title: Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters.
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.
authors.affiliation: Massachusetts Biologic Laboratories, University of Massachusetts Medical School, 305 South St., Jamaica Plain, MA 02130, and Children's Hospital Boston, Division of Emergency Medicine 02115, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Babcock
authors.forename: Teresa J
authors.initials: TJ
authors.lastname: Broering
authors.forename: Hector J
authors.initials: HJ
authors.lastname: Hernandez
authors.forename: Robert B
authors.initials: RB
authors.lastname: Mandell
authors.forename: Katherine
authors.initials: K
authors.lastname: Donahue
authors.forename: Naomi
authors.initials: N
authors.lastname: Boatright
authors.forename: Anne M
authors.initials: AM
authors.lastname: Stack
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Robert
authors.initials: R
authors.lastname: Graziano
authors.forename: Deborah
authors.initials: D
authors.lastname: Molrine
authors.forename: Donna M
authors.initials: DM
authors.lastname: Ambrosino
authors.forename: William D
authors.initials: WD
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology*; D002460:Cell Line; D016360:Clostridioides difficile / Q000276:immunology*; D006224:Cricetinae; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology / Q000401:mortality* / Q000517:prevention & control*; D004768:Enterotoxins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D012008:Recurrence
chemical_list: D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile