Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants
Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1111385/full |
| _version_ | 1797901461779120128 |
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| author | Wenjuan Du Rick Janssens Rick Janssens Anna Z. Mykytyn Wentao Li Dubravka Drabek Dubravka Drabek Rien van Haperen Rien van Haperen Marianthi Chatziandreou Melanie Rissmann Joline van der Lee Melissa van Dortmondt Itziar Serna Martin Frank J. M. van Kuppeveld Daniel L. Hurdiss Bart L. Haagmans Frank Grosveld Frank Grosveld Berend-Jan Bosch |
| author_facet | Wenjuan Du Rick Janssens Rick Janssens Anna Z. Mykytyn Wentao Li Dubravka Drabek Dubravka Drabek Rien van Haperen Rien van Haperen Marianthi Chatziandreou Melanie Rissmann Joline van der Lee Melissa van Dortmondt Itziar Serna Martin Frank J. M. van Kuppeveld Daniel L. Hurdiss Bart L. Haagmans Frank Grosveld Frank Grosveld Berend-Jan Bosch |
| author_sort | Wenjuan Du |
| collection | DOAJ |
| description | Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants. Here we describe the design of a biparatopic heavy-chain-only antibody consisting of six antigen binding sites recognizing two distinct epitopes in the spike protein NTD and RBD. The hexavalent antibody showed potent neutralizing activity against SARS-CoV-2 and variants of concern, including the Omicron sub-lineages BA.1, BA.2, BA.4 and BA.5, whereas the parental components had lost Omicron neutralization potency. We demonstrate that the tethered design mitigates the substantial decrease in spike trimer affinity seen for escape mutations for the hexamer components. The hexavalent antibody protected against SARS-CoV-2 infection in a hamster model. This work provides a framework for designing therapeutic antibodies to overcome antibody neutralization escape of emerging SARS-CoV-2 variants. |
| first_indexed | 2024-04-10T09:01:21Z |
| format | Article |
| id | doaj.art-a2e974cb90cd4149a3c38cfea0d08f4d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T09:01:21Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a2e974cb90cd4149a3c38cfea0d08f4d2023-02-21T12:13:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.11113851111385Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variantsWenjuan Du0Rick Janssens1Rick Janssens2Anna Z. Mykytyn3Wentao Li4Dubravka Drabek5Dubravka Drabek6Rien van Haperen7Rien van Haperen8Marianthi Chatziandreou9Melanie Rissmann10Joline van der Lee11Melissa van Dortmondt12Itziar Serna Martin13Frank J. M. van Kuppeveld14Daniel L. Hurdiss15Bart L. Haagmans16Frank Grosveld17Frank Grosveld18Berend-Jan Bosch19Virology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsDepartment of Cell Biology, Erasmus Medical Center, Rotterdam, NetherlandsHarbour BioMed, Rotterdam, NetherlandsDepartment of Viroscience, Erasmus Medical Center, Rotterdam, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsDepartment of Cell Biology, Erasmus Medical Center, Rotterdam, NetherlandsHarbour BioMed, Rotterdam, NetherlandsDepartment of Cell Biology, Erasmus Medical Center, Rotterdam, NetherlandsHarbour BioMed, Rotterdam, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsDepartment of Cell Biology, Erasmus Medical Center, Rotterdam, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsDepartment of Viroscience, Erasmus Medical Center, Rotterdam, NetherlandsDepartment of Cell Biology, Erasmus Medical Center, Rotterdam, NetherlandsHarbour BioMed, Rotterdam, NetherlandsVirology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsEmerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants. Here we describe the design of a biparatopic heavy-chain-only antibody consisting of six antigen binding sites recognizing two distinct epitopes in the spike protein NTD and RBD. The hexavalent antibody showed potent neutralizing activity against SARS-CoV-2 and variants of concern, including the Omicron sub-lineages BA.1, BA.2, BA.4 and BA.5, whereas the parental components had lost Omicron neutralization potency. We demonstrate that the tethered design mitigates the substantial decrease in spike trimer affinity seen for escape mutations for the hexamer components. The hexavalent antibody protected against SARS-CoV-2 infection in a hamster model. This work provides a framework for designing therapeutic antibodies to overcome antibody neutralization escape of emerging SARS-CoV-2 variants.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1111385/fullheavy-chain-only antibodyaviditySARS-CoV-2antibody-mediated neutralizationneutralization escape |
| spellingShingle | Wenjuan Du Rick Janssens Rick Janssens Anna Z. Mykytyn Wentao Li Dubravka Drabek Dubravka Drabek Rien van Haperen Rien van Haperen Marianthi Chatziandreou Melanie Rissmann Joline van der Lee Melissa van Dortmondt Itziar Serna Martin Frank J. M. van Kuppeveld Daniel L. Hurdiss Bart L. Haagmans Frank Grosveld Frank Grosveld Berend-Jan Bosch Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants Frontiers in Immunology heavy-chain-only antibody avidity SARS-CoV-2 antibody-mediated neutralization neutralization escape |
| title | Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants |
| title_full | Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants |
| title_fullStr | Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants |
| title_full_unstemmed | Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants |
| title_short | Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants |
| title_sort | avidity engineering of human heavy chain only antibodies mitigates neutralization resistance of sars cov 2 variants |
| topic | heavy-chain-only antibody avidity SARS-CoV-2 antibody-mediated neutralization neutralization escape |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1111385/full |
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