Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab.

February 7, 2017 at 3:40 pm

Infect Immun. 2015 Feb;83(2):822-31.

Yang Z1, Ramsey J1, Hamza T1, Zhang Y1, Li S1, Yfantis HG2, Lee D2, Hernandez LD3, Seghezzi W4, Furneisen JM4, Davis NM4, Therien AG5, Feng H6.

Author information

1Department of Microbial Pathogenesis, University of Maryland Dental School, Baltimore, Maryland, USA.

2Department of Pathology and Laboratory Medicine, VAMHCS, University of Maryland School of Medicine, Baltimore, Maryland, USA.

3Merck & Co., Inc., Kenilworth, New Jersey, USA.

4Merck & Co., Inc., Palo Alto, California, USA.

5Merck & Co., Inc., Kenilworth, New Jersey, USA alex_therien@merck.com hfeng@umaryland.edu

6Department of Microbial Pathogenesis, University of Maryland Dental School, Baltimore, Maryland, USA alex_therien@merck.com hfeng@umaryland.edu

Abstract

Clostridium difficile infection (CDI) represents the most prevalent cause of antibiotic-associated gastrointestinal infections in health care facilities in the developed world.

Disease symptoms are caused by the two homologous exotoxins, TcdA and TcdB. Standard therapy for CDI involves administration of antibiotics that are associated with a high rate of disease recurrence, highlighting the need for novel treatment paradigms that target the toxins rather than the organism itself.

A combination of human monoclonal antibodies, actoxumab and bezlotoxumab, directed against TcdA and TcdB, respectively, has been shown to decrease the rate of recurrence in patients treated with standard-of-care antibiotics.

However, the exact mechanism of antibody-mediated protection is poorly understood. In this study, we show that the antitoxin antibodies are protective in multiple murine models of CDI, including systemic and local (gut) toxin challenge models, as well as primary and recurrent models of infection in mice.

Systemically administered actoxumab-bezlotoxumab prevents both the damage to the gut wall and the inflammatory response, which are associated with C. difficile in these models, including in mice challenged with a strain of the hypervirulent ribotype 027.

Furthermore, mutant antibodies (N297Q) that do not bind to Fcγ receptors provide a level of protection similar to that of wild-type antibodies, demonstrating that the mechanism of protection is through direct neutralization of the toxins and does not involve host effector functions.

These data provide a mechanistic basis for the prevention of recurrent disease observed in CDI patients in clinical trials

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http://iai.asm.org/content/83/2/822.full.pdf+html

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Entry filed under: Bacterias, Biológicos, Health Care-Associated Infections, Infecciones gastrointestinales, Infecciones nosocomiales, Metodos diagnosticos, Update.

Broad coverage of genetically diverse strains of Clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling. Zinplava Tackles Toxins Of Hard-to-Treat C. Difficile.


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