Conformationally-Constrained PA Anthrax Vaccine

描述（由申请人提供）：炭疽芽孢杆菌是导致炭疽的病原体，具有几个特征，使其成为可怕的生物恐怖主义威胁。目前，开发有效炭疽疫苗的努力可分为以下几组：（1）蛋白质疫苗;（2）减毒活疫苗;（3）DNA和复制子疫苗;和（4）新抗原的鉴定。宿主细胞中毒的步骤最近已经澄清。 快速生长的B分泌83 kDa形式的保护性抗原（PA 83）。炭疽菌细胞，并通过保护性抗原（PA）的链4A-4 B之间的结构域4中的19 aa溶剂暴露环与炭疽菌细胞结合。 一种称为ATR的特异性宿主细胞表面受体。 X射线晶体学研究 将该环表征为具有互补决定区的结构 (CDR)免疫球蛋白（IG）。此应用程序的目标是开发和测试， 一系列表达构象约束的IG分子， 4 B 9 - 4 B10 PA环，抗原化抗体。此外，我们将确定是否 用抗原化以表达4 B 9 - 4 B10 PA环的抗体免疫将导致 诱导位点特异性抗体（即，针对4 B 9 - 4 B 10 PA环路）也能够 中和B的内化。炭疽毒素及其致细胞病变作用。人们希望 该应用中提出的思想和实验可以加速开发 安全有效的接种B疫苗的方法。炭疽病

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.