期刊
JOURNAL OF INFECTIOUS DISEASES
卷 210, 期 6, 页码 964-972出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiu196
关键词
Clostridium difficile; toxins; antibody; VHH; immunotherapy
资金
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01AI088748, R01DK084509, R56AI99458, N01-AI-30050, U54 AI057159]
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [R01AI088748, R01DK084509, R56AI99458, N01-AI-30050, U54 AI057159]
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 V-H (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 V(H)Hs that target both toxins and are broadly neutralizing for treating severe CDI.
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