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

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

doi:10.1126/scitranslmed.abi7826

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

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

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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.

Original language	English
Article number	eabi7826
Journal	Science Translational Medicine
Volume	13
Issue number	621
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.abi7826
Publication status	Published - 24-Nov-2021

Keywords

Animals
Antibodies, Neutralizing
Antibodies, Viral
COVID-19
Humans
Models, Animal
SARS-CoV-2
Spike Glycoprotein, Coronavirus

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10.1126/scitranslmed.abi7826Licence: CC BY

2021stmeeabi7826Final published version, 1.81 MBLicence: CC BY

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Schepens, B., van Schie, L., Nerinckx, W., Roose, K., Van Breedam, W., Fijalkowska, D., Devos, S., Weyts, W., De Cae, S., Vanmarcke, S., Lonigro, C., Eeckhaut, H., Van Herpe, D., Borloo, J., Oliveira, A. F., Catani, J. P. P., Creytens, S., De Vlieger, D., Michielsen, G., ... Saelens, X. (2021). An affinity-enhanced, broadly neutralizing heavy chain-only antibody protects against SARS-CoV-2 infection in animal models. Science Translational Medicine, 13(621), Article eabi7826. https://doi.org/10.1126/scitranslmed.abi7826

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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.",

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Schepens, B, van Schie, L, Nerinckx, W, Roose, K, Van Breedam, W, Fijalkowska, D, Devos, S, Weyts, W, De Cae, S, Vanmarcke, S, Lonigro, C, Eeckhaut, H, Van Herpe, D, Borloo, J, Oliveira, AF, Catani, JPP, Creytens, S, De Vlieger, D, Michielsen, G, Marchan, JCZ, Moschonas, GD, Rossey, I, Sedeyn, K, Van Hecke, A, Zhang, X, Langendries, L, Jacobs, S, Ter Horst, S, Seldeslachts, L, Liesenborghs, L, Boudewijns, R, Thibaut, HJ, Dallmeier, K, Velde, GV, Weynand, B, Beer, J, Schnepf, D, Ohnemus, A, Remory, I, Foo, CS, Abdelnabi, R, Maes, P, Kaptein, SJF, Rocha-Pereira, J, Jochmans, D, Delang, L, Peelman, F, Staeheli, P, Schwemmle, M, Devoogdt, N, Tersago, D, Germani, M, Heads, J, Henry, A, Popplewell, A, Ellis, M, Brady, K, Turner, A, Dombrecht, B, Stortelers, C, Neyts, J, Callewaert, N & Saelens, X 2021, 'An affinity-enhanced, broadly neutralizing heavy chain-only antibody protects against SARS-CoV-2 infection in animal models', Science Translational Medicine, vol. 13, no. 621, eabi7826. https://doi.org/10.1126/scitranslmed.abi7826

TY - JOUR

T1 - An affinity-enhanced, broadly neutralizing heavy chain-only antibody protects against SARS-CoV-2 infection in animal models

AU - Schepens, Bert

AU - van Schie, Loes

AU - Nerinckx, Wim

AU - Roose, Kenny

AU - Van Breedam, Wander

AU - Fijalkowska, Daria

AU - Devos, Simon

AU - Weyts, Wannes

AU - De Cae, Sieglinde

AU - Vanmarcke, Sandrine

AU - Lonigro, Chiara

AU - Eeckhaut, Hannah

AU - Van Herpe, Dries

AU - Borloo, Jimmy

AU - Oliveira, Ana Filipa

AU - Catani, João Paulo Portela

AU - Creytens, Sarah

AU - De Vlieger, Dorien

AU - Michielsen, Gitte

AU - Marchan, Jackeline Cecilia Zavala

AU - Moschonas, George D

AU - Rossey, Iebe

AU - Sedeyn, Koen

AU - Van Hecke, Annelies

AU - Zhang, Xin

AU - Langendries, Lana

AU - Jacobs, Sofie

AU - Ter Horst, Sebastiaan

AU - Seldeslachts, Laura

AU - Liesenborghs, Laurens

AU - Boudewijns, Robbert

AU - Thibaut, Hendrik Jan

AU - Dallmeier, Kai

AU - Velde, Greetje Vande

AU - Weynand, Birgit

AU - Beer, Julius

AU - Schnepf, Daniel

AU - Ohnemus, Annette

AU - Remory, Isabel

AU - Foo, Caroline S

AU - Abdelnabi, Rana

AU - Maes, Piet

AU - Kaptein, Suzanne J F

AU - Rocha-Pereira, Joana

AU - Jochmans, Dirk

AU - Delang, Leen

AU - Peelman, Frank

AU - Staeheli, Peter

AU - Schwemmle, Martin

AU - Devoogdt, Nick

AU - Tersago, Dominique

AU - Germani, Massimiliano

AU - Heads, James

AU - Henry, Alistair

AU - Popplewell, Andrew

AU - Ellis, Mark

AU - Brady, Kevin

AU - Turner, Alison

AU - Dombrecht, Bruno

AU - Stortelers, Catelijne

AU - Neyts, Johan

AU - Callewaert, Nico

AU - Saelens, Xavier

N1 - FTX; (CC BY 4.0)

PY - 2021/11/24

Y1 - 2021/11/24

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies, Neutralizing

KW - Antibodies, Viral

KW - COVID-19

KW - Humans

KW - Models, Animal

KW - SARS-CoV-2

KW - Spike Glycoprotein, Coronavirus

U2 - 10.1126/scitranslmed.abi7826

DO - 10.1126/scitranslmed.abi7826

M3 - A1: Web of Science-article

C2 - 34609205

SN - 1946-6234

VL - 13

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 621

M1 - eabi7826

ER -

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

Abstract

Keywords

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