Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

Kenneth Verstraete, Frank Peelman, Harald Braun, Juan Lopez, Dries Van Rompaey, Ann Dansercoer, Isabel Vandenberghe, Kris Pauwels, Jan Tavernier, Bart N. Lambrecht, Hamida Hammad, Hans De Winter, Rudi Beyaert, Guy Lippens and Savvas N. Savvides ()
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Kenneth Verstraete: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium
Frank Peelman: VIB-UGent Center for Medical Biotechnology
Harald Braun: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium
Juan Lopez: Unité de Glycobiologie Structurale et Fonctionnelle-CNRS UMR8576, Université de Lille
Dries Van Rompaey: Laboratory of Medicinal Chemistry, University of Antwerp
Ann Dansercoer: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium
Isabel Vandenberghe: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Kris Pauwels: VIB-VUB Center for Structural Biology
Jan Tavernier: VIB-UGent Center for Medical Biotechnology
Bart N. Lambrecht: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium
Hamida Hammad: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium
Hans De Winter: Laboratory of Medicinal Chemistry, University of Antwerp
Rudi Beyaert: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium
Guy Lippens: Unité de Glycobiologie Structurale et Fonctionnelle-CNRS UMR8576, Université de Lille
Savvas N. Savvides: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

Date: 2017
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DOI: 10.1038/ncomms14937

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