Introduction
IL-6 is implicated in the pathogenesis of ulcerative colitis (UC), however no IL-6 inhibitor has been approved for UC to date. Selective inhibition of IL-6 trans-signaling could ameliorate the deleterious, pro-inflammatory effects of IL-61,while preserving the homeostatic, tissue reparative activity of classical IL-6 signaling. Olamkicept 2, a fusion protein consisting of two complete extracellular domains of gp130 attached to the Fc-region of an IgG1 antibody, neutralizes IL-6 trans-signaling in vitro and has shown promising clinical effects in a recent randomized, double-blind, placebo-controlled phase II trial in moderate to severe UC (NCT03235752)3.
Aims & Methods
The objective of this study was to characterize the biological effects resulting from selective inhibition of IL-6 trans-signaling using an in silico model of colonic inflammation.
A hybrid mechanistic-statistical computational model of colonic inflammation in UC was developed using published pre-clinical and clinical studies as well as internally generated in vitro pharmacology data2-4. The output of the model included changes in IL-6 signaling pathway components (IL-6, soluble IL-6 receptor, membrane-bound IL-6 receptor, soluble gp130, and STAT-3 phosphorylation), C-reactive protein (CRP), fecal calprotectin, adaptive immune cell (CD4+ T lymphocyte) sub-populations, cytokines, and chemokines. States of tissue damage and repair (healing) were estimated.
The performance of the model was tested against clinical data generated in NCT032357523 in which patients had been allocated to receive intravenous (IV) administration of 300 mg or 600 mg olamkicept or placebo every two weeks for 12 weeks.
Simulations assessing the differential effects of modulating trans- and cis-signaling were probed using pharmacological inhibitors of trans- (olamkicept, 300-1800 mg administered IV every 2 weeks) and pan-IL-6 signaling (IL-6 receptor inhibitor and a STAT-3 phosphorylation inhibitor). Changes in concentrations of IL-6 signaling species and down-stream effects on immune cell sub-population levels were compared both in the systemic circulation and locally in the gut tissue. The initial concentrations of the signaling species were based on those typically observed in UC patients5.
Results
Based on the simulations, concentrations of free IL-6 in the systemic circulation were minimally impacted by exposure to olamkicept. In gut tissue, IL-6 concentrations decreased by approximately 10% at the highest olamkicept dose tested, returning to pre-treatment levels within a day post dose.
Suppression of IL-6 trans-signaling by olamkicept caused a transition away from aTh17-rich state in gut tissue and attenuated inflammatory chemotactic signals in a dose-dependent manner. In comparison, the pan-inhibition of IL-6 signaling reduced Th17 mediated inflammatory activity, however tissue healing pathways dependent on IL-6 cis-signaling were also suppressed.
Conclusion
In the developed in silico model of colonic inflammation, inhibition of IL-6 signaling was associated with attenuation of Th17 mediated inflammation in the gut. Pan-inhibition of IL-6 signaling was associated with impaired tissue healing, however this was not observed for olamkicept, where homeostatic, classical IL-6 signaling was preserved.
This study provides quantitative support to therapeutic strategies targeting IL-6 trans-signaling in UC to reduce the cytokine’s undesirable effects while preserving its beneficial functions.
References
- Garbers C. et al., The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol. 2015 Jun;34:75-82. doi: 10.1016/j.coi.2015.02.008.
- Schreiber S. et al., Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel Disease. Gastroenterology. 2021 Jun;160(7):2354-2366.e11. doi: 10.1053/j.gastro.2021.02.062.
- Zhang S, et al., Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial. JAMA. 2023 Mar 7;329(9):725-734. doi: 10.1001/jama.2023.1084.
- Reeh H. et al. Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling. Cell Commun Signal. 2019 May 17;17(1):46. doi: 10.1186/s12964-019-0356-0.
- Nikolaus S et al. Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases. Int J Colorectal dis. 2018 Jul;33(7):927-936. Doi: 10.1007/s00384-018-3069-8
Disclosure
O. Sternebring, A. Ravi, A. Rivollier, S. Read, R. Szabady and P. Pinton are employees of Ferring Pharmaceuticals. P. Pinton owns stocks of Takeda Pharmaceutical Company Limited. N. Patidar, R. Carcillo, M. Behar, Jørgen Sørensen and P. D’Alessandroare employees of PriceWaterhouseCoopers.