Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2
As immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and li...
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Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2212415 |
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| author | Meghan M. Verstraete Florian Heinkel Janessa Li Siran Cao Anh Tran Elizabeth C. Halverson Robert Gene Elizabeth Stangle Begonia Silva-Moreno Sifa Arrafi Jegarubee Bavananthasivam Madeline Fung Mariam Eji-Lasisi Stephanie Masterman Steve Xanthoudakis Surjit Dixit John Babcook Brandon Clavette Mark Fogg Eric Escobar-Cabrera |
| author_facet | Meghan M. Verstraete Florian Heinkel Janessa Li Siran Cao Anh Tran Elizabeth C. Halverson Robert Gene Elizabeth Stangle Begonia Silva-Moreno Sifa Arrafi Jegarubee Bavananthasivam Madeline Fung Mariam Eji-Lasisi Stephanie Masterman Steve Xanthoudakis Surjit Dixit John Babcook Brandon Clavette Mark Fogg Eric Escobar-Cabrera |
| author_sort | Meghan M. Verstraete |
| collection | DOAJ |
| description | As immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2. |
| format | Article |
| id | doaj-art-0babf0f9afc845fba1c4497a7c7e2472 |
| institution | DOAJ |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-0babf0f9afc845fba1c4497a7c7e24722025-08-20T02:50:17ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2212415Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2Meghan M. Verstraete0Florian Heinkel1Janessa Li2Siran Cao3Anh Tran4Elizabeth C. Halverson5Robert Gene6Elizabeth Stangle7Begonia Silva-Moreno8Sifa Arrafi9Jegarubee Bavananthasivam10Madeline Fung11Mariam Eji-Lasisi12Stephanie Masterman13Steve Xanthoudakis14Surjit Dixit15John Babcook16Brandon Clavette17Mark Fogg18Eric Escobar-Cabrera19Zymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaDepartment of Human Health Therapeutics, National Research Council Canada, Ottawa, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaDepartment of Human Health Therapeutics, National Research Council Canada, Ottawa, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaZymeworks Inc, Vancouver, CanadaAs immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2.https://www.tandfonline.com/doi/10.1080/19420862.2023.2212415ACE2antibody engineeringCOVID-19IgMmultivalent scaffoldreceptor decoys |
| spellingShingle | Meghan M. Verstraete Florian Heinkel Janessa Li Siran Cao Anh Tran Elizabeth C. Halverson Robert Gene Elizabeth Stangle Begonia Silva-Moreno Sifa Arrafi Jegarubee Bavananthasivam Madeline Fung Mariam Eji-Lasisi Stephanie Masterman Steve Xanthoudakis Surjit Dixit John Babcook Brandon Clavette Mark Fogg Eric Escobar-Cabrera Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2 mAbs ACE2 antibody engineering COVID-19 IgM multivalent scaffold receptor decoys |
| title | Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2 |
| title_full | Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2 |
| title_fullStr | Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2 |
| title_full_unstemmed | Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2 |
| title_short | Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2 |
| title_sort | multivalent igm scaffold enhances the therapeutic potential of variant agnostic ace2 decoys against sars cov 2 |
| topic | ACE2 antibody engineering COVID-19 IgM multivalent scaffold receptor decoys |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2212415 |
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