Protection Against Clostridium difficile Infection With Broadly Neutralizing Antitoxin Monoclonal Antibodies

The spore-forming bacterium Clostridium difficile represents the principal cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. C. difficile infection (CDI) is mediated by 2 bacterial toxins, A and B; neutralizing these toxins with monoclonal antibodies (mAbs) provides a poten...

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Bibliographic Details
Published in:The Journal of infectious diseases 2012-09, Vol.206 (5), p.706-713
Main Authors: Marozsan, Andre J., Ma, Dangshe, Nagashima, Kirsten A., Kennedy, Brian J., Kang, Yun (Kenneth), Arrigale, Robert R., Donovan, Gerald P., Magargal, Wells W., Maddon, Paul J., Olson, William C.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - biosynthesis
Antibodies, Monoclonal - pharmacology
Antibodies, Neutralizing - biosynthesis
Antibodies, Neutralizing - pharmacology
Antitoxins
BACTERIA
Bacterial Proteins - metabolism
Bacterial Toxins - metabolism
Bacteriology
Biological and medical sciences
CHO Cells
Clostridium difficile
Clostridium difficile - metabolism
Cricetinae
Disease models
Dosage
Enterocolitis, Pseudomembranous - drug therapy
Enterocolitis, Pseudomembranous - microbiology
Enterotoxins - metabolism
Epitopes
Female
Fundamental and applied biological sciences. Psychology
Infections
Infectious diseases
Major and Brief Reports
Medical sciences
Mesocricetus
Mice
Mice, Inbred BALB C
Microbiology
Miscellaneous
Monoclonal antibodies
Neutralization Tests
Ribotyping
Survival Analysis
Toxins
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Description
Summary:The spore-forming bacterium Clostridium difficile represents the principal cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. C. difficile infection (CDI) is mediated by 2 bacterial toxins, A and B; neutralizing these toxins with monoclonal antibodies (mAbs) provides a potential nonantibiotic strategy for combating the rising prevalence, severity, and recurrence of CDI. Novel antitoxin mAbs were generated in mice and were humanized. The humanized antitoxin A mAb PA-50 and antitoxin mAb PA-41 have picomolar potencies in vitro and bind to novel regions of the respective toxins. In a hamster model for CDI, 95% of animals treated with a combination of humanized PA-50 and PA-41 showed long-term survival relative to 0% survival of animals treated with standard antibiotics or comparator mAbs. These humanized mAbs provide insight into C. difficile intoxication and hold promise as potential nonantibiotic agents for improving clinical management of CDI.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jis416