Antibody-mediated protection against whooping cough

抗体介导的百日咳保护

• 批准号: 6962314
• 负责人: JENNIFER A MAYNARD
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962314
• 关键词: Bordetella pertussis; animal mortality; antibacterial antibody; bacterial antigens; bacterial genetics; bacterial proteins; biotechnology; chimeric proteins; disease /disorder model; laboratory mouse; leukocytosis; microorganism immunology; neutralizing antibody; nonhuman therapy evaluation; pertussis; pertussis toxin; phage display; protein engineering; recombinant proteins; vaccine development; vaccine evaluation; virulence; weight loss

DESCRIPTION (provided by applicant): In spite of vaccine availability for the past five decades, whooping cough remains a childhood scourge with no available therapy for established disease. Caused by the Bordetella pertussis bacterium, whooping cough is mediated by over twenty virulence factors, none of which provides a clear serological correlate of protection. We hypothesize that appropriately engineered anti-pertussis toxin antibodies will be effective in ameliorating disease. This belief is supported by three lines of evidence: (i) reduced virulence of bacteria lacking pertussis toxin genes; (ii) demonstrated efficacy of the acellular pertussis vaccines (comprised of pertussis toxin and 0-4 additional virulence factors); and (iii) passive immunotherapy studies which have demonstrated protection and even reversal of disease post-infection. Our specific aims are to: 1. Generate high-affinity humanized, neutralizing anti-pertussis toxin immunoglobulins, 2. Elucidate the structural and functional mechanisms of anti-PT protection, 3. Evaluate pre- and post-exposure protection in mice. This work involves the application of modern protein engineering technologies to an historic disease. The recombinant proteins developed will be superior to previous preparations due to the exclusive inclusion of high-affinity neutralizing antibodies with minimal potential for immunogenicity or viral contamination. We anticipate that the proposed exploratory research will lay the groundwork for phase I clinical trials and that the antibodies created may form the basis of an orphan drug therapeutic. Furthermore, these reagents can be used to probe fundamental questions regarding Bordetella immunity.

描述(由申请人提供)： 尽管过去50年里有疫苗可用，但百日咳仍然是儿童的祸害，没有针对既定疾病的有效治疗方法。百日咳由百日咳杆菌引起，由20多种毒力因子介导，没有一种提供明确的血清学保护相关性。我们假设，适当设计的抗百日咳毒素抗体将在改善疾病方面有效。这一信念得到了三条证据的支持：(1)缺乏百日咳毒素基因的细菌的毒力降低；(2)证明了无细胞百日咳疫苗的有效性(由百日咳毒素和0-4个额外的毒力因子组成)；(3)被动免疫疗法研究，证明了感染后疾病的保护甚至逆转。 我们的具体目标是： 1.产生高亲和力的人源化、中和抗百日咳毒素免疫球蛋白， 2.阐明抗PT保护的结构和作用机制。 3.评估暴露前和暴露后对小鼠的保护。 这项工作涉及现代蛋白质工程技术在一种历史性疾病上的应用。由于独家包含高亲和力中和抗体，免疫原性或病毒污染的可能性最小，因此所开发的重组蛋白将优于以前的制剂。我们预计，拟议的探索性研究将为I期临床试验奠定基础，所产生的抗体可能形成孤儿药物治疗的基础。此外，这些试剂还可用于探讨有关波尔德氏菌免疫的基本问题。