Immunogen /vaccine for anti-anthrax immune globulin

抗炭疽免疫球蛋白免疫原/疫苗

• 批准号: 6680029
• 负责人: Basil Golding
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6680029
• 关键词: anthrax; anthrax vaccines; antibiotics; antibody; antigen antibody reaction; bacterial antigens; bacterial toxins; combination chemotherapy; dosage; drug screening /evaluation; immunoglobulins; laboratory mouse; microorganism disease chemotherapy; sheep; tissue /cell culture

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.

摘要：目标如下： 1. 通过测定体外结合亲和力/亲合力和毒素中和以及体内保护作用，确定四种炭疽免疫原（AVA疫苗、CAMR疫苗、Sterne疫苗和重组PA蛋白（rPA））中哪一种可引发最有效的抗体。 2. 确定是否可以根据体内毒素水平预测中和毒素所需的抗体剂量。 3. 确定与单独使用抗生素或抗体相比，联合使用抗生素和抗体是否可以增强吸入性炭疽模型的存活率。 炭疽的三种分泌蛋白在炭疽的致病过程中起着重要作用。由于它们在附着到细胞之前在血液中循环，因此它们可能被抗体靶向和中和。 将在小动物模型中测试针对多种特异性而不是限制性特异性的抗体在预防和保护免受炭疽病方面可能具有上级有益效果的假设。 这将通过使用各种免疫抗原进行测试，包括克隆PA，并应使我们能够辨别PA单独与其他炭疽抗原相比的作用。 基于其他临床情况，其中毒素或药物被抗体中和，应该可以从毒素浓度预测所需的抗体剂量。 为了设计用于人类治疗的抗体剂量的合理方法，首先需要建立中和体外毒素中和测定（TNA）和体内（小鼠模型）测量的特定毒素浓度所需的抗体剂量。 在炭疽的情况下，靶向分子通常是PA，它允许LF和EF进入细胞。 抗PA抗体对炭疽病小鼠有保护作用。 抗体通过PA结合和中和毒素的能力取决于几个因素，包括与PA结合的亲和力/亲合力、PA对细胞受体的亲和力/亲合力、血液和组织中抗体的浓度以及PA从体内的清除。 这些参数可以使用等离子体共振、基于细胞的测定和小鼠模型来测量并与结果相关联。 研究结果应允许在不同的临床情况下，如暴露前和暴露后，以及在疾病的不同时间点，改善治疗所需的抗体剂量评估。 此外，将评估各种形式的抗体，Fc-完整、（Fab）2和Fab，因为它们可能具有不同的活性。 炭疽感染后，孢子迅速萌发，并分泌大量PA、LF和EF。 抗生素治疗单独针对细菌，而不是毒素，这可能解释了为什么尽管积极的抗生素治疗，患者仍然死亡。 由于抗体可以中和毒素，因此抗生素和抗体的联合方法可以提高存活率。