Avanir Pharmaceuticals Inc., has developed a powerful platform for the rapid generation of high affinity fully human monoclonal antibodies that can be selected on their ability to neutralize anthrax toxin PA as exemplified by our lead candidate 8C1 (Kd 1.2 x10-12M, KinExA). Here we propose to continue the development of 8C1 as well as to isolate and characterize additional totally human monoclonal antibodies (MAbs) against B. anthracis exotoxin components protective antigen (PA) and lethal factor (LF). We will evaluate and characterize Mabs for affinity (using BiaCore and KinExA) and toxin neutralization (using an in vitro cell-based assay). Selected candidates will be further evaluated in a rodent animal model, using bolus challenge with recombinant anthrax toxins. By using multiple human donors, we will access a diverse a panel of antibodies and determine the optimal candidate(s) or combination of antibodies required to neutralize anthrax exotoxin in vivo. At the completion of this proposed study we will have candidates ready to enter the next stage of animal model evaluation. Testing candidates in live animal models with exposure to aerosolized anthrax spores are beyond the scope/budget of this study and would be the logical entry point for a phase II application. The following Specific Aims will be performed: -1: Generate a panel of high affinity fully human antibodies to PA and LF components of the tripartite B. anthracis exotoxin. -2: Evaluate and characterize MAbs binding and efficacy in an in vitro protection assay. -3: Determine protective efficacy in a rodent animal model, using bolus challenge with recombinant anthrax toxins.
| Peterson, Johnny W; Comer, Jason E; Baze, Wallace B et al. (2007) Human monoclonal antibody AVP-21D9 to protective antigen reduces dissemination of the Bacillus anthracis Ames strain from the lungs in a rabbit model. Infect Immun 75:3414-24 |
| Peterson, Johnny W; Comer, Jason E; Noffsinger, David M et al. (2006) Human monoclonal anti-protective antigen antibody completely protects rabbits and is synergistic with ciprofloxacin in protecting mice and guinea pigs against inhalation anthrax. Infect Immun 74:1016-24 |
| Sapra, R; Gaucher, S P; Lachmann, J S et al. (2006) Proteomic analyses of murine macrophages treated with Bacillus anthracis lethal toxin. Microb Pathog 41:157-67 |
| Wang, Fei; Ruther, Paul; Jiang, Ivy et al. (2004) Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly. Hum Antibodies 13:105-10 |
