High Potency of a Bivalent Human V<sub>H</sub> Domain in SARS-CoV-2 Animal Models.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32941803.
- Also identified by DOI 10.1016/j.cell.2020.09.007 and PMC identifier 7473018.
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Abstract
Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody V<sub>H</sub> domain library from which we identified a high-affinity V<sub>H</sub> binder ab8. Bivalent V<sub>H</sub>, V<sub>H</sub>-Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. V<sub>H</sub>-Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of V<sub>H</sub>-Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.
Medical subject headings
- Coronavirus Infections
- Immunoglobulin Heavy Chains
- Immunoglobulin Variable Region
- Peptide Library
- Pneumonia, Viral