UMMS Affiliation

Massachusetts Biologic Laboratories; Department of Pathology

Publication Date

9-13-2006

Document Type

Article

Subjects

Animals; Antibodies, Monoclonal; purification; Bacterial Proteins; inhibitors; Bacterial Toxins; inhibitors; Cell Line; Clostridium difficile; Cricetinae; Enterocolitis, Pseudomembranous; control; Enterotoxins; Humans; Mice; Mice, Transgenic; Recurrence

Disciplines

Laboratory and Basic Science Research | Medical Pathology

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.

Rights and Permissions

Citation: Infect Immun. 2006 Nov;74(11):6339-47. Epub 2006 Sep 11. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Infection and immunity

PubMed ID

16966409

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