(1) Oral administration of CXCL12-expressing Limosilactobacillus reuteri improves colitis by local immunomodulatory actions in preclinical models
Författare/Medförfattare
Emelie Öhnstedt1,2, Cristian Doñas1, Kristel Parv1, Yanhong Pang1, Hava Lofton Tomenius1,2, Macarena Carrasco López1, Venkata Ram Gannavarapu2, Peter Frank1, Margareth Jorvid1, Stefan Roos3, Evelina Vågesjö1,2, Mia Phillipson2,4
Affiliates
1 Ilya Pharma AB, Dag Hammarskjölds Väg 30, 752 37 Uppsala, Sweden2 Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Box 571, Uppsala, Sweden 3 Department of Molecular Sciences, Swedish University of Agriculture, Box 7015, SE-750 07, Uppsala, Sweden4 The Science for Life Laboratory, Uppsala University, Box 3037, 750 03 Uppsala, Sweden
Abstract
Treatments of colitis, inflammation of the intestine, is today relying on induction of immune suppression associated with systemic adverse events including recurrent infections. This treatment strategy is specifically problematic in the increasing population of cancer patients with immune checkpoint inhibitor (ICI)-induced colitis, as immune suppression also interferes with the ICI-treatment response. Thus, there is a need for local-acting treatments which reduce inflammation and enhance intestinal healing. Here, we investigated the effect and safety of bacterial delivery of short-lived immunomodulating chemokines to the inflamed intestine in mice with colitis. Colitis was induced by DSS alone or in combination with ICI (anti-PD1, anti-CTLA-4) and L. reuteri R2LC genetically modified to express the chemokine CXCL12-1α (R2LC_CXCL12, emilimogene sigulactibac) was given perorally. In addition, pharmacology and safety of the formulated drug candidate, ILP100-Oral, was evaluated in rabbits. Peroral CXCL12-producing L. reuteri R2LC significantly improved colitis symptoms already after 2 days in mice with overt DSS and ICI-induced colitis, which in benchmarking experiments was demonstrated to be superior to treatments with anti-TNF-α, anti-α4ꞵ7 and corticosteroids. The mechanism of action involved chemokine delivery to Peyer´s Patches (PPs), confirmed by local CXCR4 signaling, and increased numbers of colonic, regulatory immune cells expressing IL-10 and TGF-β1. No systemic exposure or engraftment could be detected in mice, and product feasibility, pharmacology and safety were confirmed in rabbits. In conclusion, peroral CXCL12-producing L. reuteri R2LC efficiently ameliorates colitis and enhances mucosal healing, and has a favorable safety profile.
Colitis symptoms are efficiently reduced by peroral administration of probiotic bacteria genetically modified to deliver CXCL12 locally to the inflamed intestine in several mouse models.
