An affinity-enhanced, broadly neutralizing heavy chain-only antibody protects against SARS-CoV-2 infection in animal models

Schepens, Bert; van Schie, Loes; Nerinckx, Wim; Roose, Kenny; Van Breedam, Wander; Fijalkowska, Daria; Devos, Simon; Weyts, Wannes; De Cae, Sieglinde; Vanmarcke, Sandrine; Lonigro, Chiara; Eeckhaut, Hannah; Van Herpe, Dries; Borloo, Jimmy; Oliveira, Ana Filipa; Catani, Joao Paulo Portela; Creytens, Sarah; De Vlieger, Dorien; Michielsen, Gitte; Marchan, Jackeline Cecilia Zavala; Moschonas, George D; Rossey, Iebe; Sedeyn, Koen; Van Hecke, Annelies; Zhang, Xin; Langendries, Lana; Jacobs, Sofie; Ter Horst, Sebastiaan; Seldeslachts, Laura; Liesenborghs, Laurens; Boudewijns, Robbert; Thibaut, Hendrik Jan; Dallmeier, Kai; Vande Velde, Greetje; Weynand, Birgit; Beer, Julius; Schnepf, Daniel; Ohnemus, Annette; Remory, Isabel; Foo, Caroline S; Abdelnabi, Rana; Maes, Piet; Kaptein, Suzanne JF; Rocha-Pereira, Joana; Jochmans, Dirk; Delang, Leen; Peelman, Frank; Staeheli, Peter; Schwemmle, Martin; Devoogdt, Nick; Tersago, Dominique; Germani, Massimiliano; Heads, James; Henry, Alistair; Popplewell, Andrew; Ellis, Mark; Brady, Kevin; Turner, Alison; Dombrecht, Bruno; Stortelers, Catelijne; Neyts, Johan; Callewaert, Nico; Saelens, Xavier

doi:10.1126/scitranslmed.abi7826

An affinity-enhanced, broadly neutralizing heavy chain-only antibody protects against SARS-CoV-2 infection in animal models

Author:

Schepens, Bert

van Schie, Loes ; Nerinckx, Wim ; Roose, Kenny ; Van Breedam, Wander ; Fijalkowska, Daria ; Devos, Simon ; Weyts, Wannes ; De Cae, Sieglinde ; Vanmarcke, Sandrine ; Lonigro, Chiara ; Eeckhaut, Hannah ; Van Herpe, Dries ; Borloo, Jimmy ; Oliveira, Ana Filipa ; Catani, Joao Paulo Portela ; Creytens, Sarah ; De Vlieger, Dorien ; Michielsen, Gitte ; Marchan, Jackeline Cecilia Zavala ; Moschonas, George D ; Rossey, Iebe ; Sedeyn, Koen ; Van Hecke, Annelies ; Zhang, Xin ; Langendries, Lana ; Jacobs, Sofie ; Ter Horst, Sebastiaan ; Seldeslachts, Laura ; Liesenborghs, Laurens ; Boudewijns, Robbert ; Thibaut, Hendrik Jan ; Dallmeier, Kai ; Vande Velde, Greetje ; Weynand, Birgit ; Beer, Julius ; Schnepf, Daniel ; Ohnemus, Annette ; Remory, Isabel ; Foo, Caroline S ; Abdelnabi, Rana ; Maes, Piet ; Kaptein, Suzanne JF ; Rocha-Pereira, Joana ; Jochmans, Dirk ; Delang, Leen ; Peelman, Frank ; Staeheli, Peter ; Schwemmle, Martin ; Devoogdt, Nick ; Tersago, Dominique ; Germani, Massimiliano ; Heads, James ; Henry, Alistair ; Popplewell, Andrew ; Ellis, Mark ; Brady, Kevin ; Turner, Alison ; Dombrecht, Bruno ; Stortelers, Catelijne ; Neyts, Johan ; Callewaert, Nico ; Saelens, Xavier

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, RECEPTOR-BINDING DOMAIN, TRANSFORMATION, SITES, ACE2, Animals, Antibodies, Neutralizing, Antibodies, Viral, COVID-19, Humans, Models, Animal, SARS-CoV-2, Spike Glycoprotein, Coronavirus, C24/17/061#54270844, G0G4920N#55795248, 06 Biological Sciences, 11 Medical and Health Sciences, 3206 Medical biotechnology, 4003 Biomedical engineering

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.