Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state

Iebe Rossey, Morgan S. A. Gilman, Stephanie C. Kabeche, Koen Sedeyn, Daniel Wrapp, Masaru Kanekiyo, Man Chen, Vicente Mas, Jan Spitaels, José A. Melero, Barney S. Graham, Bert Schepens (), Jason S. McLellan () and Xavier Saelens ()
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Iebe Rossey: Medical Biotechnology Center
Morgan S. A. Gilman: Geisel School of Medicine at Dartmouth
Stephanie C. Kabeche: Geisel School of Medicine at Dartmouth
Koen Sedeyn: Medical Biotechnology Center
Daniel Wrapp: Geisel School of Medicine at Dartmouth
Masaru Kanekiyo: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Man Chen: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Vicente Mas: Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias
Jan Spitaels: Medical Biotechnology Center
José A. Melero: Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias
Barney S. Graham: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Bert Schepens: Medical Biotechnology Center
Jason S. McLellan: Geisel School of Medicine at Dartmouth
Xavier Saelens: Medical Biotechnology Center

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV.

Date: 2017
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DOI: 10.1038/ncomms14158

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