Conformationally-Constrained PA Anthrax Vaccine

构象受限 PA 炭疽疫苗

• 批准号: 6708489
• 负责人: MAURIZIO ZANETTI
• 金额: $ 20.9万
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708489
• 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）：炭疽杆菌（Bacillus anthracis）是引起炭疽病的病原体，它具有多种特征，使其成为可怕的生物恐怖威胁。目前开发有效炭疽疫苗的努力可分为以下几类： (1) 蛋白质疫苗； （二）减毒活疫苗； (3) DNA 和复制子疫苗：以及 (4) 新抗原的鉴定。宿主细胞中毒的步骤最近已被阐明。 83 kDa 形式的保护性抗原 (PA83) 由快速生长的炭疽芽孢杆菌细胞分泌，并通过保护性抗原 (PA) 的 4A-4B 链之间的结构域 4 中的 19 个氨基酸暴露于溶剂的环结合到 称为 ATR 的特定宿主细胞表面受体。 X射线晶体学研究 将该环表征为具有互补决定区的结构 免疫球蛋白 (Ig) 的 (CDR)。该应用程序的目标是开发和测试 一系列表达构象限制的 Ig 分子的原理验证 4B9-4B10 PA环，抗原化抗体。此外，我们将确定是否 使用抗原化表达 4B9-4B 10 PA 环的抗体进行免疫将导致 诱导位点特异性抗体（即针对 4B9-4B 10 PA 环）也能够 中和炭疽杆菌毒素的内化及其细胞病变性。希望 本申请中提出的想法和实验可以加快开发 安全有效的炭疽杆菌疫苗接种方法。