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Selective engagement of FcγRIV by a M2e-specific single domain antibody construct protects against influenza A virus infection

DOI: 10.3389/fimmu.2019.02920 DOI Help

Authors: Dorien De Vlieger (VIB-UGent Center for Medical Biotechnology) , Katja Hoffmann (University of Freiburg) , Inge Van Molle (Vrije Universiteit Brussel; VIB-VUB Center for Structural Biology) , Wim Nerinckx (VIB-UGent Center for Medical Biotechnology; Ghent University) , Lien Van Hoecke (VIB-UGent Center for Medical Biotechnology; Ghent University) , Marlies Ballegeer (VIB-UGent Center for Medical Biotechnology; Ghent University) , Sarah Creytens (VIB-UGent Center for Medical Biotechnology; Ghent University) , Han Remaut (Vrije Universiteit Brussel; VIB-VUB Center for Structural Biology) , Hartmut Hengel (Vrije Universiteit Brussel; VIB-VUB Center for Structural Biology) , Bert Schepens (VIB-UGent Center for Medical Biotechnology; Ghent University) , Xavier Saelens (VIB-UGent Center for Medical Biotechnology; Ghent University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Frontiers In Immunology , VOL 10

State: Published (Approved)
Published: December 2019

Open Access Open Access

Abstract: Lower respiratory tract infections, such as infections caused by influenza A viruses, are a constant threat for public health. Antivirals are indispensable to control disease caused by epidemic as well as pandemic influenza A. We developed a novel anti-influenza A virus approach based on an engineered single-domain antibody (VHH) construct that can selectively recruit innate immune cells to the sites of virus replication. This protective construct comprises two VHHs. One VHH binds with nanomolar affinity to the conserved influenza A matrix protein 2 (M2) ectodomain (M2e). Co-crystal structure analysis revealed that the complementarity determining regions 2 and 3 of this VHH embrace M2e. The second selected VHH specifically binds to the mouse Fcγ Receptor IV (FcγRIV) and was genetically fused to the M2e-specific VHH, which resulted in a bi-specific VHH-based construct that could be efficiently expressed in Pichia pastoris. In the presence of M2 expressing or influenza A virus-infected target cells, this single domain antibody construct selectively activated the mouse FcγRIV. Moreover, intranasal delivery of this bispecific FcγRIV-engaging VHH construct protected wild type but not FcγRIV−/− mice against challenge with an H3N2 influenza virus. These results provide proof of concept that VHHs directed against a surface exposed viral antigen can be readily armed with effector functions that trigger protective antiviral activity beyond direct virus neutralization.

Journal Keywords: influenza; matrix protein 2 ectodomain; single domain antibody; Fcγ receptor; effector functions

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Documents:
fimmu-10-02920.pdf