A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling

Juliane Lokau; Yvonne Garbers; Joachim Grötzinger; Christoph Garbers

doi:10.1016/j.isci.2021.103309

A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling

iScience. 2021 Oct 16;24(11):103309. doi: 10.1016/j.isci.2021.103309. eCollection 2021 Nov 19.

Authors

Juliane Lokau^{1

2}, Yvonne Garbers³, Joachim Grötzinger⁴, Christoph Garbers^{1

2}

Affiliations

¹ Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, 39120 Magdeburg, Germany.
² Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
³ Institute of Psychology, Kiel University, 24118 Kiel, Germany.
⁴ Institute of Biochemistry, Kiel University, 24118 Kiel, Germany.

Abstract

Blocking the activity of cytokines is an efficient strategy to combat inflammatory diseases. Interleukin-6 (IL-6) fulfills its pro-inflammatory properties via its soluble receptor (IL-6 trans-signaling). The selective trans-signaling inhibitor olamkicept (sgp130Fc) is currently in clinical development. We have previously shown that sgp130Fc can also efficiently block trans-signaling of the closely related cytokine IL-11, which elicits the question how selectivity for one of the two cytokines can be achieved. Using structural information, we show that the interfaces between IL-6R-gp130 and IL-11R-gp130, respectively, within the so-called site III are different between the two cytokines. Modification of an aromatic cluster around Q113 of gp130 within these interfaces allows the discrimination between IL-6 and IL-11 trans-signaling. Using recombinant sgp130Fc variants, we demonstrate that these differences can indeed be exploited to generate a truly selective IL-6 trans-signaling inhibitor. Our data highlight how the selectivity of a clinically relevant designer protein can be further improved.

Keywords: Biochemistry; Cell biology; Immunology; Medical biochemistry.