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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Barnes, Christopher O ; Jette, Claudia A ; Abernathy, Morgan E ; Dam, Kim-Marie A ; Esswein, Shannon R ; Gristick, Harry B ; Malyutin, Andrey G ; Sharaf, Naima G ; Huey-Tubman, Kathryn E ; Lee, Yu E ; Robbiani, Davide F ; Nussenzweig, Michel C ; West, Jr, Anthony P ; Bjorkman, Pamela J

Nature (London), 2020-12, Vol.588 (7839), p.682-687 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies
Autor: Barnes, Christopher O ; Jette, Claudia A ; Abernathy, Morgan E ; Dam, Kim-Marie A ; Esswein, Shannon R ; Gristick, Harry B ; Malyutin, Andrey G ; Sharaf, Naima G ; Huey-Tubman, Kathryn E ; Lee, Yu E ; Robbiani, Davide F ; Nussenzweig, Michel C ; West, Jr, Anthony P ; Bjorkman, Pamela J
Assuntos: ACE2 ; Analysis ; Angiotensin-converting enzyme 2 ; Angiotensin-Converting Enzyme 2 - chemistry ; Angiotensin-Converting Enzyme 2 - metabolism ; Angiotensin-Converting Enzyme 2 - ultrastructure ; Antibodies ; Antibodies, Neutralizing - chemistry ; Antibodies, Neutralizing - immunology ; Antibodies, Neutralizing - therapeutic use ; Antibodies, Neutralizing - ultrastructure ; Antigenic determinants ; Antigens ; Avidity ; Binding sites ; Binding Sites - genetics ; Binding Sites - immunology ; Blocking ; Cell Line ; Conformation ; Coronaviridae ; Coronaviruses ; COVID-19 ; COVID-19 - immunology ; COVID-19 Drug Treatment ; Cryoelectron Microscopy ; Epidemics ; Epitope mapping ; Evaluation ; Glycoproteins ; Health aspects ; Humans ; Hydrophobicity ; Immune response ; Locking ; Mapping ; Models, Molecular ; Mutation ; N-glycans ; Neutralization ; Neutralizing ; Pandemics ; Physiological aspects ; Polysaccharides ; Receptors, Coronavirus - chemistry ; Receptors, Coronavirus - metabolism ; Receptors, Coronavirus - ultrastructure ; SARS-CoV-2 - chemistry ; SARS-CoV-2 - immunology ; SARS-CoV-2 - metabolism ; SARS-CoV-2 - ultrastructure ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Spike Glycoprotein, Coronavirus - chemistry ; Spike Glycoprotein, Coronavirus - genetics ; Spike Glycoprotein, Coronavirus - immunology ; Spike Glycoprotein, Coronavirus - ultrastructure ; Spikes ; Structure ; Trimers ; Viral antibodies ; Viral diseases
É parte de: Nature (London), 2020-12, Vol.588 (7839), p.682-687
Notas: C.O.B., M.C.N., A.P.W., and P.J.B. conceived the study and analyzed data; D.F.R. and M.C.N. provided monoclonal antibody sequences and plasmids derived from COVID-19 convalescent donors. C.O.B. and K.H.T. performed protein purifications and C.O.B. assembled complexes for cryo-EM and X-ray crystallography studies. C.O.B. performed cryo-EM and interpreted structures with assistance from M.E.A., K.A.D, S.R.E., A.G.M., and N.G.S. C.A.J. and C.O.B. performed and analyzed crystallographic structures, with refinement assistance from M.E.A. and K.M.D. Y.E.L. performed polyreactivity assays. H.B.G. performed and analyzed SPR experiments. A.P.W. analyzed antibody sequences. C.O.B., M.C.N., A.P.W., and P.J.B. wrote the paper with contributions from other authors.
Author contributions
Descrição: The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein show promise therapeutically and are being evaluated clinically . Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs . Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
Editor: England: Nature Publishing Group
Idioma: Inglês

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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Barnes, Christopher O ; Jette, Claudia A ; Abernathy, Morgan E ; Dam, Kim-Marie A ; Esswein, Shannon R ; Gristick, Harry B ; Malyutin, Andrey G ; Sharaf, Naima G ; Huey-Tubman, Kathryn E ; Lee, Yu E ; Robbiani, Davide F ; Nussenzweig, Michel C ; West, Jr, Anthony P ; Bjorkman, Pamela J

England: Nature Publishing Group

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