A Novel, Orally Delivered Antibody Therapy and Its Potential to Prevent Clostridioides difficile Infection in Pre-clinical Models.
A Novel, Orally Delivered Antibody Therapy and Its Potential to Prevent Clostridioides difficile Infection in Pre-clinical Models.
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DOI：
10.3389/fmicb.2020.578903
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发表时间：
2020
影响因子：
5.2
通讯作者：
Donev R
中科院分区：
文献类型：
--
作者：
Roberts AK;Harris HC;Smith M;Giles J;Polak O;Buckley AM;Clark E;Ewin D;Moura IB;Spitall W;Shone CC;Wilcox M;Chilton C;Donev R
艰难梭菌感染（CDI）是一种毒素介导的肠道感染，是全球医疗机构的主要负担。我们合理地认为，设计一种抗体疗法将是有益的，该抗体疗法被递送到毒素产生部位并在毒素产生部位具有活性，而不是在肠层发生显著损伤后中和循环和管腔毒素。在这里，我们描述了一种高效的治疗，OraCAb，具有高抗体滴度和配方，保护抗体在胃肠道消化/失活。在体内仓鼠模型和体外人结肠模型中评估了OraCAb预防CDI的潜力。在仓鼠模型中，我们优化了针对C.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。观察到给予优化OraCAb制剂的动物与未处理对照组的动物存活率存在高度显著差异。这是首次在接种人粪便接种物的体外肠道模型中测试口服抗体治疗CDI的效果的研究。在该模型中，OraCAb治疗成功中和了毒素产生，并且不干扰结肠微生物群。此外，与万古霉素单独治疗不同，万古霉素和OraCAb联合治疗可预防模拟CDI复发。这些数据证明了OraCAb制剂在临床前模型中治疗CDI的疗效。
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.
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美国梭菌艰难梭菌感染和结果负担的趋势。
DOI：
10.1056/nejmoa1910215
发表时间：
2020-04-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guh AY;Mu Y;Winston LG;Johnston H;Olson D;Farley MM;Wilson LE;Holzbauer SM;Phipps EC;Dumyati GK;Beldavs ZG;Kainer MA;Karlsson M;Gerding DN;McDonald LC;Emerging Infections Program Clostridioides difficile Infection Working Group
通讯作者：
Emerging Infections Program Clostridioides difficile Infection Working Group
影响因子：
3.1
作者：
Babcock, Gregory J.;Broering, Teresa J.;Thomas, William D., Jr.
通讯作者：
Thomas, William D., Jr.
影响因子：
5.5
作者：
Cole, Leah E.;Li, Lu;Anosova, Natalie G.
通讯作者：
Anosova, Natalie G.
影响因子：
5.2
作者：
Crowther, Grace S.;Chilton, Caroline H.;Wilcox, Mark H.
通讯作者：
Wilcox, Mark H.
影响因子：
8
作者：
Harris, M. Scott;Hartman, Deborah;Fox, Barbara S.
通讯作者：
Fox, Barbara S.