Journal
MABS
Volume 15, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2023.2212415
Keywords
ACE2; antibody engineering; COVID-19; IgM; multivalent scaffold; receptor decoys; SARS-CoV-2
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Researchers have developed an IgM-based ACE2 decoy that shows efficacy against different variants of SARS-CoV-2. In experiments, this decoy outperforms existing antibody therapies and provides therapeutic benefit against Delta variant infection.
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.
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