Human Monoclonal Antibodies Directed against Toxins A and B Prevent Clostridium difficile-Induced Mortality in Hamsters▿
Autor: | Robert Mandell, Naomi K. Boatright, Katherine Donahue, Teresa J. Broering, Israel Lowy, Anne M. Stack, William D. Thomas, Deborah C. Molrine, Gregory J. Babcock, Donna M. Ambrosino, Hector Javier Hernandez, Robert F. Graziano |
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Jazyk: | angličtina |
Rok vydání: | 2006 |
Předmět: |
Immunology
Bacterial Toxins Clostridium difficile toxin A Hamster Clostridium difficile toxin B Mice Transgenic Enterotoxin medicine.disease_cause Microbiology Cell Line Enterotoxins Mice Bacterial Proteins Recurrence Cricetinae medicine Animals Humans Enterocolitis Pseudomembranous biology Toxin Clostridioides difficile Antibodies Monoclonal Clostridium difficile Virology Infectious Diseases Bezlotoxumab Microbial Immunity and Vaccines biology.protein Parasitology Antibody |
Popis: | Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile- associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficile disease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% ( P < 0.0001) in the primary disease hamster model and from 78% to 32% ( P < 0.0001) in the less stringent relapse model. |
Databáze: | OpenAIRE |
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