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

Kenneth Verstraete (1, 2) , Frank Peelman (3) , Harald Braun (1, 4) , Juan Lopez (5, 6) , Dries van Rompaey (7) , Ann Dansercoer (1, 2) , Isabel Vandenberghe (2) , Kris Pauwels (8, 9) , Jan Tavernier (3) , Bart N. Lambrecht (1, 10) , Hamida Hammad (1, 10) , Hans de Winter (7) , Rudi Beyaert (1, 4) , Guy Lippens (11, 5) , Savvas N. Savvides (1, 2)

1 IRC - VIB-UGent Center for Inflammation Research [Gand, Belgique]
2 Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology
3 VIB-UGent Center for Medical Biotechnology
4 Department of Biomedical Molecular Biology
5 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576
6 PUCP - Pontificia Universidad Católica del Perú = Pontifical Catholic University of Peru
7 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences
8 VIB-VUB Center for Structural Biology
9 Structural Biology Brussels, Bio-Engineering Sciences Department
10 Department of Respiratory Medicine
11 LISBP - Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés

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 a-chain (IL-7Ra) 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-7Ra extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

Mots clés: allergy; bronchial asthma; skin disease

Mots clés: allergie; asthme; dermatite; pathophysiologie; cytokine anti inflammatoire

Domaines: Médecine humaine et pathologie

Kenneth Verstraete, Frank Peelman, Harald Braun, Juan Lopez, Dries van Rompaey, et al.. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nature Communications, 2017, 8 (1), 17 p. ⟨10.1038/ncomms14937⟩. ⟨hal-01605011⟩