Archive for February 7, 2017

Zinplava Tackles Toxins Of Hard-to-Treat C. Difficile.

Manag Care. 2017 Jan;26(1):30-31.

Morrow T.

Abstract

Merck has recently received FDA approval for bezlotoxumab (Zinplava), as a treatment to reduce recurrence of C. diffcile in patients 18 years of age or older who are receiving antibiotic treatment for the infection and for whom there is a high risk of recurrence.

FULL TEXT

https://www.managedcaremag.com/linkout/2017/1/30

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February 7, 2017 at 3:41 pm

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

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

PDF

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

February 7, 2017 at 3:40 pm

Broad coverage of genetically diverse strains of Clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling.

Antimicrob Agents Chemother. 2015 Feb;59(2):1052-60.

Hernandez LD1, Racine F1, Xiao L1, DiNunzio E1, Hairston N1, Sheth PR1, Murgolo NJ1, Therien AG2.

Author information

1Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey, USA.

2Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey, USA alex_therien@merck.com.

Abstract

Clostridium difficile infections (CDIs) are the leading cause of hospital-acquired infectious diarrhea and primarily involve two exotoxins, TcdA and TcdB. Actoxumab and bezlotoxumab are human monoclonal antibodies that neutralize the cytotoxic/cytopathic effects of TcdA and TcdB, respectively. In a phase II clinical study, the actoxumab-bezlotoxumab combination reduced the rate of CDI recurrence in patients who were also treated with standard-of-care antibiotics.

However, it is not known whether the antibody combination will be effective against a broad range of C. difficile strains. As a first step toward addressing this, we tested the ability of actoxumab and bezlotoxumab to neutralize the activities of toxins from a number of clinically relevant and geographically diverse strains of C. difficile.

Neutralization potencies, as measured in a cell growth/survival assay with purified toxins from various C. difficile strains, correlated well with antibody/toxin binding affinities.

Actoxumab and bezlotoxumab neutralized toxins from culture supernatants of all clinical isolates tested, including multiple isolates of the BI/NAP1/027 and BK/NAP7/078 strains, at antibody concentrations well below plasma levels observed in humans.

We compared the bezlotoxumab epitopes in the TcdB receptor binding domain across known TcdB sequences and found that key substitutions within the bezlotoxumab epitopes correlated with the relative differences in potencies of bezlotoxumab against TcdB of some strains, including ribotypes 027 and 078.

Combined with in vitro neutralization data, epitope modeling will enhance our ability to predict the coverage of new and emerging strains by actoxumab-bezlotoxumab in the clinic.

PDF

http://aac.asm.org/content/59/2/1052.full.pdf+html

February 7, 2017 at 3:38 pm


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