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.