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）： 炭疽仍然是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制剂，并通过非人类灵长类动物水平进行测试。因此，它将为最终的批准过程和部署做好准备。我们将生产完整的 IgG1 人类形式的工程 1H 抗体，并将研究其在豚鼠孢子激发研究中的治疗能力。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极其有效。 1H 工作正在加速，因为我们需要这些数据作为判断其他抗体制剂的基准。此外，考虑到当前世界紧张局势，明智的做法是尽快、尽可能长期地使用这种有前途的治疗方法。请注意，如果我们的豚鼠孢子挑战研究结果如我们预期的那样有希望（和/或世界事件决定），我们将能够在第一年内开始 1H 的非人类灵长类动物试验。 除了开发 1H 之外，还将在该项目的前两年生产针对所有三种毒素的超高亲和力抗体组。 1H 具有中和作用，因为它会破坏 PA 的巨噬细胞受体结合位点。通过使用额外的抗体（通过破坏与致死因子（LF）和水肿因子（EF）毒素的结合来中和 PA）以及防止 PA 七聚化的抗体，可以实现额外的治疗益处。此外，最有效的策略，也是最有可能规避对新炭疽菌株进行抗性改造的尝试的策略，可能是使用一组超高亲和力抗体，这些抗体具有中和三方炭疽毒素活性所有方面的冗余能力。这些工程化抗体组中最有前途的配方将通过与圣安东尼奥西南生物医学研究基金会 Jean Patterson 博士领导的分包商团队合作，在豚鼠以及最终恒河猴中进行炭疽孢子攻击研究来确定。