Immunogen /vaccine for anti-anthrax immune globulin

摘要：目标如下：

Summary: The objectives are as follows: 1. To determine which of four anthrax immunogens, AVA Vaccine, CAMR Vaccine, Sterne Vaccine, and recombinant PA protein (rPA), elicit the most potent antibodies, as measured by binding affinity/avidity and toxin neutralization in vitro, and protection in vivo. 2. To determine whether the dose of antibodies required to neutralize toxins can be predicted based on in vivo toxin levels. 3. To determine whether combined antibiotic and antibody administration can potentiate survival in an inhalational anthrax model compared to antibiotic or antibody alone. The three secreted proteins of anthrax play a critical role in pathogenesis. Since they circulate in the blood before attaching to cells they can potentially be targeted and neutralized by antibodies. The hypothesis that antibodies against multiple rather than restricted specificities may have superior beneficial effects in preventing and protecting against anthrax disease will be tested in small animal models. This will be tested by using various immunizing antigens, including cloned PA, and should allow us to discern the role of PA alone compared to other anthrax antigens. Based on other clinical situations, wherein a toxin or drug is neutralized by antibodies, it should be possible to predict the dose of antibody required from the toxin concentration. In order to devise a rational approach to antibody dosing for human therapy it is first necessary to establish the dose of antibody required to neutralize a particular toxin concentration measured in vitro Toxin Neutralization Assay (TNA) and in vivo (mouse model). In the case of anthrax, the molecule targeted is usually PA, which allows LF and EF to enter cells. Antibody against PA has been effective in protecting mice from anthrax disease. The ability of antibody to bind and neutralize the toxin, via PA, depends on several factors including, affinity/avidity of binding to PA, affinity/avidity of PA to cell receptors, concentration of antibody in the blood and tissues, and clearance of PA from the body. These parameters can be measured and correlated with outcome using plasmon resonance, cell-based assays and mouse models. The findings should allow improved assessments of dose of antibody required for treatment in different clinical situations such as, pre- and post-exposure, and at different points in the disease. In addition, various forms of the antibody, Fc-intact, (Fab)2 and Fab, will be assessed because they may have different activities. Following anthrax infection, the spores germinate at a remarkable rate and large amounts of PA, LF and EF are secreted into the host. Antibiotic therapy alone targets the bacteria, but not the toxins, probably explaining why patients have died despite aggressive antibiotic treatment. Since antibodies could neutralize the toxins, a combined approach of antibiotics and antibody may enhance survival.