Open AccessNovel Clostridium difficile Anti-Toxin (TcdA and TcdB) Humanized Monoclonal Antibodies Demonstrate In Vitro Neutralization across a Broad Spectrum of Clinical Strains and In Vivo Potency in a Hamster Spore Challenge Model
Author(s) -
Hongyu Qiu,
Robyn Cassan,
Darrell Johnstone,
Xiaobing Han,
Antony George Joyee,
Monica McQuoid,
Andrea Masi,
John Merluza,
Bryce Hrehorak,
Ross Reid,
Kieron Kennedy,
Bonnie Tighe,
Carla Rak,
Melanie Leonhardt,
Brian Dupas,
Laura Saward,
Jody D. Berry,
Cory L. Nykiforuk
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0157970
Subject(s) - clostridium difficile toxin a , clostridium difficile , neutralization , monoclonal antibody , clostridium difficile toxin b , microbiology and biotechnology , antibody , virology , toxin , antibiotics , potency , biology , enterotoxin , in vitro , immunology , biochemistry , escherichia coli , gene
Clostridium difficile ( C . difficile ) infection (CDI) is the main cause of nosocomial antibiotic-associated colitis and increased incidence of community-associated diarrhea in industrialized countries. At present, the primary treatment of CDI is antibiotic administration, which is effective but often associated with recurrence, especially in the elderly. Pathogenic strains produce enterotoxin, toxin A (TcdA), and cytotoxin, toxin B (TcdB), which are necessary for C . difficile induced diarrhea and gut pathological changes. Administration of anti-toxin antibodies provides an alternative approach to treat CDI, and has shown promising results in preclinical and clinical studies. In the current study, several humanized anti-TcdA and anti-TcdB monoclonal antibodies were generated and their protective potency was characterized in a hamster infection model. The humanized anti-TcdA (CANmAbA4) and anti-TcdB (CANmAbB4 and CANmAbB1) antibodies showed broad spectrum in vitro neutralization of toxins from clinical strains and neutralization in a mouse toxin challenge model. Moreover, co-administration of humanized antibodies (CANmAbA4 and CANmAbB4 cocktail) provided a high level of protection in a dose dependent manner (85% versus 57% survival at day 22 for 50 mg/kg and 20 mg/kg doses, respectively) in a hamster gastrointestinal infection (GI) model. This study describes the protective effects conferred by novel neutralizing anti-toxin monoclonal antibodies against C . difficile toxins and their potential as therapeutic agents in treating CDI.