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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., 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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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: 24 Oct 2021 09:18

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