Stefan Schreiber1, Konrad Aden2, Joana P Bernardes3, Claudio Conrad4, Florian Tran2, Hanna Höper4, Valery Volk5, Neha Mishra3, Johanna Ira Blase3, Susanna Nikolaus4, Johannes Bethge4, Tanja Kühbacher6, Christoph Röcken7, Minhu Chen8, Ian Cottingham9, Niclas Petri9, Birgitte B Rasmussen9, Juliane Lokau10, Lennart Lenk11, Christoph Garbers10, Friedrich Feuerhake5, Stefan Rose-John12, Georg H Waetzig13, Philip Rosenstiel14. 1. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: s.schreiber@mucosa.de. 2. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 3. Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 4. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 5. Institute for Pathology, Medizinische Hochschule Hannover, Hannover, Germany. 6. Asklepios Westklinikum Hamburg, Hamburg, Germany. 7. Department of Pathology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 8. The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 9. Ferring Pharmaceuticals A/S, Copenhagen S, Denmark. 10. Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany. 11. Department of Pediatrics I, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 12. Institute of Biochemistry, Kiel University, Kiel, Germany. 13. Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Conaris Research Institute AG, Kiel, Germany. 14. Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: p.rosenstiel@mucosa.de.
Abstract
BACKGROUND & AIMS: A large unmet therapeutic need exists in inflammatory bowel disease (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression. Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor without the need for membrane-bound IL6R. We have developed a decoy protein, sgp130Fc, that exclusively blocks IL6 proinflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression. METHODS: We present a 12-week, open-label, prospective phase 2a trial (FUTURE) in 16 patients with active IBD treated with the trans-signaling inhibitor olamkicept (sgp130Fc) to assess the molecular mechanisms, safety, and effectiveness of IL6 trans-signaling blockade in vivo. We performed in-depth molecular profiling at various timepoints before and after therapy induction to identify the mechanism of action of olamkicept. RESULTS: Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) therapies was identified. CONCLUSIONS: Our data suggest that blockade of IL6 trans-signaling holds great promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy for IBD. (EudraCT no., Nu 2016-000205-36).
BACKGROUND & AIMS: A large unmet therapeutic need exists in inflammatory bowel disease (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression. Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor without the need for membrane-bound IL6R. We have developed a decoy protein, sgp130Fc, that exclusively blocks IL6 proinflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression. METHODS: We present a 12-week, open-label, prospective phase 2a trial (FUTURE) in 16 patients with active IBD treated with the trans-signaling inhibitor olamkicept (sgp130Fc) to assess the molecular mechanisms, safety, and effectiveness of IL6 trans-signaling blockade in vivo. We performed in-depth molecular profiling at various timepoints before and after therapy induction to identify the mechanism of action of olamkicept. RESULTS: Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) therapies was identified. CONCLUSIONS: Our data suggest that blockade of IL6 trans-signaling holds great promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy for IBD. (EudraCT no., Nu 2016-000205-36).
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