Selective inhibition of IL-6 trans-signaling by a miniaturized, optimized chimeric soluble gp130 inhibits TH17 cell expansion

Heise, Denise, Derrac Soria, Alicia, Hansen, Selina, Dambietz, Christine, Akbarzadeh, Mohammad, Berg, Anna F., Waetzig, Georg H., Jones, Simon A. ORCID: https://orcid.org/0000-0001-7297-9711, Dvorsky, Radovan, Ahmadian, Mohammad R., Scheller, Jürgen and Moll, Jens M. 2021. Selective inhibition of IL-6 trans-signaling by a miniaturized, optimized chimeric soluble gp130 inhibits TH17 cell expansion. Science Signaling 14 (696) , eabc3480. 10.1126/scisignal.abc3480

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Abstract

The cytokine interleukin-6 (IL-6) signals through three mechanisms called classic signaling, trans-signaling, and trans-presentation. IL-6 trans-signaling is distinctly mediated through a soluble form of its transmembrane receptor IL-6R (sIL-6R) and the coreceptor gp130 and is implicated in multiple autoimmune diseases. Although a soluble form of gp130 (sgp130) inhibits only IL-6 trans-signaling, it also blocks an analogous trans-signaling mechanism of IL-11 and its soluble receptor sIL-11R. Here, we report miniaturized chimeric soluble gp130 variants that efficiently trap IL-6:sIL-6R but not IL-11:sIL-11R complexes. We designed a novel IL-6 trans-signaling trap by fusing a miniaturized sgp130 variant to an IL-6:sIL-6R complex–binding nanobody and the Fc portion of immunoglobulin G (IgG). This trap, called cs-130Fc, exhibited improved inhibition of as well as increased selectivity for IL-6 trans-signaling compared to the conventional fusion protein sgp130Fc. We introduced affinity-enhancing mutations in cs-130Fc and sgp130Fc that further improved selectivity toward IL-6 trans-signaling. Moreover, cs-130Fc efficiently inhibited the expansion of T helper 17 (TH17) cells in cultures of mouse CD4+ T cells treated with IL-6:sIL-6R. Thus, these variants may provide or lead to the development of more precisely targeted therapeutics for inflammatory disorders associated with IL-6 trans-signaling.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	1945-0877
Date of First Compliant Deposit:	9 September 2021
Date of Acceptance:	24 July 2021
Last Modified:	06 Nov 2023 14:27
URI:	https://orca.cardiff.ac.uk/id/eprint/143977

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