Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain
Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is...
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| Format: | Article |
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Taylor & Francis Group
2024-12-01
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| Series: | Human Vaccines & Immunotherapeutics |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21645515.2024.2388344 |
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| author | Denise Guerra Laura Radić Mitch Brinkkemper Meliawati Poniman Lara van der Maas Jonathan L. Torres Andrew B. Ward Kwinten Sliepen Janke Schinkel Rogier W. Sanders Marit J. van Gils Tim Beaumont |
| author_facet | Denise Guerra Laura Radić Mitch Brinkkemper Meliawati Poniman Lara van der Maas Jonathan L. Torres Andrew B. Ward Kwinten Sliepen Janke Schinkel Rogier W. Sanders Marit J. van Gils Tim Beaumont |
| author_sort | Denise Guerra |
| collection | DOAJ |
| description | Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is a growing interest in bispecific antibodies (bsAbs) which can simultaneously target different spike epitopes and thereby increase neutralizing breadth and prevent viral escape. Here, we generate and characterize a panel of 30 novel broadly reactive bsAbs using an efficient controlled Fab-arm exchange protocol. We specifically combine some of the broadest mAbs described so far, which target conserved epitopes on the receptor binding domain (RBD). Several bsAbs show superior cross-binding and neutralization compared to the parental mAbs and cocktails against sarbecoviruses from diverse clades, including recent SARS-CoV-2 variants. BsAbs which include mAb COVA2–02 are among the most potent and broad combinations. As a result, we study the unknown epitope of COVA2–02 and show that this mAb targets a distinct conserved region at the base of the RBD, which could be of interest when designing next-generation bsAb constructs to contribute to a better pandemic preparedness. |
| format | Article |
| id | doaj-art-1fbcc6e3d1d94ac096e091f76a23bb0a |
| institution | DOAJ |
| issn | 2164-5515 2164-554X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Human Vaccines & Immunotherapeutics |
| spelling | doaj-art-1fbcc6e3d1d94ac096e091f76a23bb0a2025-08-20T03:21:46ZengTaylor & Francis GroupHuman Vaccines & Immunotherapeutics2164-55152164-554X2024-12-0120110.1080/21645515.2024.2388344Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domainDenise Guerra0Laura Radić1Mitch Brinkkemper2Meliawati Poniman3Lara van der Maas4Jonathan L. Torres5Andrew B. Ward6Kwinten Sliepen7Janke Schinkel8Rogier W. Sanders9Marit J. van Gils10Tim Beaumont11Department of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, USADepartment of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, USADepartment of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, USADepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam UMC Location University of Amsterdam, Amsterdam, The NetherlandsMonoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is a growing interest in bispecific antibodies (bsAbs) which can simultaneously target different spike epitopes and thereby increase neutralizing breadth and prevent viral escape. Here, we generate and characterize a panel of 30 novel broadly reactive bsAbs using an efficient controlled Fab-arm exchange protocol. We specifically combine some of the broadest mAbs described so far, which target conserved epitopes on the receptor binding domain (RBD). Several bsAbs show superior cross-binding and neutralization compared to the parental mAbs and cocktails against sarbecoviruses from diverse clades, including recent SARS-CoV-2 variants. BsAbs which include mAb COVA2–02 are among the most potent and broad combinations. As a result, we study the unknown epitope of COVA2–02 and show that this mAb targets a distinct conserved region at the base of the RBD, which could be of interest when designing next-generation bsAb constructs to contribute to a better pandemic preparedness.https://www.tandfonline.com/doi/10.1080/21645515.2024.2388344SARS-CoV-2variantssarbecovirusesbispecific antibodiescross-reactivitybreadth |
| spellingShingle | Denise Guerra Laura Radić Mitch Brinkkemper Meliawati Poniman Lara van der Maas Jonathan L. Torres Andrew B. Ward Kwinten Sliepen Janke Schinkel Rogier W. Sanders Marit J. van Gils Tim Beaumont Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain Human Vaccines & Immunotherapeutics SARS-CoV-2 variants sarbecoviruses bispecific antibodies cross-reactivity breadth |
| title | Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain |
| title_full | Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain |
| title_fullStr | Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain |
| title_full_unstemmed | Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain |
| title_short | Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain |
| title_sort | broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain |
| topic | SARS-CoV-2 variants sarbecoviruses bispecific antibodies cross-reactivity breadth |
| url | https://www.tandfonline.com/doi/10.1080/21645515.2024.2388344 |
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