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

Summary: 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...

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Autores principales:	Juliane Lokau, Yvonne Garbers, Joachim Grötzinger, Christoph Garbers
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biochemistry Medical biochemistry Immunology Cell biology Science Q
Acceso en línea:	https://doaj.org/article/b3dee9db303a4a72ae6b113f86f759f1
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spelling	oai:doaj.org-article:b3dee9db303a4a72ae6b113f86f759f12021-11-20T05:09:46ZA single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling2589-004210.1016/j.isci.2021.103309https://doaj.org/article/b3dee9db303a4a72ae6b113f86f759f12021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221012785https://doaj.org/toc/2589-0042Summary: 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.Juliane LokauYvonne GarbersJoachim GrötzingerChristoph GarbersElsevierarticleBiochemistryMedical biochemistryImmunologyCell biologyScienceQENiScience, Vol 24, Iss 11, Pp 103309- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biochemistry Medical biochemistry Immunology Cell biology Science Q
spellingShingle	Biochemistry Medical biochemistry Immunology Cell biology Science Q Juliane Lokau Yvonne Garbers Joachim Grötzinger Christoph Garbers A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
description	Summary: 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.
format	article
author	Juliane Lokau Yvonne Garbers Joachim Grötzinger Christoph Garbers
author_facet	Juliane Lokau Yvonne Garbers Joachim Grötzinger Christoph Garbers
author_sort	Juliane Lokau
title	A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
title_short	A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
title_full	A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
title_fullStr	A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
title_full_unstemmed	A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
title_sort	single aromatic residue in sgp130fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/b3dee9db303a4a72ae6b113f86f759f1
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A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling

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