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

Zhiyong Yang, Diane Schmidt, Weilong Liu, Shan Li, Lianfa Shi, Jinliang Sheng, Kevin Chen, Hua Yu, Jacqueline M. Tremblay, Xinhua Chen, Kurt H. Piepenbrink, Eric J. Sundberg, Ciaran P. Kelly, Guang Bai, Charles B. Shoemaker, Hanping Feng

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)964-972
Number of pages9
JournalJournal of Infectious Diseases
Volume210
Issue number6
DOIs
StatePublished - Jan 1 2014

Keywords

  • Antibody
  • Clostridium difficile
  • Immunotherapy
  • Toxins
  • VHH

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Yang, Z., Schmidt, D., Liu, W., Li, S., Shi, L., Sheng, J., Chen, K., Yu, H., Tremblay, J. M., Chen, X., Piepenbrink, K. H., Sundberg, E. J., Kelly, C. P., Bai, G., Shoemaker, C. B., & Feng, H. (2014). A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant clostridium difficile infection in mice. Journal of Infectious Diseases, 210(6), 964-972. https://doi.org/10.1093/infdis/jiu196