Cryptosporidum parvum remains a major cause of persisten diarrheal illneess among AIDS patients. Crytosportidiosis in AIDS patients is exacerbated by the absecnce of an effective chemotherapy. Collective studi8es have provided evidence,however, that hyperimmune polyclonal antibody preparations or MAbs given orally may reduce the severity of diesease. We have focused on a monoclonal antibody (MAb) approach to prophylazis and treatment because these reagents have uniformity, can be produced in unlimited quantity, specificaly target important parasite antigens, can be validated for efficacy using in vitro and in vivo model systems, and based on results to date are likely to be useful in preventive or treatment strategies. In this 2 year final proposal we will continue with an integrated approach to complete pre-clinical efforts in developing an immunologic strategy aimed for preventing and treating crytosporitdiosis. Core facility B at Arizona will provide parasites for study to all projects. Projects 1 and 2 at Arizona will interact extensively to define optimal formulations of previously produced neurtalizing MAbs ddirected against the merozoite the sporozoite stages respectively and to define mechanisms of antibody- mediated neutralization. Project 3 at North Carolina State will use recombinant strategies to produce and characterize dimeric lgA MAbs agaisnt protective antigens which can be used in a strategy to control extraintestinal cryptosporidiosis. COre C at North Carolina State University will conduct the final pre-clinical testing and validation of MAbs for efficacy against peristent intestinal and extraintestinal cryptosporidiosis in immunodeficient mice. The entire project will be directed by Arizona (Core A). Upon completion of these objectives the business partner has entered a binding agreement to assume full responsibility for pre-clinical development and clinical trials.
