Engineered Escherichia coli for the in situ secretion of therapeutic nanobodies in the gut.
Engineered Escherichia coli for the in situ secretion of therapeutic nanobodies in the gut.
复制标题
工程大肠杆菌用于在肠道中原位分泌治疗性纳米抗体。
DOI：
10.1016/j.chom.2023.03.007
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发表时间：
2023
影响因子：
30.3
通讯作者：
Garrett,WendyS
中科院分区：
文献类型：
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作者：
Lynch,JasonP;González-Prieto,Coral;Reeves,AnaliseZ;Bae,Sena;Powale,Urmila;Godbole,NehaP;Tremblay,JacquelineM;Schmidt,FlorianI;Ploegh,HiddeL;Kansra,Vikram;Glickman,JonathanN;Leong,JohnM;Shoemaker,CharlesB;Garrett,WendyS
需要能够将治疗药物定向输送到疾病部位以最大限度地提高疗效并限制脱靶效应的药物平台。在此，我们报告了 PROT3EcT 的开发，这是一套经过改造的共生大肠杆菌，可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：改良的细菌蛋白分泌系统、相关的可调节转录激活剂和分泌的治疗有效负载。 PROT3EcT 分泌功能性单域抗体、纳米抗体 (Nbs)，并在小鼠肠道内稳定定殖并维持活跃的分泌系统。此外，分泌肿瘤坏死因子-α (TNF-α) 中和 Nb 的 PROT3EcT 变体的单次预防剂量足以消除促炎性 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 PROT3EcT 作为治疗胃肠道疾病的平台奠定了基础。
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 commensalEscherichia coliengineered 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.