Leppla, Stephen (NIAID)
Emerson, Suzanne (NIAID)
Purcell, Robert (NIAID)
Moayeri, Mahtab (NIDCR)
Schneerson, Rachel (NICHD)
Kubler-kielb, Joanna (NICHD)
Dai, Lily Zhongdong (NICHD)
Anthrax, whether resulting from natural or bioterrorist-associated exposure, is a constant threat to human health. Bacillus anthracis is the causative agent of anthrax. It is surrounded by a polypeptide capsule of poly-gamma-D-glutamic acid (gamma-D-PGA), which is essential for virulence, is poorly immunogenic and has anti-phagocytic properties. Antibodies to the capsule have been shown to enhance phagocytosis and killing of encapsulated bacilli. The lethality of anthrax is primarily the result of the effects of anthrax toxin, which has 3 components: a receptor-binding protein known as "protective antigen" (PA) and 2 catalytic proteins known as "lethal factor" (LF) and "edema factor" (EF). Although production of an efficient anthrax vaccine is an ultimate goal, the benefits of vaccination can be expected only if a large proportion of the population at risk is immunized. The low incidence of anthrax suggests that large-scale vaccination may not be the most efficient means of controlling this disease. In contrast, passive administration of neutralizing human or chimpanzee monoclonal antibody to a subject at risk for anthrax or exposed to anthrax could provide immediate efficacy for emergency prophylaxis against or treatment of anthrax.
Several monoclonal antibodies (mAbs) against gamma-D-PGA, PA, LF and EF of anthrax were isolated from a phage display library generated from immunized chimpanzees. Two anti-PA, and two anti-LF mAbs efficiently neutralized the cytotoxicity of lethal toxin in a macrophage lysis assay. One anti-EF mAb efficiently neutralized edema toxin in cell culture. All of these five neutralizing mAbs protected animals from anthrax toxin challenge. There are two anti-gamma-D-PGA mAbs that showed strong opsonophagocytic killing of bacilli in vitro assays. These two mAbs were also tested for protection of mice challenged with virulent anthrax spores and results showed that both mAbs provided full or nearly full protection. Since chimpanzee immunoglobulins are virtually identical to human immunoglobulins, these chimeric chimpanzee mAbs may have clinically useful applications.
- Prophylaxis, therapeutics or diagnostics against B. anthracis antigens
- Strongly neutralizing antibodies
- Known regulatory pathway
- Potential for use as both a prophylaxis and therapy