title: A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice.
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.
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Tufts Cummings School of Veterinary Medicine, North Grafton.
authors.forename: Diane
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Tufts Cummings School of Veterinary Medicine, North Grafton.
authors.forename: Weilong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Lianfa
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.affiliation: Tufts Cummings School of Veterinary Medicine, North Grafton.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tremblay
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Human Virology.
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Piepenbrink
authors.affiliation: Institute of Human Virology Department of Medicine Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ciaran P
authors.initials: CP
authors.lastname: Kelly
authors.affiliation: Department of Neural and Pain Sciences, University of Maryland Dental School.
authors.forename: Guang
authors.initials: G
authors.lastname: Bai
authors.affiliation: Tufts Cummings School of Veterinary Medicine, North Grafton.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shoemaker
authors.affiliation: Department of Microbial Pathogenesis.
authors.forename: Hanping
authors.initials: H
authors.lastname: Feng
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000276:immunology; D016360:Clostridioides difficile / Q000276:immunology*; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology / Q000517:prevention & control*; D004768:Enterotoxins / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051379:Mice; D009500:Neutralization Tests
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile
keywords: Clostridium difficile; VHH; antibody; immunotherapy; toxins