Exclusive inhibition of IL-6 trans-signaling by soluble gp130FlyRFc

Anna F Berg; Julia Ettich; Hendrik T Weitz; Matthias Krusche; Doreen M Floss; Jürgen Scheller; Jens M Moll

doi:10.1016/j.cytox.2021.100058

Exclusive inhibition of IL-6 trans-signaling by soluble gp130^FlyRFc

Cytokine X. 2021 Nov 29;3(4):100058. doi: 10.1016/j.cytox.2021.100058. eCollection 2021 Dec.

Authors

Anna F Berg¹, Julia Ettich¹, Hendrik T Weitz¹, Matthias Krusche¹, Doreen M Floss¹, Jürgen Scheller¹, Jens M Moll¹

Affiliation

¹ Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.

Abstract

gp130 is the signal-transducing receptor for the Interleukin (IL)-6 type cytokines IL-6 and IL-11. To induce signaling, IL-6 forms a complex with IL-6 receptor (IL-6R) and IL-11 with IL-11 receptor (IL-11R). Membrane-bound IL-6R and IL-11R in complex with gp130 and the cytokine mediate classic-signaling, whereas trans-signaling needs soluble IL-6R and IL-11R variants. Interleukin (IL)-6 trans-signaling is of particular importance because it drives the development of autoimmune diseases, including rheumatoid arthritis and chronic inflammatory bowel diseases, whereas a role for IL-11 trans-signaling remains elusive. Soluble gp130 selectively inhibits trans-signaling of IL-6 whereas both, classic- and trans-signaling are abrogated by IL-6- and IL-6R-antibodies. Recently, we described an optimized sgp130 variant, which carries three amino acid substitutions T102Y/Q113F/N114L (sgp130^FlyFc) resulting in reduced inhibition of IL-11 trans-signaling by increasing the affinity of sgp130 for the site I of IL-6. Moreover, we described that the patient mutation R281Q in gp130 results in reduced IL-11 signaling. Here, we show that the combination of T102Y/Q113F/N114L and R281Q in the new variant sgp130^FlyRFc results in complete preservation of IL-11 mediated trans-signaling, whereas inhibition of IL-6 trans-signaling is maintained. Since sgp130Fc (olamkicept) has successfully completed a phase IIa trial in Crohn's disease (CD) and ulcerative colitis, sgp130^FlyRFc might serve as second-generation therapeutic to diminish IL-11 trans-signaling cross-reactivity.

Keywords: Cytokine; IL-11; IL-6; Sgp130; Soluble gp130; Trans-signaling.