Clostridium difficile infection, the cause of antibiotic-associated pseudomembraneous colitis, is a growing national health problem. The incidence of primary Clostridium difficile-infection in the hospitalized U.S. population is greater than 400,000 cases annually. There is a high incidence of relapse. C. difficile infection is also a significant problem among patients with ulcerative colitis. This infection is often difficult to differentiate from the manifestations of the underlying inflammatory bowel disease. Therapies for C. difficile infection are a special emphasis area of the NIAID. For these reasons there is an urgent need for new non-antibiotic based prophylactic and therapeutic approaches to treat this potentially life threatening disease. The novel therapeutic approach proposed in this application is an orally administered immunotherapy consisting of affinity purified polyclonal human secretory IgA (sIgA) formed by the innovative technical process of combining plasma derived dimeric IgA with recombinant human secretory component. Secretory IgA derived from plasma IgA1 is resistant to digestion. Affinity purification will provide consistent high titer antibodies. Tons of the starting material are discarded annually as a byproduct of the manufacture of intravenous immunoglobulin. This innovative oral immunotherapy will provide a significant clinical advantage over passive immunization with parenterally administered recombinant monoclonal and polyclonal IgG antibodies. We have already demonstrated that plasma derived IgA binds to C. difficile toxins A and B and neutralizes these toxins in a cell-based assay. We have also demonstrated the ability to synthesize sIgA in the laboratory. CSL Behring, Ltd. has found that plasma derived sIgA is effective in preventing recurrent C. difficile disease in a mouse model. The long-term goal of this project is to commercialize orally administered semisynthetic human secretory immunoglobulin A for the prophylaxis and treatment of Clostridium difficile infection.
The Specific Aims are: 1) to demonstrate scalable production of affinity purified sIgA, our lead candidate for oral sIgA immunotherapy of C. difficile disease; 2) demonstrate that affinity purified sIgA neutralizes C. difficile toxins A and B in a cell-based assay; and 3) demonstrate that oral immunotherapy with affinity purified semi-synthetic sIgA is efficacious in protection against C. difficile colitis using our established mouse model of this disease.
The proposed research is relevant to the NIH's mission to reduce the burdens of human disease and disability because there is an unmet and urgent need for new prophylactic and therapeutic approaches to combat Clostridium difficile infection, a bacterial infection of the gut that leads to severe diarrhea, fever, abdominal pain and even death. The incidence of Clostridium difficile infection in hospitalized patients is greater than 400,000 cases per year in the U.S. while treatment of this disease costs an additional $35,000 per patient, and leads to over $3B in excess health care costs annually (APIC National US Inpatient Healthcare Facility Clostridium difficile Survey, 2008). Secretory IgA, Inc. will develop and commercialize an orally administered antibody therapy for the prophylaxis and treatment of Clostridium difficile infection which consists of a semi- synthetic purified human secretory IgA antibody which acts in the intestines by neutralizing the gut-damaging toxins produced by the infecting bacteria.
