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Infection and Immunity, July 2007, p. 3414-3424, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00352-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Monoclonal Antibody AVP-21D9 to Protective Antigen Reduces Dissemination of the Bacillus anthracis Ames Strain from the Lungs in a Rabbit Model{triangledown}

Johnny W. Peterson,1,2* Jason E. Comer,1,2 Wallace B. Baze,4 David M. Noffsinger,1,2 Autumn Wenglikowski,1,2 Kristin G. Walberg,1,2 Jason Hardcastle,1,2 Jennifer Pawlik,1,2 Kathryn Bush,1,2 Joanna Taormina,1,2 Scott Moen,1,2 John Thomas,1,2 Bagram M. Chatuev,1,2 Laurie Sower,1,2 Ashok K. Chopra,1,2 Lawrence R. Stanberry,1,3 Ritsuko Sawada,5 Wolfgang W. Scholz,5 and Jagadish Sircar5

Sealy Center for Vaccine Development and Center for Biodefense and Emerging Infections,1 Departments of Microbiology and Immunology,2 Pediatrics, University of Texas Medical Branch, Galveston, Texas 77555-1070,3 University of Texas M.D. Anderson Cancer Center, Bastrop, Texas,4 Avanir Pharmaceuticals, Inc., San Diego, California5

Received 6 March 2007/ Accepted 10 April 2007

Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis disseminated to the bloodstream in some naïve animals as early as 24 h postchallenge and increased in frequency with time. AVP-21D9 significantly reduced the dissemination of the bacteria to the bloodstream and to various organs following infection. Examination of tissue sections from infected control animals, stained with hematoxylin-eosin and the Gram stain, showed edema and/or hemorrhage in the lungs and the presence of bacteria in mediastinal lymph nodes, with necrosis and inflammation. Tissue sections from infected rabbits dosed with AVP-21D9 appeared comparable to corresponding tissues from uninfected animals despite lethal challenge with B. anthracis Ames spores. Concomitant treatment with AVP-21D9 at the time of challenge conferred complete protection in the rabbit inhalation anthrax model. Early treatment increased the efficacy progressively and in a dose-dependent manner. Thus, AVP-21D9 could offer an adjunct or alternative clinical treatment regimen against inhalation anthrax.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1070. Phone: (409) 772-4910. Fax: (409) 772-4924. E-mail: johnny.peterson{at}utmb.edu

{triangledown} Published ahead of print on 23 April 2007.

Editor: J. B. Bliska

Infection and Immunity, July 2007, p. 3414-3424, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00352-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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