Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
© 2023. Springer Nature Limited..
The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 13. Sept., Seite 5650 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chapman, Nathaniel S [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Monoclonal |
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| Anmerkungen: |
Date Completed 15.09.2023 Date Revised 14.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-41171-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Stass, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Paesen, Guido C |e verfasserin |4 aut | |
| 700 | 1 | |a Binshtein, Elad |e verfasserin |4 aut | |
| 700 | 1 | |a Reidy, Joseph X |e verfasserin |4 aut | |
| 700 | 1 | |a Engdahl, Taylor B |e verfasserin |4 aut | |
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| 700 | 1 | |a Bowden, Thomas A |e verfasserin |4 aut | |
| 700 | 1 | |a Crowe, James E |c Jr |e verfasserin |4 aut | |
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