Conformationally-Constrained PA Anthrax Vaccine

构象受限 PA 炭疽疫苗

• 批准号: 6953770
• 负责人: MAURIZIO ZANETTI
• 金额: $ 19.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953770
• 关键词: Bacillus anthracis; anthrax toxin; anthrax vaccines; antigen antibody reaction; binding sites; biotechnology; bioterrorism /chemical warfare; cell surface receptors; conformation; cytotoxicity; guinea pigs; immunoglobulin structure; immunoglobulins; laboratory mouse; laboratory rabbit; protein engineering; receptor binding; vaccine development

DESCRIPTION (provided by applicant): Bacillus anthracis, the agent that causes anthrax, has several characteristics that make it a formidable bioterrorist threat. Presently efforts to develop an effective anthrax vaccine can be categorized into the following groups: (1) Protein vaccines; (2) Live attenuated vaccines; (3) DNA and replicon vaccines: and (4) Identification of new antigens. The steps in host-cell intoxication have been recently clarified. An 83-kDa form of protective antigen (PA83) is secreted from rapidly growing B. Anthracis cells and binds via a 19aa solvent-exposed loop in domain 4 between strand 4A-4B of the protective antigen (PA) to a specific host cell surface receptor termed ATR. X-ray crystallography studies characterized this loop as having the structure of the complementarity-determining region (CDR) of an immunoglobulin (Ig). It is the goal of this application to develop and test as a proof-of-principle a series of Ig molecules expressing a conformationally-constrained 4B9-4B10 PA loop, antigenized antibodies. Furthermore, we will ascertain whether immunization with antibodies antigenized to express 4B9-4B 10 PA loop will result in the induction of site specific antibodies (i.e., directed at the 4B9-4B 10 PA loop) also able to neutralize the internalization of B. anthracis toxin and its cytopathicity. It is hoped that the idea and experiments proposed in this application can speed up the development of a safe and effective method to vaccinate against B. anthracis.

描述（由申请人提供）：导致炭疽的代理商炭疽菌具有多种特征，使其成为强大的生物恐怖主义威胁。目前，可以将开发有效炭疽疫苗的努力分为以下组：（1）蛋白质疫苗； （2）活疫苗的活疫苗； （3）DNA和复制疫苗：（4）新抗原的鉴定。最近已经阐明了宿主细胞中毒的步骤。 一种83 kDa形式的保护性抗原（PA83）是从迅速生长的炭疽芽孢杆菌细胞中分泌的，并通过在保护性抗原（PA）之间的域4 A之间的19AA溶剂暴露环结合到域4 特定的宿主细胞表面受体称为ATR。 X射线晶体学研究 将此循环描述为具有互补性区域的结构 免疫球蛋白（IG）的（CDR）。该应用程序的目的是开发和测试 原理证明A表达构象约束的一系列IG分子 4B9-4B10 PA环，抗原化抗体。此外，我们将确定是否 用抗原表达4B9-4B 10 PA环的抗体免疫将导致 诱导位点特异性抗体（即针对4B9-4B 10 PA回路）也能够 中和炭疽芽孢杆菌毒素及其细胞病变的内在化。希望 本应用程序中提出的想法和实验可以加快开发 安全有效的方法可以接种炭疽芽孢杆菌。