Anthrax Antidote in Animals

动物炭疽解毒剂

• 批准号: 6786620
• 负责人: BRENT L IVERSON
• 金额: $ 42.94万
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786620
• 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)： 炭疽病仍然是一个重大的国土安全和军事威胁。拟议的工作将提供一种优化的、基于抗毒素抗体的治疗配方，该配方通过非人类灵长类水平进行测试。因此，它将为最后的批准程序和部署做好准备。我们将生产我们设计的1H抗体的全人型IgG1，并将在豚鼠孢子攻击研究中研究其治疗能力。此前，我们已经证明这种超高亲和力的抗保护性抗原(PA)抗体在大鼠体内毒素中和试验中非常有效。1H的工作正在加速，因为我们将需要这个数据作为基准，以此作为判断其他抗体配方的基准。此外，鉴于当前的世界紧张局势，谨慎的做法是尽可能早地进行这种有希望的治疗。请注意，如果我们的豚鼠孢子挑战研究结果像我们预期的那样有希望(和/或世界事件所规定的)，我们将在第一年内开始1H的非人类灵长类试验。 除了1H的开发，在该项目的头两年，还将生产针对所有三种毒素的超高亲和力抗体。1H是中和的，因为它破坏了PA的巨噬细胞受体结合部位。额外的治疗益处可以通过使用额外的抗体来实现，这些抗体通过破坏与致死因子(LF)和水肿因子(EF)毒素的结合而中和PA，以及防止PA七聚体的抗体。此外，最有效的策略可能是使用一组超高亲和力抗体，这些抗体具有多余的能力来中和三方炭疽毒素活性的所有方面，这可能是最有效的策略，也是最有可能绕过对新炭疽病毒株进行抗药性改造的策略。我们将与圣安东尼奥西南生物医学研究基金会的Jean Patterson博士领导的分包商团队合作，通过在豚鼠中进行炭疽孢子挑战研究，并最终在恒河猴中进行测试，确定这些工程抗体面板最有希望的配方。