| Literature DB >> 34609205 |
Bert Schepens1,2, Loes van Schie1,2, Wim Nerinckx1,2, Kenny Roose1,2, Wander Van Breedam1,2, Daria Fijalkowska1,2, Simon Devos1,2, Wannes Weyts1,2, Sieglinde De Cae1,2, Sandrine Vanmarcke1,2, Chiara Lonigro1,2, Hannah Eeckhaut1,2, Dries Van Herpe1,2, Jimmy Borloo3, Ana Filipa Oliveira3, João Paulo Portela Catani1,2, Sarah Creytens1,2, Dorien De Vlieger1,2, Gitte Michielsen1,2, Jackeline Cecilia Zavala Marchan1,2, George D Moschonas1,2, Iebe Rossey1,2, Koen Sedeyn1,2, Annelies Van Hecke1,2, Xin Zhang4,5, Lana Langendries4,5, Sofie Jacobs4,5, Sebastiaan Ter Horst4,5, Laura Seldeslachts6, Laurens Liesenborghs4,5, Robbert Boudewijns4,5,7, Hendrik Jan Thibaut4,7,8, Kai Dallmeier4,5,7, Greetje Vande Velde6, Birgit Weynand9, Julius Beer10, Daniel Schnepf10, Annette Ohnemus10, Isabel Remory11, Caroline S Foo4, Rana Abdelnabi4,5, Piet Maes12, Suzanne J F Kaptein4,5, Joana Rocha-Pereira4,5, Dirk Jochmans4,5, Leen Delang4,5, Frank Peelman1,13, Peter Staeheli10,14, Martin Schwemmle10,14, Nick Devoogdt11, Dominique Tersago15, Massimiliano Germani16, James Heads16, Alistair Henry16, Andrew Popplewell16, Mark Ellis16, Kevin Brady16, Alison Turner16, Bruno Dombrecht3, Catelijne Stortelers3, Johan Neyts4,5,7, Nico Callewaert1,2, Xavier Saelens1,2.
Abstract
Broadly neutralizing antibodies are an important treatment for individuals with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antibody-based therapeutics are also essential for pandemic preparedness against future Sarbecovirus outbreaks. Camelid-derived single domain antibodies (VHHs) exhibit potent antimicrobial activity and are being developed as SARS-CoV-2–neutralizing antibody-like therapeutics. Here, we identified VHHs that neutralize both SARS-CoV-1 and SARS-CoV-2, including now circulating variants. We observed that the VHHs bound to a highly conserved epitope in the receptor binding domain of the viral spike protein that is difficult to access for human antibodies. Structure-guided molecular modeling, combined with rapid yeast-based prototyping, resulted in an affinity enhanced VHH-human immunoglobulin G1 Fc fusion molecule with subnanomolar neutralizing activity. This VHH-Fc fusion protein, produced in and purified from cultured Chinese hamster ovary cells, controlled SARS-CoV-2 replication in prophylactic and therapeutic settings in mice expressing human angiotensin converting enzyme 2 and in hamsters infected with SARS-CoV-2. These data led to affinity-enhanced selection of the VHH, XVR011, a stable anti–COVID-19 biologic that is now being evaluated in the clinic.Entities:
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Year: 2021 PMID： 34609205 DOI： 10.1126/scitranslmed.abi7826
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956