title: Human monoclonal anti-protective antigen antibody completely protects rabbits and is synergistic with ciprofloxacin in protecting mice and guinea pigs against inhalation anthrax.
abstract: Prevention of inhalation anthrax requires early and extended antibiotic therapy, and therefore, alternative treatment strategies are needed. We investigated whether a human monoclonal antibody (AVP-21D9) to protective antigen (PA) would protect mice, guinea pigs, and rabbits against anthrax. Control animals challenged with Bacillus anthracis Ames spores by the intranasal route died within 3 to 7 days. AVP-21D9 alone provided minimal protection against anthrax in the murine model, but its efficacy was notably better in guinea pigs. When Swiss-Webster mice, challenged with five 50% lethal doses (LD50s) of anthrax spores, were given a single 16.7-mg/kg of body weight AVP-21D9 antibody dose combined with ciprofloxacin (30 mg/kg/day for 6 days) 24 h after challenge, 100% of the mice were protected for more than 30 days, while ciprofloxacin or AVP-21D9 alone showed minimal protection. Similarly, when AVP-21D9 antibody (10 to 50 mg/kg) was combined with a low, nonprotective dose of ciprofloxacin (3.7 mg/kg/day) and administered to guinea pigs for 6 days, synergistic protection against anthrax was observed. In contrast, a single dose of AVP-21D9 antibody (1, 5, 10, or 20 mg/kg) but not 0.2 mg/kg alone completely protected rabbits against challenge with 100 LD50s of B. anthracis Ames spores, and 100% of the rabbits survived rechallenge. Further, administration of AVP-21D9 (10 mg/kg) to rabbits at 0, 6, and 12 h after challenge with anthrax spores resulted in 100% survival; however, delay of antibody treatment by 24 and 48 h reduced survival to 80% and 60%, respectively. Serological analysis of sera from various surviving animals 30 days postprimary infection showed development of a species-specific PA enzyme-linked immunosorbent assay antibody titer that correlated with protection against reinfection. Taken together, the effectiveness of human anti-PA antibody alone or in combination with low ciprofloxacin levels may provide the basis for an improved strategy for prophylaxis or treatment following inhalation anthrax infection.
authors.affiliation: Sealy Center for Vaccine Development, Center for Biodefense and Emerging Infections, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1070, USA. johnny.peterson@utmb.edu
authors.forename: Johnny W
authors.initials: JW
authors.lastname: Peterson
authors.forename: Jason E
authors.initials: JE
authors.lastname: Comer
authors.forename: David M
authors.initials: DM
authors.lastname: Noffsinger
authors.forename: Autumn
authors.initials: A
authors.lastname: Wenglikowski
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Walberg
authors.forename: Bagram M
authors.initials: BM
authors.lastname: Chatuev
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chopra
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Stanberry
authors.forename: Angray S
authors.initials: AS
authors.lastname: Kang
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Scholz
authors.forename: Jagadish
authors.initials: J
authors.lastname: Sircar
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D000942:Antigens, Bacterial / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000627:therapeutic use; D004357:Drug Synergism; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D011817:Rabbits
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D002939:Ciprofloxacin