Development of an Orally Available Therapeutic for Neutralizing C. difficile Toxin B

Infection with the bacterium C. difficile is the most common and increasingly prevalent cause of diarrhea. In the United States, cases of C. difficile infection (CDI) are estimated to number 500,000 annually and to result in an estimated 15,000 to 30,000 deaths. The cost of these cases is thought to exceed $4.8 billion annually. CDI continues to cause discomfort, serious illness and sometimes death despite several available lines of treatment. Current treatments include antibiotics, fecal transplant, and an antibody. The antibody represents a new approach to treating CDI by neutralizing toxins secreted by C. difficile rather than killing the bacteria or stopping their growth. One limitation of the antibody is that it needs to be delivered via an injection instead of taken by mouth. The long-term objective of the proposed research is to develop a new treatment that binds to and neutralize the toxins made by C. difficile and that may be taken by mouth. The treatment is based on a novel nanoCLAMP protein similar to antibodies in its structure and potential to neutralize C. difficile toxin. However, compared with antibodies, nanoCLAMPs are much more resistant to the destructive effect of digestive enzymes. Resistance to digestive enzymes may enable patients to take this medicine orally and avoid a painful injection. The objectives of the current proposal are to 1. Select lead anti-TcdB nanoCLAMPs with TcdB-neutralizing activity and developable biophysical properties. 2. Assess dose-exposure relationship for anti-TcdB nanoCLAMPs in enteric capsules. 3. Evaluate efficacy in acute and recurrence mouse models of C. difficile infection.