A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity

Author:

Roehlen Natascha1ORCID,Saviano Antonio12ORCID,El Saghire Houssein1,Crouchet Emilie1,Nehme Zeina1ORCID,Del Zompo Fabio1ORCID,Jühling Frank1ORCID,Oudot Marine A.1,Durand Sarah C.1,Duong François H. T.1,Cherradi Sara1ORCID,Gonzalez Motos Victor1ORCID,Almeida Nuno1ORCID,Ponsolles Clara1,Heydmann Laura1ORCID,Ostyn Tessa3,Lallement Antonin14ORCID,Pessaux Patrick12,Felli Emanuele12ORCID,Cavalli Andrea5ORCID,Sgrignani Jacopo5,Thumann Christine1,Koutsopoulos Olga1,Fuchs Bryan C.6ORCID,Hoshida Yujin7ORCID,Hofmann Maike8ORCID,Vyberg Mogens910ORCID,Viuff Birgitte Martine11ORCID,Galsgaard Elisabeth D.11,Elson Greg12,Toso Alberto12,Meyer Markus12ORCID,Iacone Roberto12,Schweighoffer Tamas12ORCID,Teixeira Geoffrey12,Moll Solange13,De Vito Claudio13ORCID,Roskams Tania3ORCID,Davidson Irwin4ORCID,Heide Danijela14ORCID,Heikenwälder Mathias14ORCID,Zeisel Mirjam B.1ORCID,Lupberger Joachim1ORCID,Mailly Laurent1ORCID,Schuster Catherine1,Baumert Thomas F.1215ORCID

Affiliation:

1. Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France.

2. Institut Hospitalo-Universitaire (IHU), Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.

3. Department of Imaging and Pathology, University of Leuven, 3000 Leuven, Belgium.

4. Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, 67400 Illkirch, France.

5. Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.

6. Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02215, USA.

7. Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

8. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

9. Center of RNA Medicine, Department of Clinical Medicine, Aalborg University Copenhagen, 2450 København, Denmark.

10. Department of Pathology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark.

11. Novo Nordisk A/S, 2760 Måløv, Denmark.

12. Alentis Therapeutics, 4123 Allschwil, Switzerland.

13. Department of Pathology, University Hospital of Geneva, 1205 Geneva, Switzerland.

14. Division of Chronic Inflammation and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany.

15. Institut Universitaire de France, 75006 Paris, France.

Abstract

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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