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

February 7, 2017 at 3:38 pm

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

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

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