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

Authors

Zhiyong Yang, University of Maryland Dental School
Diane Schmidt, Tufts Cummings School of Veterinary Medicine
Weilong Liu, Tufts Cummings School of Veterinary Medicine
Shan Li, University of Maryland Dental School
Lianfa Shi, University of Maryland Dental School
Jinliang Sheng, University of Maryland Dental School
Kevin Chen, University of Maryland Dental School
Hua Yu, University of Maryland Dental School
Jacqueline M. Tremblay, Tufts Cummings School of Veterinary Medicine
Xinhua Chen, Harvard Medical School
Kurt H. Piepenbrink, University of Maryland School of MedicineFollow
Eric J. Sundberg, University of Maryland School of Medicine
Ciaran P. Kelly, Harvard Medical School
Guang Bai, University of Maryland Dental School
Charles B. Shoemaker, Tufts Cummings School of Veterinary Medicine
Hanping Feng, University of Maryland Dental School

Date of this Version

3-27-2014

Document Type

Article

Citation

J Infect Dis. 2014 Sep 15; 210(6): 964–972. Published online 2014 Mar 27. doi: 10.1093/infdis/jiu196 PMCID: PMC4192054 PMID: 24683195

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 V_H (V_HH) 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.