Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses
Summary: SARS-CoV-2 variants evade current monoclonal antibody therapies. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies taking advantage of the avidity and synergy provided by targeting different epitopes. Here we used controlled Fab-arm exchange to produce bsAbs...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422300617X |
| _version_ | 1797847300215668736 |
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| author | Laura Radić Kwinten Sliepen Victor Yin Mitch Brinkkemper Joan Capella-Pujol Angela I. Schriek Jonathan L. Torres Sandhya Bangaru Judith A. Burger Meliawati Poniman Ilja Bontjer Joey H. Bouhuijs David Gideonse Dirk Eggink Andrew B. Ward Albert J.R. Heck Marit J. Van Gils Rogier W. Sanders Janke Schinkel |
| author_facet | Laura Radić Kwinten Sliepen Victor Yin Mitch Brinkkemper Joan Capella-Pujol Angela I. Schriek Jonathan L. Torres Sandhya Bangaru Judith A. Burger Meliawati Poniman Ilja Bontjer Joey H. Bouhuijs David Gideonse Dirk Eggink Andrew B. Ward Albert J.R. Heck Marit J. Van Gils Rogier W. Sanders Janke Schinkel |
| author_sort | Laura Radić |
| collection | DOAJ |
| description | Summary: SARS-CoV-2 variants evade current monoclonal antibody therapies. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies taking advantage of the avidity and synergy provided by targeting different epitopes. Here we used controlled Fab-arm exchange to produce bsAbs that neutralize SARS-CoV and SARS-CoV-2 variants, including Omicron and its subvariants, by combining potent SARS-CoV-2-specific neutralizing antibodies with broader antibodies that also neutralize SARS-CoV. We demonstrated that the parental antibodies rely on avidity for neutralization using bsAbs containing one irrelevant Fab arm. Using mass photometry to measure the formation of antibody:spike complexes, we determined that bsAbs increase binding stoichiometry compared to corresponding cocktails, without a loss of binding affinity. The heterogeneous binding pattern of bsAbs to spike, observed by negative-stain electron microscopy and mass photometry provided evidence for both intra- and inter-spike crosslinking. This study highlights the utility of cross-neutralizing antibodies for designing bivalent agents to combat circulating and future SARS-like coronaviruses. |
| first_indexed | 2024-04-09T18:09:05Z |
| format | Article |
| id | doaj.art-7d8f8ca04b814e959ae9c06f1301b35e |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T18:09:05Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-7d8f8ca04b814e959ae9c06f1301b35e2023-04-14T04:19:39ZengElsevieriScience2589-00422023-04-01264106540Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecovirusesLaura Radić0Kwinten Sliepen1Victor Yin2Mitch Brinkkemper3Joan Capella-Pujol4Angela I. Schriek5Jonathan L. Torres6Sandhya Bangaru7Judith A. Burger8Meliawati Poniman9Ilja Bontjer10Joey H. Bouhuijs11David Gideonse12Dirk Eggink13Andrew B. Ward14Albert J.R. Heck15Marit J. Van Gils16Rogier W. Sanders17Janke Schinkel18Amsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsBiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Center, 3584 CH Utrecht, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsDepartment of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USAAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the NetherlandsCenter for Infectious Disease Control, WHO COVID-19 reference laboratory, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, the NetherlandsCenter for Infectious Disease Control, WHO COVID-19 reference laboratory, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, the NetherlandsDepartment of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USABiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Center, 3584 CH Utrecht, the NetherlandsAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the Netherlands; Corresponding authorAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the Netherlands; Corresponding authorAmsterdam UMC location University of Amsterdam, Department of Medical Microbiology and Infection prevention, Laboratory of Experimental Virology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam, the Netherlands; Corresponding authorSummary: SARS-CoV-2 variants evade current monoclonal antibody therapies. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies taking advantage of the avidity and synergy provided by targeting different epitopes. Here we used controlled Fab-arm exchange to produce bsAbs that neutralize SARS-CoV and SARS-CoV-2 variants, including Omicron and its subvariants, by combining potent SARS-CoV-2-specific neutralizing antibodies with broader antibodies that also neutralize SARS-CoV. We demonstrated that the parental antibodies rely on avidity for neutralization using bsAbs containing one irrelevant Fab arm. Using mass photometry to measure the formation of antibody:spike complexes, we determined that bsAbs increase binding stoichiometry compared to corresponding cocktails, without a loss of binding affinity. The heterogeneous binding pattern of bsAbs to spike, observed by negative-stain electron microscopy and mass photometry provided evidence for both intra- and inter-spike crosslinking. This study highlights the utility of cross-neutralizing antibodies for designing bivalent agents to combat circulating and future SARS-like coronaviruses.http://www.sciencedirect.com/science/article/pii/S258900422300617XImmunologyVirologyStructural biology |
| spellingShingle | Laura Radić Kwinten Sliepen Victor Yin Mitch Brinkkemper Joan Capella-Pujol Angela I. Schriek Jonathan L. Torres Sandhya Bangaru Judith A. Burger Meliawati Poniman Ilja Bontjer Joey H. Bouhuijs David Gideonse Dirk Eggink Andrew B. Ward Albert J.R. Heck Marit J. Van Gils Rogier W. Sanders Janke Schinkel Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses iScience Immunology Virology Structural biology |
| title | Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses |
| title_full | Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses |
| title_fullStr | Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses |
| title_full_unstemmed | Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses |
| title_short | Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses |
| title_sort | bispecific antibodies combine breadth potency and avidity of parental antibodies to neutralize sarbecoviruses |
| topic | Immunology Virology Structural biology |
| url | http://www.sciencedirect.com/science/article/pii/S258900422300617X |
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