A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection

Clostridium difficile infection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe, and Asia. CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increas...

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Published in:	Clinical and vaccine immunology Vol. 23; no. 9; pp. 774 - 784
Main Authors:	Schmidt, Diane J, Beamer, Gillian, Tremblay, Jacqueline M, Steele, Jennifer A, Kim, Hyeun Bum, Wang, Yaunkai, Debatis, Michele, Sun, Xingmin, Kashentseva, Elena A, Dmitriev, Igor P, Curiel, David T, Shoemaker, Charles B, Tzipori, Saul
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-09-2016
Subjects:	Adenoviridae Adenoviridae - genetics Adenovirus Animals Antibodies, Bacterial - therapeutic use Antibodies, Neutralizing - therapeutic use Antitoxins - therapeutic use Bacterial Proteins - antagonists & inhibitors Bacterial Toxins - antagonists & inhibitors Clinical Immunology Clostridium difficile Clostridium difficile - isolation & purification Clostridium Infections - microbiology Clostridium Infections - therapy Disease Models, Animal Drug Carriers Drug Evaluation, Preclinical Enterotoxins - antagonists & inhibitors Genetic Therapy - methods Mesocricetus Mice, Inbred C57BL Swine Treatment Outcome
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Summary:	Clostridium difficile infection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe, and Asia. CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse, complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. Therefore, it is critical to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here, we describe the construction of a single heteromultimeric VHH-based neutralizing agent (VNA) that targets the two primary virulence factors of Clostridium difficile, toxins A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has subnanomolar toxin neutralization potencies for both C. difficile toxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus that promoted the expression of VNA2-Tcd.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Schmidt DJ, Beamer G, Tremblay JM, Steele JA, Kim HB, Wang Y, Debatis M, Sun X, Kashentseva EA, Dmitriev IP, Curiel DT, Shoemaker CB, Tzipori S. 2016. A tetraspecific VHH-based neutralizing antibody modifies disease outcome in three animal models of Clostridium difficile infection. Clin Vaccine Immunol 23:774–784. doi:10.1128/CVI.00730-15.
ISSN:	1556-6811 1556-679X
DOI:	10.1128/CVI.00730-15