Tags

Type your tag names separated by a space and hit enter

SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Nature. 2020 Dec; 588(7839):682-687.Nat

Abstract

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^1-5 show promise therapeutically and are being evaluated clinically^6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies⁵ 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 RBDs⁹. 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.

Links

Authors+Show Affiliations

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Beckman Institute, California Institute of Technology, Pasadena, CA, USA.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA. Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.

Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. bjorkman@caltech.edu.

MeSH

Angiotensin-Converting Enzyme 2Antibodies, NeutralizingBinding SitesCOVID-19Cell LineCryoelectron MicroscopyHumansModels, MolecularMutationReceptors, CoronavirusSARS-CoV-2Spike Glycoprotein, CoronavirusCOVID-19 Drug Treatment

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

33045718

Clinical Trial Links

RU Anti-SARS-CoV-2 (COVID-19) mAbs in Healthy Volunteers

Citation

Barnes, Christopher O., et al. "SARS-CoV-2 Neutralizing Antibody Structures Inform Therapeutic Strategies." Nature, vol. 588, no. 7839, 2020, pp. 682-687.

Barnes CO, Jette CA, Abernathy ME, et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature. 2020;588(7839):682-687.

Barnes, C. O., Jette, C. A., Abernathy, M. E., Dam, K. A., Esswein, S. R., Gristick, H. B., Malyutin, A. G., Sharaf, N. G., Huey-Tubman, K. E., Lee, Y. E., Robbiani, D. F., Nussenzweig, M. C., West, A. P., & Bjorkman, P. J. (2020). SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature, 588(7839), 682-687. https://doi.org/10.1038/s41586-020-2852-1

Barnes CO, et al. SARS-CoV-2 Neutralizing Antibody Structures Inform Therapeutic Strategies. Nature. 2020;588(7839):682-687. PubMed PMID: 33045718.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. AU - Barnes,Christopher O, AU - Jette,Claudia A, AU - Abernathy,Morgan E, AU - Dam,Kim-Marie A, AU - Esswein,Shannon R, AU - Gristick,Harry B, AU - Malyutin,Andrey G, AU - Sharaf,Naima G, AU - Huey-Tubman,Kathryn E, AU - Lee,Yu E, AU - Robbiani,Davide F, AU - Nussenzweig,Michel C, AU - West,Anthony P,Jr AU - Bjorkman,Pamela J, Y1 - 2020/10/12/ PY - 2020/8/30/received PY - 2020/10/6/accepted PY - 2020/10/13/pubmed PY - 2021/1/7/medline PY - 2020/10/12/entrez SP - 682 EP - 687 JF - Nature JO - Nature VL - 588 IS - 7839 N2 - 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 protein1-5 show promise therapeutically and are being evaluated clinically6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 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 RBDs9. 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/33045718/SARS_CoV_2_neutralizing_antibody_structures_inform_therapeutic_strategies_ DB - PRIME DP - Unbound Medicine ER -