| Abstract |
Emerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively, show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of the spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented an immune response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies, such as 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.
|
| MeSH term(s) |
Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/immunology ; Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/metabolism ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/genetics ; Antibodies, Neutralizing/immunology ; Antibodies, Neutralizing/metabolism ; Antibodies, Viral/chemistry ; Antibodies, Viral/genetics ; Antibodies, Viral/immunology ; Antibodies, Viral/metabolism ; Binding Sites ; Cloning, Molecular ; Cryoelectron Microscopy ; Epitopes/chemistry ; Epitopes/genetics ; Epitopes/immunology ; Epitopes/metabolism ; Gene Expression ; HEK293 Cells ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Receptors, Virus/chemistry ; Receptors, Virus/genetics ; Receptors, Virus/immunology ; Receptors, Virus/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/immunology ; Recombinant Proteins/metabolism ; SARS-CoV-2/chemistry ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology ; Spike Glycoprotein, Coronavirus/metabolism |
| Chemical Substances |
Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Receptors, Virus ; Recombinant Proteins ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) |
| Language |
English |
| Publishing date |
2021-06-09 |
| Publishing country |
United States |
| Document type |
Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID |
1213087-4 |
| ISSN |
1878-4186 ; 0969-2126 |
| ISSN (online) |
1878-4186 |
| ISSN |
0969-2126 |
| DOI |
10.1016/j.str.2021.05.014 |
| Database |
MEDical Literature Analysis and Retrieval System OnLINE |
