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J Infect Dis. 2014 Sep 15;210(6):964-72. doi: 10.1093/infdis/jiu196. Epub 2014 Mar 27.

A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice.

Author information

1
Department of Microbial Pathogenesis.
2
Tufts Cummings School of Veterinary Medicine, North Grafton.
3
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
4
Institute of Human Virology.
5
Institute of Human Virology Department of Medicine Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland.
6
Department of Neural and Pain Sciences, University of Maryland Dental School.

Abstract

The incidence of Clostridium difficile infection (CDI) and associated mortality have increased rapidly worldwide in recent years. Therefore, it is critical to develop new therapies for CDI. In this study, we generated a novel, potently neutralizing, tetravalent, and bispecific antibody composed of 2 heavy-chain-only VH (VHH) binding domains against both TcdA and TcdB (designated "ABA") that reverses fulminant CDI in mice infected with an epidemic 027 strain after a single injection of the antibody. We demonstrated that ABA bound to both toxins simultaneously and displayed a significantly enhanced neutralizing activity both in vitro and in vivo. Additionally, ABA was able to broadly neutralize toxins from clinical C. difficile isolates that express both TcdA and TcdB but failed to neutralize the toxin from TcdA(-)TcdB(+) C. difficile strains. This study thus provides a rationale for the development of multivalent VHHs that target both toxins and are broadly neutralizing for treating severe CDI.

KEYWORDS:

Clostridium difficile; VHH; antibody; immunotherapy; toxins

PMID:
24683195
PMCID:
PMC4192054
DOI:
10.1093/infdis/jiu196
[Indexed for MEDLINE]
Free PMC Article

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