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A Protein Microarray Assay for Serological Determination of Antigen-specific Antibody Responses Following Clostridium difficile Infection
Published on: June 15, 2018
Novel Clostridium difficile Anti-Toxin (TcdA and TcdB) Humanized Monoclonal Antibodies Demonstrate In Vitro
Hongyu Qiu1, Robyn Cassan1, Darrell Johnstone1
1Cangene Corporation, a subsidiary of Emergent BioSolutions Inc., 155 Innovation Drive, Winnipeg, MB, R3T 5Y3, Canada.
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.
Insights
Novel humanized monoclonal antibodies targeting Clostridium difficile toxins A and B offer a promising therapeutic strategy. These antibodies neutralize toxins in vitro and in vivo, significantly protecting hamsters against infection and reducing mortality.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Clostridium difficile infection (CDI) is a major cause of antibiotic-associated colitis and diarrhea.
- Current antibiotic treatments for CDI are effective but frequently lead to recurrence, particularly in elderly patients.
- Pathogenic C. difficile strains produce toxins A (TcdA) and B (TcdB), essential for disease development.
Purpose of the Study:
- To generate and characterize humanized monoclonal antibodies targeting C. difficile toxins A and B.
- To evaluate the in vitro and in vivo efficacy of these antibodies in preventing CDI.
Main Methods:
- Generation of humanized anti-TcdA and anti-TcdB monoclonal antibodies.
- In vitro toxin neutralization assays using clinical C. difficile strains.
- In vivo efficacy studies in mouse toxin challenge and hamster gastrointestinal infection models.
Main Results:
- Humanized antibodies CANmAbA4 (anti-TcdA), CANmAbB4, and CANmAbB1 (anti-TcdB) demonstrated broad in vitro toxin neutralization.
- These antibodies neutralized toxins in a mouse model.
- A cocktail of CANmAbA4 and CANmAbB4 provided dose-dependent protection in a hamster CDI model, with 85% survival at 50 mg/kg.
Conclusions:
- Novel humanized monoclonal antibodies effectively neutralize C. difficile toxins.
- These antibodies show significant protective potential against CDI in preclinical models.
- The anti-toxin antibody cocktail represents a promising therapeutic candidate for treating C. difficile infection.
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