Journal
GASTROENTEROLOGY
Volume 160, Issue 7, Pages 2354-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2021.02.062
Keywords
Inflammatory Bowel Disease; Cytokine; Transsignaling; STAT3
Categories
Funding
- University Hospital Schleswig-Holstein (UKSH)
- German Ministry of Education and Research grant E:med sysINFLAME
- Cluster of Excellence Inflammation at Interfaces (Deutsche Forschungsgemeinschaft)
- European Union Horizon 2020 SYSCID program [733100]
- EU H2020 Innovative Medicines Initiative 2 Joint Undertaking 3TR [831434]
- Ferring A/S
- German Ministry of Education and Research grant iTREAT [01ZX1902]
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The study on the treatment of IBD patients with the trans-signaling inhibitor olamkicept (sgp130Fc) showed that patients tolerated the treatment well, with 44% showing clinical response and 19% achieving clinical remission. The clinical effectiveness was associated with target inhibition and marked transcriptional changes in the inflamed mucosa.
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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