Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel Disease
Open accessAbstract
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…
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In a phase IIa open label trial, over 20% of patients with active IBD treated with olamkicept were completely alleviated in clinical symptoms and inflammatory markers.
“For example, a phase IIa open label trial evaluating olamkicept in patients with active inflammatory bowel disease (IBD) showed that over 20% patients treated with olamkicept were completely alleviated in clinical symptoms and inflammatory markers [93].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [93]
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Targeting IL-6 trans-signalling: past, present and future prospects
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00856-y · Cited by 524 · see citing works
Self-citationNew insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
Self-citationIL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease
Park, J., Zhao, Y., Zhang, F., Zhang, S., Kwong, A. C., Zhang, Y., Hoffmann, H.-H., Bushweller, L., Wu, X., Ashbrook, A. W., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2022.08.022 · Cited by 138 · see citing works
The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
Wang, M.-J., Zhang, H.-L., Chen, F., Guo, X.-J., Liu, Q.-G., & Hou, J. (2024) · Experimental Hematology & Oncology · doi:10.1186/s40164-024-00527-1 · Cited by 84 · see citing works
“For example, a phase IIa open label trial evaluating olam-kicept in patients with active inflammatory bowel disease (IBD) showed that over 20% patients treated with olamki-cept were completely alleviated in clinical symptoms and inflammatory markers [93].”
Background
- Authors
- Schreiber, S., Aden, K., Bernardes, J. P., Conrad, C., Tran, F., Höper, H., Volk, V., Mishra, N., Blase, J. I., Nikolaus, S., Bethge, J., Kühbacher, T., Röcken, C., Chen, M., Cottingham, I., Petri, N., Rasmussen, B. B., Lokau, J., Lenk, L., Garbers, C., Feuerhake, F., Rose-John, S., Waetzig, G. H., & Rosenstiel, P.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- Medizinische Hochschule Hannover (DE)
- Asklepios (DE)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Ferring Pharmaceuticals (Denmark) (DK)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Corresponding author
- Schreiber, Stefan
- Rosenstiel, Philip
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 160
- Issue
- 7
- Pages
- 2354-2366.e11
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W3133637024
- Cited by
- 259
- References
- 2
- Citations by year
- 2026: 40 · 2025: 46 · 2024: 62 · 2023: 48 · 2022: 34 · 2021: 29
- FWCI
- 24.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Gastroenterology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- DFG
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- sgp130Fc, inflammatory bowel disease, decoy receptor, STAT3 phosphorylation, clinical remission, immunomodulatory therapy, drug safety and tolerability
- MeSH terms
- Interleukin-6 Inhibitors, Adult, Aged, Colitis, Ulcerative, Crohn Disease, Female, Humans, Male, Middle Aged, Prospective Studies, Recombinant Fusion Proteins, Severity of Illness Index, Signal Transduction, Interleukin-6, Treatment Outcome, Receptors, Interleukin-6, Young Adult
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