在肠道内工程化的大肠杆菌，用来原地分泌治疗性纳米抗体。
Engineered Escherichia coli for the in situ secretion of therapeutic nanobodies in the gut.
发表日期：2023 Mar 22
作者：
Jason P Lynch, Coral González-Prieto, Analise Z Reeves, Sena Bae, Urmila Powale, Neha P Godbole, Jacqueline M Tremblay, Florian I Schmidt, Hidde L Ploegh, Vikram Kansra, Jonathan N Glickman, John M Leong, Charles B Shoemaker, Wendy S Garrett, Cammie F Lesser
来源：
Cell Host & Microbe
摘要：
需要药物平台来实现给药物到疾病部位，以最大化疗效，并减少非靶向效应。我们在这里报道了PROT3EcT的开发，这是一套共生大肠杆菌，通过改造可以将蛋白质直接分泌到周围环境中。这些细菌由三个模块化组件组成：修改的细菌蛋白分泌系统、相关可调节转录激活剂和分泌的治疗药物。PROT3EcT分泌功能性的单域抗体、纳米抗体（Nbs），并在小鼠肠道内稳定地定殖和维持活性分泌系统。此外，一剂预防性的PROT3EcT变体足以分泌抗肿瘤坏死因子α（TNF-α）的中和Nb，从而消除炎症性TNF水平，并在化学诱导的结肠炎模型中防止损伤和炎症的发展。这项工作为将PROT3EcT作为治疗胃肠疾病的平台奠定了基础。版权所有©2023 Elsevier Inc.。保留所有权利。
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 PROT3EcT, 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. PROT3EcT 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 PROT3EcT 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 PROT3EcT as a platform for the treatment of gastrointestinal-based diseases.Copyright © 2023 Elsevier Inc. All rights reserved.