This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vitale, L. Articles by Keler, T. Search for Related Content PubMed PubMed Citation Articles by Vitale, L. Articles by Keler, T.

 Previous Article  |  Next Article 

Infection and Immunity, October 2006, p. 5840-5847, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00712-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Prophylaxis and Therapy of Inhalational Anthrax by a Novel Monoclonal Antibody to Protective Antigen That Mimics Vaccine-Induced Immunity

Laura Vitale,^1, Diann Blanset,¹ Israel Lowy,¹ Thomas O'Neill,^1, Joel Goldstein,¹ Stephen F. Little,² Gerard P. Andrews,^2, Gary Dorough,³ Ronald K. Taylor,⁴ and Tibor Keler^1*

Medarex, Inc., Bloomsbury, New Jersey 08804,¹ United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702,² PharmAthene, Inc., Annapolis, Maryland 21401,³ Department of Microbiology and Immunology, Dartmouth Medical School, and Institute for Security Technology Studies, Dartmouth College, Hanover, New Hampshire 03755⁴

Received 3 May 2006/ Returned for modification 31 May 2006/ Accepted 7 July 2006

The neutralizing antibody response to the protective antigen (PA) component of anthrax toxin elicited by approved anthrax vaccines is an accepted correlate for vaccine-mediated protection against anthrax. We reasoned that a human anti-PA monoclonal antibody (MAb) selected on the basis of superior toxin neutralization activity might provide potent protection against anthrax. The fully human MAb (also referred to as MDX-1303 or Valortim) was chosen from a large panel of anti-PA human MAbs generated using transgenic mice immunized with recombinant PA solely on the basis of in vitro anthrax toxin neutralization. This MAb was effective in prophylactic and postsymptomatic treatment of rabbits exposed to aerosolized anthrax spores, and a single intramuscular injection of 1 mg/kg of body weight fully protected cynomolgus monkeys challenged with aerosolized anthrax spores. Importantly, MAb 1303 defines a novel neutralizing epitope that requires Fc receptor engagement for maximal activity. F(ab')2 fragments of MAb 1303, which retain equivalent affinity for PA, are 10- to 100-fold less potent in neutralizing anthrax toxin in vitro. Addition of Fc receptor-blocking antibodies also greatly reduced the activity of MAb 1303. Moreover, we found that the neutralizing activity of mouse, rabbit, and human antisera elicited by PA vaccines was effectively abrogated by blocking Fc receptors. Selection of an anti-PA MAb by using a functional assay that is a surrogate for protection has resulted in the identification of a fully human MAb with potent activity in vivo and uncovered a previously unrecognized mechanism of antibody-mediated toxin neutralization that is important for currently used anthrax vaccines.

Editor: A. D. O'Brien

Present address: Celldex Therapeutics, Inc., Philipsburg, NJ 08865.

Present address: Department of Veterinary Science, University of Wyoming, Wyoming State Veterinary Laboratory, Laramie, WY 82070.