Anthrax Antidote in Animals

动物炭疽解毒剂

• 批准号: 6861713
• 负责人: BRENT L IVERSON
• 金额: $ 44.07万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-05 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861713
• 关键词: Macaca mulatta; anthrax; anthrax toxin; antibody; antidotes; antitoxins; cell surface receptors; cooperative study; guinea pigs; immunoglobulin G; immunologic substance development /preparation; macrophage; toxin

DESCRIPTION (provided by applicant): Anthrax remains a significant homeland security and military threat. The proposed work will deliver an optimized, anti-toxin antibody based therapeutic formulation that is tested through the non-human primate level. It will thus be ready for the final approval process and deployment. The whole IgG1 human form of our engineered 1H antibody will be produced and its therapeutic ability in a guinea pig spore challenge study will be investigated. Previously, we have shown that this ultra high affinity, anti-protective antigen (PA) antibody was extremely effective in an in vivo toxin neutralization assay using rats. The 1H work is being accelerated because we will need this data as a benchmark against which the other antibody formulations will be judged. In addition, given the current world tensions, it is prudent to have this promising therapeutic as far along as possible, as soon as possible. Note that if our results from the guinea pig spore challenge studies are as promising as we expect (and/or world events dictate), we will be in position to commence non-human primate trials of 1H within the first year. In addition to development of 1H, panels of ultra-high affinity antibodies will be produced to all three toxins in the first two years of the project. 1H is neutralizing because it disrupts the macrophage receptor-binding site of PA. Added therapeutic benefit may be realized by using additional antibodies that neutralize PA through disruption of binding to the lethal factor (LF) and edema factor (EF) toxins, as well as antibodies that prevent PA heptamerization. Further, the most effective strategy, and the one most likely to circumvent attempts to engineer resistance into new anthrax strains, may be to use a panel of ultra high affinity antibodies that have the redundant capacity to neutralize all aspects of the tripartite anthrax toxin activity. The most promising formulation of these engineered antibody panels will be determined by testing with anthrax spore challenge studies in guinea pigs, and ultimately, rhesus macaque monkeys, in collaboration with our subcontractor team led by Dr. Jean Patterson at the Southwest Foundation for Biomedical Research in San Antonio.

描述（由申请人提供）： 炭疽仍然是巨大的国土安全和军事威胁。拟议的工作将提供优化的，抗毒素抗体的治疗配方，该制剂通过非人类灵长类动物水平进行了测试。因此，它将为最终的批准过程和部署做好准备。我们的工程1H抗体的整个IgG1人类形式将被产生，并将研究其在豚鼠孢子挑战研究中的治疗能力。以前，我们已经表明，这种超高亲和力抗保护抗原（PA）抗体在使用大鼠的体内毒素中和测定中非常有效。 1H工作之所以加速，是因为我们将需要这些数据作为基准，以此来判断其他抗体配方。此外，鉴于当前的世界紧张局势，尽快拥有这种有希望的治疗方法是谨慎的。请注意，如果我们来自豚鼠孢子挑战研究的结果如我们所期望的（和/或世界事件所决定的）一样有希望，那么我们将在第一年内开始1H的非人类灵长类动物试验。 除开发1小时外，在该项目的前两年中，将对所有三种毒素产生一组超高亲和力抗体。 1H之所以中和，是因为它破坏了PA的巨噬细胞受体结合位点。通过使用其他抗体，可以通过破坏与致死因子（LF）和水肿因子（EF）毒素的结合以及防止PA七聚体的抗体来中和PA来实现增加的治疗益处。此外，最有效的策略，也是最有可能避免试图将耐药性锻炼到新的炭疽菌株中的尝试，可能是使用一组超高亲和力抗体，该抗体具有冗余能力来中和三方炭疽毒素活性的所有方面。这些工程抗体面板的最有希望的表述将通过与豚鼠的炭疽孢子挑战研究进行测试，最终与我们的分包商团队合作，由我们的分包商团队合作，由我们的分包商团队在圣安东尼奥的Southwest Biomedical Foundation L. Jean Patterson领导。