title: Novel 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.
abstract: 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.
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Robyn
authors.initials: R
authors.lastname: Cassan
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Darrell
authors.initials: D
authors.lastname: Johnstone
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Han
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Antony George
authors.initials: AG
authors.lastname: Joyee
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: McQuoid
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Masi
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Merluza
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Bryce
authors.initials: B
authors.lastname: Hrehorak
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Ross
authors.initials: R
authors.lastname: Reid
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Kieron
authors.initials: K
authors.lastname: Kennedy
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Tighe
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Carla
authors.initials: C
authors.lastname: Rak
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Leonhardt
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Dupas
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Saward
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Jody D
authors.initials: JD
authors.lastname: Berry
authors.affiliation: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
authors.forename: Cory L
authors.initials: CL
authors.lastname: Nykiforuk
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000992:Antitoxins / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D016360:Clostridioides difficile / Q000276:immunology / Q000302:isolation & purification; D003015:Clostridium Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D006224:Cricetinae; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D009500:Neutralization Tests; D013171:Spores, Bacterial
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D007074:Immunoglobulin G; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile