Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/pharmacology , COVID-19 Drug Treatment , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/immunology , COVID-19/virology , Enzyme-Linked Immunosorbent Assay , Gene Expression , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Lung/drug effects , Lung/immunology , Lung/virology , Mice , Protein Binding/drug effects , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/growth & development , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.
