A Combination of Three Fully Human Toxin A- and Toxin B-Specific Monoclonal Antibodies Protects against Challenge with Highly Virulent Epidemic Strains of Clostridium difficile in the Hamster Model.
Clostridium difficile infection (CDI) is the principal cause of nosocomial diarrhea and pseudomembranous colitis associated with antibiotic therapy. Recent increases in the number of outbreaks attributed to highly virulent antibiotic-resistant strains underscore the importance of identifying efficacious alternatives to antibiotics to control this infection. CDI is mediated by two large exotoxins, toxins A and B. Strong humoral toxin-specific immune responses are associated with recovery and a lack of disease recurrence, whereas insufficient humoral responses are associated with recurrent CDI. Multiple approaches targeting these toxins, including intravenous immunoglobulin, neutralizing polymers, active vaccines, and, most recently, monoclonal antibodies (MAbs), have been explored, with various degrees of success. In this study, we describe the characterization of the first MAbs isolated from healthy human donors using a high-throughput B-cell cloning strategy. The MAbs were selected based on their ability to inhibit the actions of toxins A and B in vitro and because of their in vivo efficacy in a hamster challenge model. A potent 2-MAb cocktail was identified and then further potentiated by the addition of a second anti-toxin B MAb. This 3-MAb combination protected animals against mortality and also reduced the severity and duration of diarrhea associated with challenge with highly virulent strains of C. difficile toxinotypes 0 and III. This highly efficacious cocktail consists of one MAb specific to the receptor binding domain of toxin A and two MAbs specific to nonoverlapping regions of the glucosyltransferase domain of toxin B. This MAb combination offers great potential as a nonantibiotic treatment for the prevention of recurrent CDI.
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA natalie.anosova@sanofipasteur.com.
Natalie G
http://orcid.org/0000-0002-1920-8245
NG
Anosova
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Leah E
LE
Cole
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Lu
L
Li
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Jinrong
J
Zhang
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Anna M
AM
Brown
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Sophia
S
Mundle
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Jianxin
J
Zhang
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Satyajit
S
Ray
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Fuqin
F
Ma
BliNK Biomedical SAS, Lyon, France.
Pierre
P
Garrone
BliNK Biomedical SAS, Lyon, France.
Nicola
N
Bertraminelli
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Harry
H
Kleanthous
Sanofi Pasteur Biologics, Cambridge, Massachusetts, USA.
Stephen F
SF
Anderson
D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000992:Antitoxins / Q000008:administration & dosage / Q000276:immunology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D016360:Clostridioides difficile / Q000276:immunology*; D003015:Clostridium Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003967:Diarrhea / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008647:Mesocricetus; D016019:Survival Analysis; D016896:Treatment Outcome
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile