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.

艰难梭菌感染（CDI）是肠道中毒素介导的感染，是全球医疗机构的主要负担。我们认为，设计一种可在毒素产生部位传递并在毒素产生部位具有活性的抗体疗法将是有益的，而不是在发生肠层严重损伤后中和循环毒素和腔内毒素。在这里，我们描述了一种具有高抗体滴度的高效治疗药物OraCAb，该制剂可保护抗体免于胃肠道的消化/失活。OraCAb预防动物体内CDI的潜力体内 仓鼠模型和 体外评估人类结肠模型。在仓鼠模型中，我们优化了抗体对每种毒素产生的比例艰难梭菌（毒素A和B）。确定在CDI仓鼠模型中有效的免疫球蛋白浓度。观察到优化的OraCAb配方的动物与未治疗的对照组的动物存活率存在显着差异。这是第一个测试口服抗体治疗CDI的效果的研究。体外肠道模型接种人粪便接种物。用OraCAb治疗成功中和了毒素的产生，并且在该模型中不干扰结肠微生物群。此外，与单独使用万古霉素治疗不同，用万古霉素和OraCAb联合治疗可防止模拟CDI复发。这些数据证明了OraCAb制剂在临床前模型中治疗CDI的功效。