隆，就可以生产无限量的人单克隆病毒特异性抗体，并有可能在临床上用于预防和治疗用途。该研究的重点是这些新感染中的两种，它们均引起严重的呼吸道疾病：SARS和禽流感。；我建立了噬菌体抗体文库平台，用于鉴定特异性抗体。在研究的第一部分中，我试图鉴定出针对SARS-CoV的抗体。选择负责诱导病毒进入的刺突蛋白上的两个片段作为选择抗体的靶标。鉴定了可以选择性识别SARS-CoV感染的细胞但不能识别未感染的细胞的抗体。尽管发现该抗体不具有中和能力，但该特异性抗体可能具有开发用于诊断目的的潜力。在本研究的第二部分中，选择了禽流感病毒基质蛋白的胞外域作为选择抗抗体。我成功地鉴定了可以中和禽流感病毒感染的抗体。这一有希望的结果表明该抗体具有开发用于治疗用途的潜力，并且可以无限量地容易地制造这些抗体以用于临床应用。在两种传染病模型中成功地证明了用于诊断或治疗用途的特异性抗体的鉴定。噬菌体抗体平台提供了一种快速且经济高效的方法来鉴定噬菌体抗体，该抗体可以轻松转化为人病毒特异性单克隆抗体以用于临床。

著录项

  • 作者

    Leung, Ka Man.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Biology Virology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 181 p.
  • 总页数 181
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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