Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models

Franziska K Kaiser; Mariana Gonzalez Hernandez; Nadine Krüger; Ellinor Englund; Wenjuan Du; Anna Z Mykytyn; Mathijs P Raadsen; Mart M Lamers; Francine Rodrigues Ianiski; Tatiana M Shamorkina; Joost Snijder; Federico Armando; Georg Beythien; Malgorzata Ciurkiewicz; Tom Schreiner; Eva Gruber-Dujardin; Martina Bleyer; Olga Batura; Lena Erffmeier; Rabea Hinkel; Cheila Rocha; Monica Mirolo; Dubravka Drabek; Berend-Jan Bosch; Mark Emalfarb; Noelia Valbuena; Ronen Tchelet; Wolfgang Baumgärtner; Markku Saloheimo; Stefan Pöhlmann; Frank Grosveld; Bart L Haagmans; Albert D M E Osterhaus

doi:10.1038/s41467-024-46443-0

Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models

Franziska K Kaiser, Mariana Gonzalez Hernandez, Nadine Krüger, Ellinor Englund, Wenjuan Du, Anna Z Mykytyn, Mathijs P Raadsen, Mart M Lamers, Francine Rodrigues Ianiski, Tatiana M Shamorkina, Joost Snijder, Federico Armando, Georg Beythien, Malgorzata Ciurkiewicz, Tom Schreiner, Eva Gruber-Dujardin, Martina Bleyer, Olga Batura, Lena Erffmeier, Rabea HinkelCheila Rocha, Monica Mirolo, Dubravka Drabek, Berend-Jan Bosch, Mark Emalfarb, Noelia Valbuena, Ronen Tchelet, Wolfgang Baumgärtner, Markku Saloheimo, Stefan Pöhlmann, Frank Grosveld, Bart L Haagmans, Albert D M E Osterhaus^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Monoclonal antibodies are an increasingly important tool for prophylaxis and treatment of acute virus infections like SARS-CoV-2 infection. However, their use is often restricted due to the time required for development, variable yields and high production costs, as well as the need for adaptation to newly emerging virus variants. Here we use the genetically modified filamentous fungus expression system Thermothelomyces heterothallica (C1), which has a naturally high biosynthesis capacity for secretory enzymes and other proteins, to produce a human monoclonal IgG1 antibody (HuMab 87G7) that neutralises the SARS-CoV-2 variants of concern (VOCs) Alpha, Beta, Gamma, Delta, and Omicron. Both the mammalian cell and C1 produced HuMab 87G7 broadly neutralise SARS-CoV-2 VOCs in vitro and also provide protection against VOC Omicron in hamsters. The C1 produced HuMab 87G7 is also able to protect against the Delta VOC in non-human primates. In summary, these findings show that the C1 expression system is a promising technology platform for the development of HuMabs in preventive and therapeutic medicine.

Original language	English
Article number	2319
Number of pages	14
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-46443-0
Publication status	Published - 14 Mar 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We thank Caroline Schütz, Julia Baskas, Kerstin Rohn, Kerstin Schöne, and Jana Svea Harre for excellent technical support and Martin Ludlow for English editing and suggestions. Part of the work was funded by the MANCO project, a European Union’s Horizon 2020 research and innovation program (grant agreement No 101003651, D.D., B.J.B., F.G., B.L.H., A.O.). The study was also supported by the COVID-19 Research Network of the State of Lower Saxony (COFONI) with funding from the Ministry of Science and Culture of Lower Saxony, Germany (14–76403–184, F.A., M.C., W.B.). This research was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation, G.B., L.H., F.K., W.B., and A.O.) -398066876/GRK 2485/1-VIPER-GRK. S.P. acknowledges funding by BMBF (01KI2006D, 01KI20328A, 01KX2021), the Ministry for Science and Culture of Lower Saxony (14-76103-184, COFONI Network, including projects 7FF22, 6FF22, 10FF22), and the German Research Foundation (DFG; PO 716/11-1, PO 716/14-1). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009). T.S. was supported by the Luxemburgish National Research Fund (FNR, Project Reference: 15686728). This open access publication was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)- 491094227 “Open Access Publication Funding” and “the University of Veterinary Medicine Hannover, Foundation.” We thank Caroline Schütz, Julia Baskas, Kerstin Rohn, Kerstin Schöne, and Jana Svea Harre for excellent technical support and Martin Ludlow for English editing and suggestions. Part of the work was funded by the MANCO project, a European Union’s Horizon 2020 research and innovation program (grant agreement No 101003651, D.D., B.J.B., F.G., B.L.H., A.O.). The study was also supported by the COVID-19 Research Network of the State of Lower Saxony (COFONI) with funding from the Ministry of Science and Culture of Lower Saxony, Germany (14–76403–184, F.A., M.C., W.B.). This research was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation, G.B., L.H., F.K., W.B., and A.O.) -398066876/GRK 2485/1-VIPER-GRK. S.P. acknowledges funding by BMBF (01KI2006D, 01KI20328A, 01KX2021), the Ministry for Science and Culture of Lower Saxony (14-76103-184, COFONI Network, including projects 7FF22, 6FF22, 10FF22), and the German Research Foundation (DFG; PO 716/11-1, PO 716/14-1). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009). T.S. was supported by the Luxemburgish National Research Fund (FNR, Project Reference: 15686728). This open access publication was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)- 491094227 “Open Access Publication Funding” and “the University of Veterinary Medicine Hannover, Foundation.”

Funders	Funder number
Luxemburgish National Research Fund
COFONI
State of Lower Saxony
Stiftung Tierärztliche Hochschule Hannover
Niedersächsisches Ministerium für Wissenschaft und Kultur	14-76103-184
Niedersächsisches Ministerium für Wissenschaft und Kultur
Deutsche Forschungsgemeinschaft	-398066876/GRK 2485/1-VIPER-GRK
Deutsche Forschungsgemeinschaft
Bundesministerium für Bildung und Forschung	01KI20328A, 01KI2006D, 01KX2021
Bundesministerium für Bildung und Forschung
Fachagentur Nachwachsende Rohstoffe	15686728, 491094227
Fachagentur Nachwachsende Rohstoffe
Ministry of Science and Culture of Lower Saxony	14–76403–184
Dutch Research Council NWO	024.002.009
Horizon 2020	101003651
Horizon 2020
COFONI Network	7FF22, PO 716/11-1, 10FF22, PO 716/14-1, 6FF22

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kaiser, F. K., Hernandez, M. G., Krüger, N., Englund, E., Du, W., Mykytyn, A. Z., Raadsen, M. P., Lamers, M. M., Rodrigues Ianiski, F., Shamorkina, T. M., Snijder, J., Armando, F., Beythien, G., Ciurkiewicz, M., Schreiner, T., Gruber-Dujardin, E., Bleyer, M., Batura, O., Erffmeier, L., ... Osterhaus, A. D. M. E. (2024). Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models. Nature Communications, 15(1), Article 2319. https://doi.org/10.1038/s41467-024-46443-0

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title = "Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models",

abstract = "Monoclonal antibodies are an increasingly important tool for prophylaxis and treatment of acute virus infections like SARS-CoV-2 infection. However, their use is often restricted due to the time required for development, variable yields and high production costs, as well as the need for adaptation to newly emerging virus variants. Here we use the genetically modified filamentous fungus expression system Thermothelomyces heterothallica (C1), which has a naturally high biosynthesis capacity for secretory enzymes and other proteins, to produce a human monoclonal IgG1 antibody (HuMab 87G7) that neutralises the SARS-CoV-2 variants of concern (VOCs) Alpha, Beta, Gamma, Delta, and Omicron. Both the mammalian cell and C1 produced HuMab 87G7 broadly neutralise SARS-CoV-2 VOCs in vitro and also provide protection against VOC Omicron in hamsters. The C1 produced HuMab 87G7 is also able to protect against the Delta VOC in non-human primates. In summary, these findings show that the C1 expression system is a promising technology platform for the development of HuMabs in preventive and therapeutic medicine.",

author = "Kaiser, {Franziska K} and Hernandez, {Mariana Gonzalez} and Nadine Kr{\"u}ger and Ellinor Englund and Wenjuan Du and Mykytyn, {Anna Z} and Raadsen, {Mathijs P} and Lamers, {Mart M} and {Rodrigues Ianiski}, Francine and Shamorkina, {Tatiana M} and Joost Snijder and Federico Armando and Georg Beythien and Malgorzata Ciurkiewicz and Tom Schreiner and Eva Gruber-Dujardin and Martina Bleyer and Olga Batura and Lena Erffmeier and Rabea Hinkel and Cheila Rocha and Monica Mirolo and Dubravka Drabek and Berend-Jan Bosch and Mark Emalfarb and Noelia Valbuena and Ronen Tchelet and Wolfgang Baumg{\"a}rtner and Markku Saloheimo and Stefan P{\"o}hlmann and Frank Grosveld and Haagmans, {Bart L} and Osterhaus, {Albert D M E}",

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Kaiser, FK, Hernandez, MG, Krüger, N, Englund, E, Du, W, Mykytyn, AZ, Raadsen, MP, Lamers, MM, Rodrigues Ianiski, F , Shamorkina, TM , Snijder, J, Armando, F, Beythien, G, Ciurkiewicz, M, Schreiner, T, Gruber-Dujardin, E, Bleyer, M, Batura, O, Erffmeier, L, Hinkel, R, Rocha, C, Mirolo, M, Drabek, D, Bosch, B-J, Emalfarb, M, Valbuena, N, Tchelet, R, Baumgärtner, W, Saloheimo, M, Pöhlmann, S, Grosveld, F, Haagmans, BL & Osterhaus, ADME 2024, 'Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models', Nature Communications, vol. 15, no. 1, 2319. https://doi.org/10.1038/s41467-024-46443-0

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AU - Englund, Ellinor

AU - Du, Wenjuan

AU - Mykytyn, Anna Z

AU - Raadsen, Mathijs P

AU - Lamers, Mart M

AU - Rodrigues Ianiski, Francine

AU - Shamorkina, Tatiana M

AU - Snijder, Joost

AU - Armando, Federico

AU - Beythien, Georg

AU - Ciurkiewicz, Malgorzata

AU - Schreiner, Tom

AU - Gruber-Dujardin, Eva

AU - Bleyer, Martina

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AU - Erffmeier, Lena

AU - Hinkel, Rabea

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AU - Mirolo, Monica

AU - Drabek, Dubravka

AU - Bosch, Berend-Jan

AU - Emalfarb, Mark

AU - Valbuena, Noelia

AU - Tchelet, Ronen

AU - Baumgärtner, Wolfgang

AU - Saloheimo, Markku

AU - Pöhlmann, Stefan

AU - Grosveld, Frank

AU - Haagmans, Bart L

AU - Osterhaus, Albert D M E

PY - 2024/3/14

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AB - Monoclonal antibodies are an increasingly important tool for prophylaxis and treatment of acute virus infections like SARS-CoV-2 infection. However, their use is often restricted due to the time required for development, variable yields and high production costs, as well as the need for adaptation to newly emerging virus variants. Here we use the genetically modified filamentous fungus expression system Thermothelomyces heterothallica (C1), which has a naturally high biosynthesis capacity for secretory enzymes and other proteins, to produce a human monoclonal IgG1 antibody (HuMab 87G7) that neutralises the SARS-CoV-2 variants of concern (VOCs) Alpha, Beta, Gamma, Delta, and Omicron. Both the mammalian cell and C1 produced HuMab 87G7 broadly neutralise SARS-CoV-2 VOCs in vitro and also provide protection against VOC Omicron in hamsters. The C1 produced HuMab 87G7 is also able to protect against the Delta VOC in non-human primates. In summary, these findings show that the C1 expression system is a promising technology platform for the development of HuMabs in preventive and therapeutic medicine.

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Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models

Abstract

Bibliographical note

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