Clostridium difficile associated disease (CDAD) is an important cause of morbidity in hospital and nursing home patients, and is being increasingly recognized as an important cause of mortality. The objective of this project is to produce human monoclonal antibodies (Mabs) for the prevention and therapy of CDAD. Human Mabs have been generated against the two toxins of C. difficile using transgenic mice containing human immunoglobulin gene loci. In the first specific aim, Mabs will be characterized for their toxin neutralizing activity in vitro, as well as their specificity and antigen binding kinetics. The most potent neutralizing Mabs with the most desirable toxin-binding kinetics will be selected for production in a hollow fiber system to generate sufficient quantities for in vivo experiments. The second specific aim will evaluate these Mabs in a hamster model of C. difficile infection. Oral administration of the Mabs will be tested for prophylactic and therapeutic efficacy against CDAD, and the most effective Mabs will be chosen for clinical development. ? ? ?