Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies.
The spore-forming bacterium Clostridium difficile represents the principal cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. C. difficile infection (CDI) is mediated by 2 bacterial toxins, A and B; neutralizing these toxins with monoclonal antibodies (mAbs) provides a potential nonantibiotic strategy for combating the rising prevalence, severity, and recurrence of CDI. Novel antitoxin mAbs were generated in mice and were humanized. The humanized antitoxin A mAb PA-50 and antitoxin B mAb PA-41 have picomolar potencies in vitro and bind to novel regions of the respective toxins. In a hamster model for CDI, 95% of animals treated with a combination of humanized PA-50 and PA-41 showed long-term survival relative to 0% survival of animals treated with standard antibiotics or comparator mAbs. These humanized mAbs provide insight into C. difficile intoxication and hold promise as potential nonantibiotic agents for improving clinical management of CDI.
Progenics Pharmaceuticals, Inc, Tarrytown, New York, USA. ajmphd@yahoo.com
Andre J
AJ
Marozsan
Dangshe
D
Ma
Kirsten A
KA
Nagashima
Brian J
BJ
Kennedy
Yun Kenneth
YK
Kang
Robert R
RR
Arrigale
Gerald P
GP
Donovan
Wells W
WW
Magargal
Paul J
PJ
Maddon
William C
WC
Olson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D016466:CHO Cells; D016360:Clostridioides difficile / Q000378:metabolism*; D006224:Cricetinae; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology; D004768:Enterotoxins / Q000378:metabolism*; D005260:Female; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D016019:Survival Analysis
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile