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

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

doi:10.3389/fmicb.2020.578903

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.

Highlights

Clostridioides difficile infection (CDI) is a leading cause of infectious antibiotic associated diarrhea and a major burden on healthcare facilities worldwide (Wiegand et al, 2012; Lessa et al, 2015; Guh et al, 2020)
Using platform technologies established by MicroPharm and Public Health England (PHE), we have developed OraCAb, a novel orally delivered ovine polyclonal antibody product targeted toward C. difficile toxins
The lower neutralizing capacity of antibodies to TxB4 was taken into account in the design of the protocols used in the hamster model and the in vitro gut model

Summary

Introduction

Clostridioides difficile infection (CDI) is a leading cause of infectious antibiotic associated diarrhea and a major burden on healthcare facilities worldwide (Wiegand et al, 2012; Lessa et al, 2015; Guh et al, 2020). Alternative therapies directed at neutralizing TcdA and TcdB and restoring the disrupted microbiome are in development. These include antibody-based therapies, vaccines and fecal microbiome transfer (FMT) and are summarized by Madoff et al (2019). It should be noted that despite the promising benefits reported for FMT, the transmission of an extended-spectrum beta-lactamase producing Escherichia coli to two patients in two independent clinical trials has been reported. Both patients developed bacteraemia and one died. The screening of FMT donors requires improvement (DeFilipp et al, 2019)

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