Human Monoclonal Antibodies Directed against Toxins A and B Prevent Clostridium difficile-Induced Mortality in Hamsters

GJ Babcock, TJ Broering, HJ Hernandez… - Infection and …, 2006 - Am Soc Microbiol
GJ Babcock, TJ Broering, HJ Hernandez, RB Mandell, K Donahue, N Boatright, AM Stack
Infection and immunity, 2006Am Soc Microbiol
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 …
Abstract
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.
American Society for Microbiology