Bispecific soluble cytokine receptor-nanobody fusions inhibit Interleukin (IL-)6 trans-signaling and IL-12/23 or tumor necrosis factor (TNF) signaling.
In: Journal of Biological Chemistry, Jg. 299 (2023-11-01), Heft 11, S. 1-13
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Zugriff:
At least 0.5% of people in the Western world develop inflammatory bowel disease (IBD). While antibodies that block tumor necrosis factor (TNF) α and Interleukin (IL-)23 have been approved for the treatment of IBD, IL-6 antibodies failed in the phase II clinical trial due to non-tolerable side effects. However, two clinical phase II studies suggest that inhibiting IL-6/soluble IL-6R (sIL-6R)-induced trans-signaling via the cytokine receptor gp130 benefit IBD patients with fewer adverse events. Here we develop inhibitors targeting a combination of IL-6/sIL-6R and TNF or IL-12/IL-23 signaling, named cs130-TNFVHHFc and cs130-IL-12/23VHHFc. Surface plasmon resonance experiments showed that recombinant cs130-TNFVHHFc and cs130- IL-12/23VHHFc bind with high affinity to IL-6/sIL-6R complexes and human TNFα (hTNFα) or IL-12/IL-23, respectively. Immunoprecipitation experiments have verified the higher ordered complex formation of the inhibitors with IL-6/sIL-6R and IL-12. We demonstrated that cs130-TNFVHHFc and cs130-IL12/23VHHFc block IL-6/sIL-6R trans-signaling-induced proliferation and STAT3 phosphorylation of Ba/F3-gp130 cells, as well as hTNFα- or IL-23-induced signaling, respectively. In conclusion, cs130-TNFVHHFc and cs130-IL-12/23VHHFc represent a class of dimeric and bispecific chimeric cytokine inhibitors that consist of a soluble cytokine receptor fused to anticytokine nanobodies. [ABSTRACT FROM AUTHOR]
Titel: |
Bispecific soluble cytokine receptor-nanobody fusions inhibit Interleukin (IL-)6 trans-signaling and IL-12/23 or tumor necrosis factor (TNF) signaling.
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Autor/in / Beteiligte Person: | Gesiorowski, Annika ; Ettich, Julia ; Werner, Julia ; Wittich, Christoph ; Pieper, Stephan ; Padrini, Giacomo ; Behnke, Kristina ; Floss, Doreen M. ; Lang, Philipp A. ; Moll, Jens M. ; Scheller, Jürgen |
Zeitschrift: | Journal of Biological Chemistry, Jg. 299 (2023-11-01), Heft 11, S. 1-13 |
Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
ISSN: | 0021-9258 (print) |
DOI: | 10.1016/j.jbc.2023.105343 |
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