期刊
FRONTIERS IN MICROBIOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2020.578903
关键词
Clostridioides difficileinfection (CDI); immunotherapy of CDI; oral antibodies; formulation protecting antibodies from digestion; inactivation; in vivohamster model of CDI; in vitrohuman gut model of CDI
类别
资金
- Biomedical Catalyst Award (Innovate UK) [102845]
- SMARTCymru Project [1086-ED-RDI 286]
- UK Department of Health
- Innovate UK [102845] Funding Source: UKRI
- MRC [MC_PC_14092] Funding Source: UKRI
Clostridioides difficileinfection (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 anin vivohamster model and anin vitrohuman colon model was assessed. In the hamster model we optimized the ratio of the antibodies against each of the toxins produced byC. 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 anin vitrogut 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.
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