Conformationally-Constrained PA Anthrax Vaccine

描述（由申请人提供）：炭疽芽孢杆菌是引起炭疽的病原体，它有几个特点，使它成为一种可怕的生物恐怖威胁。目前研制有效炭疽疫苗的工作可分为以下几类：(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得到了澄清。一种83 kda的保护性抗原（PA83）从快速生长的炭疽芽孢杆菌细胞中分泌出来，并通过保护性抗原（PA）链4A-4B之间的4结构域19aa的溶剂暴露环结合到

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.