Oral Immunotherapy with IgA to Treat Clostridium difficile Infection

Clostridium difficile infectionthe cause of antibiotic associated pseudomembraneous colitisis a growing national health problemThe incidence of primary Clostridium difficile infection in the hospitalized U Spopulation is greater thancases annuallyThere is a high incidence of relapseCdifficile infection is also a significant problem among patients with ulcerative colitisThis infection is often difficult to differentiate from the manifestations of the underlying inflammatory bowel diseaseTherapies for Cdifficile infection are a special emphasis area of the NIAIDFor these reasons there is an urgent need for new non antibiotic based prophylactic and therapeutic approaches to treat this potentially life threatening diseaseThe novel therapeutic approach proposed in this application is an orally administered immunotherapy consisting of affinity purified polyclonal human secretory IgAsIgAformed by the innovative technical process of combining plasma derived dimeric IgA with recombinant human secretory componentSecretory IgA derived from plasma IgAis resistant to digestionAffinity purification will provide consistent high titer antibodiesTons of the starting material are discarded annually as a byproduct of the manufacture of intravenous immunoglobulinThis innovative oral immunotherapy will provide a significant clinical advantage over passive immunization with parenterally administered recombinant monoclonal and polyclonal IgG antibodiesWe have already demonstrated that plasma derived IgA binds to Cdifficile toxins A and B and neutralizes these toxins in a cell based assayWe have also demonstrated the ability to synthesize sIgA in the laboratoryCSL BehringLtdhas found that plasma derived sIgA is effective in preventing recurrent Cdifficile disease in a mouse modelThe long term goal of this project is to commercialize orally administered semisynthetic human secretory immunoglobulin A for the prophylaxis and treatment of Clostridium difficile infectionThe Specific Aims areto demonstrate scalable production of affinity purified sIgAour lead candidate for oral sIgA immunotherapy of Cdifficile diseasedemonstrate that affinity purified sIgA neutralizes Cdifficile toxins A and B in a cell based assayanddemonstrate that oral immunotherapy with affinity purified semi synthetic sIgA is efficacious in protection against Cdifficile colitis using our established mouse model of this disease