Clostridium difficile is a common cause of both hospital- and community acquired gastrointestinal infection that may occur after patients have been treated for other infections with a variety of antimicrobial agents. While mostly causing antibiotic-associated diarrhea, C. difficile infection may cause more severe disease and may be refractory to current standard forms of therapy. In recent years, a more virulent strain of C. difficile has emerged that has caused serious disease in some patients. The pathogenesis of C. difficile infection, while not completely understood, involves the action of two toxins, toxin-A (TcdA) and toxin-B (TcdB), produced by the organism, on the gut epithelium. There is very good evidence showing that antibodies against TcdA and TcdB have protective effects against disease in humans and in animal models of C. difficile colitis. The purpose of the current study is to develop an antibody-based immunotherapy for C. difficile infection by cloning human monoclonal antibodies (mAbs) from individuals with C. difficile and determine whether these antibodies can protect against disease using a hamster model of infection. The antibodies will be produced in vitro by cloning patients'antibodies using a phage display system, a technique for which Dr. Donald Siegel, Co- Investigator of the study, is among the pioneers. Toxin specific antibodies will be produced in vitro and will be tested for the ability of these antibodies to protect animals from developing C. difficile colitis. Use of this technology over the past 15 years has produced human monoclonal antibodies with specificities against a large number of human auto- and alloantigens, and human infectious agents. Thus, phage display technology is an ideal approach for producing completely human proteins in a way that exploits the human immune system's ability to generate large repertoires of high affinity, antigen selected, antibodies with varying specificities for disease- associated epitopes. Given the multitude of antibodies that will be developed in this proposal, the strategy will provide enough reagents for characterization and allow us to choose optimal antibodies (or combinations of antibodies) as lead compounds for therapeutic use.

Public Health Relevance

C difficile is one of the most common causes of antibiotic associated diarrhea in healthcare settings as is being increasingly recognized as a community acquired infection. Patients with nosocomially acquired C. difficile disease incur significantly higher hospital costs and length of stay and has been estimated to exceed 1 billion dollars in the US. Thus, C. difficile disease is of considerable public health concern.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Ranallo, Ryan
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University of Pennsylvania
Schools of Medicine
United States
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