A Novel Multivalent, Single-Domain Antibody Targeting TcdA and TcdB Prevents Fulminant Clostridium difficile Infection in Mice

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

来源：Journal of Infectious Diseases, 2014, 210(6): 964-972.

DOI：10.1093/infdis/jiu196

• Clostridium difficile
• toxins
• antibody
• VHH
• immunotherapy

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.

• 出版日期2014-9-15