A Novel, Orally Delivered Antibody Therapy and Its Potential to Prevent Clostridioides difficile Infection in Pre-clinical Models

April K. Roberts, Hannah C. Harris, Michael Smith, Joanna Giles, Oktawia Polak, Anthony M. Buckley, Emma Clark, Duncan Ewin, Ines B. Moura, William Spitall, Clifford Shone, Mark Wilcox, Caroline Chilton, Rossen Donev

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Abstract

Clostridioides difficile infection (CDI) is a toxin-mediated infection in the gut and a major burden on healthcare facilities worldwide. We rationalized that it would be beneficial to design an antibody therapy that is delivered to, and is active at the site of toxin production, rather than neutralizing the circulating and luminal toxins after significant damage of the layers of the intestines has occurred. Here we describe a highly potent therapeutic, OraCAb, with high antibody titers and a formulation that protects the antibodies from digestion/inactivation in the gastrointestinal tract. The potential of OraCAb to prevent CDI in an in vivo hamster model and an in vitro human colon model was assessed. In the hamster model we optimized the ratio of the antibodies against each of the toxins produced by C. difficile (Toxins A and B). The concentration of immunoglobulins that is effective in a hamster model of CDI was determined. A highly significant difference in animal survival for those given an optimized OraCAb formulation versus an untreated control group was observed. This is the first study testing the effect of oral antibodies for treatment of CDI in an in vitro gut model seeded with a human fecal inoculum. Treatment with OraCAb successfully neutralized toxin production and did not interfere with the colonic microbiota in this model. Also, treatment with a combination of vancomycin and OraCAb prevented simulated CDI recurrence, unlike vancomycin therapy alone. These data demonstrate the efficacy of OraCAb formulation for the treatment of CDI in pre-clinical models.

Original languageEnglish
Article number578903
JournalFrontiers in Microbiology
Volume11
DOIs
Publication statusPublished - 22 Sep 2020

Keywords

  • Clostridioides difficile infection (CDI)
  • formulation protecting antibodies from digestion/inactivation
  • immunotherapy of CDI
  • in vitro human gut model of CDI
  • in vivo hamster model of CDI
  • oral antibodies

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