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Engineered <i>E. coli</i> for the Targeted Deposition of Therapeutic Payloads to Sites of Disease

2022; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.4133893

1556-5068

Jason P. Lynch, Coral González-Prieto, Analise Z. Reeves, Urmila Powale, Neha Godbole, Jacqueline M. Tremblay, Florian I. Schmidt, Hidde L. Ploegh, Jonathan N. Glickman, John M. Leong, Charles B. Shoemaker, Wendy S. Garrett, Cammie F. Lesser,

Bacterial Genetics and Biotechnology

New drug platforms are needed which enable the directed delivery of therapeutics to sites of disease to maximize efficacy and limit off-target effects. Here, we report the development of PROT3EcT, commensal Escherichia coli engineered for the direct secretion of proteins into their surroundings. PROT3EcT are composed of four modular components: an E. coli chassis, a modified bacterial protein secretion system, a regulatable transcriptional activator, and a secretable therapeutic payload. PROT3EcT that secrete functional single-domain antibodies, nanobodies (Nb), stably colonize and maintain a functional secretion system within the intestines of mice. A single prophylactic dose of PROT3EcT that secretes a tumor necrosis factor alpha (TNFα) neutralizing Nb is sufficient to ablate TNF levels and prevent the development of injury and inflammation in a chemically-induced model of inflammatory bowel disease. This work lays the foundation for the development of PROT3EcT as a therapeutic platform for the treatment of at least gastrointestinal-based diseases.Funding Information: Supported by NIH grants (AI064285, DK113599), a Kenneth Rainin Foundation grant and the Brit d'Arbeloff Research Scholar award to C.F.L, Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery Postdoctoral Fellowship Awards to C.G.P and A.Z.R., and an Endeavour Australia Research Fellowship and a Crohn's & Colitis Foundation Research Fellow Award, award number 654758, to J.P.L.Declaration of Interests: The authors declare no competing financial interests. Related to this work, C.F.L is on the scientific advisory board (SAB) of Synlogic Therapeutics and W.S.G is on the SABs of Kintai Therapeutics, SanaRx, Evelo Biosciences and Tenza. F.I.S. is a consultant and shareholder of IFM Therapeutics and NewCo (to be changed if public), as well as cofounders and shareholders of Dioscure Therapeutics SE.Ethics Approval Statement: Animal experiments were approved and carried out in accordance with Harvard Medical School's Standing Committee on Animals and the National Institutes of Health guidelines for animal use and care.