期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 32, 页码 14070-14074出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1006473107
关键词
anthrax toxin; neutralizing antibody 1G3; passive immunization; protein therapeutics; single-particle analysis
资金
- University of Auckland
- University of Texas
- National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK060827]
- National Institutes of Health, National Institute of Allergy and Infectious Diseases
The tripartite protein exotoxin secreted by Bacillus anthracis, a major contributor to its virulence and anthrax pathogenesis, consists of binary complexes of the protective antigen (PA) heptamer (PA63h), produced by proteolytic cleavage of PA, together with either lethal factor or edema factor. The mouse monoclonal anti-PA antibody 1G3 was previously shown to be a potent antidote that shares F-C domain dependency with the human monoclonal antibody MDX-1303 currently under clinical development. Here we demonstrate that 1G3 instigates severe perturbation of the PA63h structure and creates a PA supercomplex as visualized by electron microscopy. This phenotype, produced by the unconventional mode of antibody action, highlights the feasibility for optimization of vaccines based on analogous structural modification of PA63h as an additional strategy for future remedies against anthrax.
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