Conformationally-Constrained PA Anthrax Vaccine

描述(申请人提供)：炭疽芽孢杆菌，引起炭疽病的媒介，有几个特点，使其成为一个可怕的生物恐怖威胁。目前，研制有效的炭疽疫苗的努力可分为以下几类：(1)蛋白质疫苗；(2)减毒活疫苗；(3)DNA和复制子疫苗；(4)新抗原的鉴定。宿主细胞中毒的步骤最近已被阐明。83 kDa的保护性抗原(PA83)是从快速生长的炭疽杆菌细胞中分泌出来的，并通过保护性抗原(PA)链4A-4B之间结构域4中暴露于19AA溶剂的环结合到 一种特定的宿主细胞表面受体，称为ATR。X射线结晶学研究 将该环描述为具有互补决定区域的结构 (Cdr)免疫球蛋白(Ig)。此应用程序的目标是开发和测试为 一系列表达构象受限的免疫球蛋白分子的原理证明 4B9-4B10 PA环，抗原性抗体。此外，我们将确定是否 用表达4B9-4B 10PA环的抗原化抗体免疫将导致 诱导部位特异性抗体(即，针对4B9-4B 10PA环)也能够 中和炭疽杆菌毒素的内化及其细胞病变。人们希望， 本申请中提出的思想和实验可以加快开发一种 安全有效的炭疽疫苗接种方法。

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.