Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA; Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Departments of Immunology and Infectious Diseases and Harvard T.H. Chan Center for the Microbiome in Public Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Cell Host Microbe. 2023 Apr 12;31(4):634-649.e8. doi: 10.1016/j.chom.2023.03.007. Epub 2023 Mar 31.
Drug platforms that enable the directed delivery of therapeutics to sites of diseases to maximize efficacy and limit off-target effects are needed. Here, we report the development of PROTEcT, a suite of commensal Escherichia coli engineered to secrete proteins directly into their surroundings. These bacteria consist of three modular components: a modified bacterial protein secretion system, the associated regulatable transcriptional activator, and a secreted therapeutic payload. PROTEcT secrete functional single-domain antibodies, nanobodies (Nbs), and stably colonize and maintain an active secretion system within the intestines of mice. Furthermore, a single prophylactic dose of a variant of PROTEcT that secretes a tumor necrosis factor-alpha (TNF-α)-neutralizing Nb is sufficient to ablate pro-inflammatory TNF levels and prevent the development of injury and inflammation in a chemically induced model of colitis. This work lays the foundation for developing PROTEcT as a platform for the treatment of gastrointestinal-based diseases.
需要开发药物平台，使治疗药物能够靶向递送到疾病部位，以最大限度地提高疗效并限制脱靶效应。在这里，我们报告了 PROTEcT 的开发，这是一系列经过工程改造的共生大肠杆菌，可以将蛋白质直接分泌到其周围环境中。这些细菌由三个模块化组件组成：改良的细菌蛋白分泌系统、相关可调节的转录激活因子和分泌的治疗有效载荷。PROTEcT 分泌功能性的单域抗体、纳米抗体 (Nbs)，并在小鼠的肠道中稳定定植并维持活跃的分泌系统。此外，预防性给予 PROTEcT 的一种变体，该变体分泌一种肿瘤坏死因子-α (TNF-α) 中和 Nb，足以消除促炎 TNF 水平，并防止化学诱导的结肠炎模型中损伤和炎症的发展。这项工作为开发 PROTEcT 作为治疗胃肠道疾病的平台奠定了基础。
