Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

Jensen, Jaime L.; Sankhala, Rajeshwer S.; Dussupt, Vincent; Bai, Hongjun; Hajduczki, Agnes; Lal, Kerri G.; Chang, William C.; Martinez, Elizabeth J.; Peterson, Caroline E.; Golub, Emily S.; Rees, Phyllis A.; Mendez-Rivera, Letzibeth; Zemil, Michelle; Kavusak, Erin; Mayer, Sandra V.; Wieczorek, Lindsay; Kannan, Shruthi; Doranz, Benjamin J.; Davidson, Edgar; Yang, Eun Sung; Zhang, Yi; Chen, Man; Choe, Misook; Wang, Lingshu; Gromowski, Gregory D.; Koup, Richard A.; Michael, Nelson L.; Polonis, Victoria R.; Rolland, Morgane; Modjarrad, Kayvon; Krebs, Shelly J.; Joyce, M. Gordon

doi:10.1128/jvi.01596-22

Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

Journal Article · Mon Jul 03 00:00:00 EDT 2023 · Journal of Virology

DOI:https://doi.org/10.1128/jvi.01596-22· OSTI ID:2423689

Jensen, Jaime L. ^[1]; Sankhala, Rajeshwer S. ^[1]; Dussupt, Vincent ^[1]; Bai, Hongjun ^[1]; Hajduczki, Agnes ^[1]; Lal, Kerri G. ^[1]; Chang, William C. ^[1]; Martinez, Elizabeth J. ^[1]; Peterson, Caroline E. ^[1]; Golub, Emily S. ^[1]; Rees, Phyllis A. ^[1]; Mendez-Rivera, Letzibeth ^[1]; Zemil, Michelle ^[2]; Kavusak, Erin ^[2]; ^[3]; Wieczorek, Lindsay ^[2]; Kannan, Shruthi ^[4]; Doranz, Benjamin J. ^[4]; Davidson, Edgar ^[4]; Yang, Eun Sung ^[5] more »

Walter Reed Army Institute of Research, Silver Spring, MD (United States); Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Inc., Bethesda, MD (United States)
Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Inc., Bethesda, MD (United States); Walter Reed Army Institute of Research, Silver Spring, MD (United States)
Walter Reed Army Institute of Research, Silver Spring, MD (United States)
Integral Molecular, Philadelphia, PA (United States)
National Institutes of Health (NIH), Bethesda, MD (United States)
Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Inc., Bethesda, MD (United States)

Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, in this study, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOD; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357; W-31109-ENG-38

OSTI ID:: 2423689

Journal Information:: Journal of Virology, Journal Name: Journal of Virology Journal Issue: 7 Vol. 97; ISSN 0022-538X; ISSN 1098-5514

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

References (59)

Current developments in Coot for macromolecular model building of Electron Cryo‐microscopy and Crystallographic Data Casañal, Ana; Lohkamp, Bernhard; Emsley, Paul Protein Science, Vol. 29, Issue 4 https://doi.org/10.1002/pro.3791	journal	March 2020
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding Starr, Tyler N.; Greaney, Allison J.; Hilton, Sarah K. Cell, Vol. 182, Issue 5 https://doi.org/10.1016/j.cell.2020.08.012	journal	September 2020
Emerging Pandemic Diseases: How We Got to COVID-19 Morens, David M.; Fauci, Anthony S. Cell, Vol. 183, Issue 3 https://doi.org/10.1016/j.cell.2020.10.022	journal	October 2020
The antigenic anatomy of SARS-CoV-2 receptor binding domain Dejnirattisai, Wanwisa; Zhou, Daming; Ginn, Helen M. Cell, Vol. 184, Issue 8 https://doi.org/10.1016/j.cell.2021.02.032	journal	April 2021
N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2 McCallum, Matthew; De Marco, Anna; Lempp, Florian A. Cell, Vol. 184, Issue 9 https://doi.org/10.1016/j.cell.2021.03.028	journal	April 2021
Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein Suryadevara, Naveenchandra; Shrihari, Swathi; Gilchuk, Pavlo Cell, Vol. 184, Issue 9 https://doi.org/10.1016/j.cell.2021.03.029	journal	April 2021
In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies Li, Dapeng; Edwards, Robert J.; Manne, Kartik Cell, Vol. 184, Issue 16 https://doi.org/10.1016/j.cell.2021.06.021	journal	August 2021
SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity Joyce, M. Gordon; Chen, Wei-Hung; Sankhala, Rajeshwer S. Cell Reports, Vol. 37, Issue 12 https://doi.org/10.1016/j.celrep.2021.110143	journal	December 2021
Rapid identification of neutralizing antibodies against SARS-CoV-2 variants by mRNA display Tanaka, Shiho; Olson, C. Anders; Barnes, Christopher O. Cell Reports, Vol. 38, Issue 6 https://doi.org/10.1016/j.celrep.2022.110348	journal	February 2022
Potent SARS-CoV-2 neutralizing antibodies directed against spike N-terminal domain target a single supersite Cerutti, Gabriele; Guo, Yicheng; Zhou, Tongqing Cell Host & Microbe, Vol. 29, Issue 5 https://doi.org/10.1016/j.chom.2021.03.005	journal	May 2021
N-terminal domain mutations of the spike protein are structurally implicated in epitope recognition in emerging SARS-CoV-2 strains Klinakis, Apostolos; Cournia, Zoe; Rampias, Theodoros Computational and Structural Biotechnology Journal, Vol. 19 https://doi.org/10.1016/j.csbj.2021.10.004	journal	January 2021
COVID-19 pandemic: lessons learned from more than a century of pandemics and current vaccine development for pandemic control Buchy, Philippe; Buisson, Yves; Cintra, Otavio International Journal of Infectious Diseases, Vol. 112 https://doi.org/10.1016/j.ijid.2021.09.045	journal	November 2021
The ACE2-binding Interface of SARS-CoV-2 Spike Inherently Deflects Immune Recognition Hattori, Takamitsu; Koide, Akiko; Noval, Maria G. Journal of Molecular Biology, Vol. 433, Issue 3 https://doi.org/10.1016/j.jmb.2020.166748	journal	February 2021
Rapid decline in vaccine-boosted neutralizing antibodies against SARS-CoV-2 Omicron variant Lyke, Kirsten E.; Atmar, Robert L.; Islas, Clara Dominguez Cell Reports Medicine, Vol. 3, Issue 7 https://doi.org/10.1016/j.xcrm.2022.100679	journal	July 2022
Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy Lee, Ju Yeon; Lee, Hyun Tae; Shin, Woori Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms13354	journal	October 2016
Molecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25 Scally, Stephen W.; McLeod, Brandon; Bosch, Alexandre Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-01924-3	journal	November 2017
Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants Li, Tingting; Xue, Wenhui; Zheng, Qingbing Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-25997-3	journal	September 2021
Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody Pinto, Dora; Park, Young-Jun; Beltramello, Martina Nature, Vol. 583, Issue 7815 https://doi.org/10.1038/s41586-020-2349-y	journal	May 2020
Human neutralizing antibodies elicited by SARS-CoV-2 infection Ju, Bin; Zhang, Qi; Ge, Jiwan Nature, Vol. 584, Issue 7819 https://doi.org/10.1038/s41586-020-2380-z	journal	May 2020
A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2 Shi, Rui; Shan, Chao; Duan, Xiaomin Nature, Vol. 584, Issue 7819 https://doi.org/10.1038/s41586-020-2381-y	journal	May 2020
Convergent antibody responses to SARS-CoV-2 in convalescent individuals Robbiani, Davide F.; Gaebler, Christian; Muecksch, Frauke Nature, Vol. 584, Issue 7821 https://doi.org/10.1038/s41586-020-2456-9	journal	June 2020
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies Barnes, Christopher O.; Jette, Claudia A.; Abernathy, Morgan E. Nature, Vol. 588, Issue 7839 https://doi.org/10.1038/s41586-020-2852-1	journal	October 2020
Evolution of antibody immunity to SARS-CoV-2 Gaebler, Christian; Wang, Zijun; Lorenzi, Julio C. C. Nature, Vol. 591, Issue 7851 https://doi.org/10.1038/s41586-021-03207-w	journal	January 2021
SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape Starr, Tyler N.; Czudnochowski, Nadine; Liu, Zhuoming Nature https://doi.org/10.1038/s41586-021-03807-6	journal	July 2021
Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift Cameroni, Elisabetta; Bowen, John E.; Rosen, Laura E. Nature, Vol. 602, Issue 7898 https://doi.org/10.1038/s41586-021-04386-2	journal	December 2021
Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations Dussupt, Vincent; Sankhala, Rajeshwer S.; Mendez-Rivera, Letzibeth Nature Immunology, Vol. 22, Issue 12 https://doi.org/10.1038/s41590-021-01068-z	journal	October 2021
SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects Wrobel, Antoni G.; Benton, Donald J.; Xu, Pengqi Nature Structural & Molecular Biology, Vol. 27, Issue 8 https://doi.org/10.1038/s41594-020-0468-7	journal	July 2020
The neutralizing breadth of antibodies targeting diverse conserved epitopes between SARS-CoV and SARS-CoV-2 Xiong, Hualong; Sun, Hui; Wang, Siling Proceedings of the National Academy of Sciences, Vol. 119, Issue 34 https://doi.org/10.1073/pnas.2204256119	journal	August 2022
Structural Basis of Neutralization by a Human Anti-severe Acute Respiratory Syndrome Spike Protein Antibody, 80R Hwang, William C.; Lin, Yaqiong; Santelli, Eugenio Journal of Biological Chemistry, Vol. 281, Issue 45 https://doi.org/10.1074/jbc.M603275200	journal	September 2006
Adenovirus Vector-Based Vaccines for Human Immunodeficiency Virus Type 1 Barouch, Dan H.; Nabel, Gary J. Human Gene Therapy, Vol. 16, Issue 2 https://doi.org/10.1089/hum.2005.16.149	journal	February 2005
CoV-AbDab: the coronavirus antibody database Raybould, Matthew I. J.; Kovaltsuk, Aleksandr; Marks, Claire Bioinformatics, Vol. 37, Issue 5 https://doi.org/10.1093/bioinformatics/btaa739	journal	August 2020
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Generalized X-ray and neutron crystallographic analysis: more accurate and complete structures for biological macromolecules Adams, Paul D.; Mustyakimov, Marat; Afonine, Pavel V. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 6 https://doi.org/10.1107/S0907444909011548	journal	May 2009
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
A high-throughput shotgun mutagenesis approach to mapping B-cell antibody epitopes Davidson, Edgar; Doranz, Benjamin J. Immunology, Vol. 143, Issue 1 https://doi.org/10.1111/imm.12323	journal	July 2014
Highly Conserved Protective Epitopes on Influenza B Viruses Dreyfus, C.; Laursen, N. S.; Kwaks, T. Science, Vol. 337, Issue 6100 https://doi.org/10.1126/science.1222908	journal	August 2012
In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector Naldini, L.; Blomer, U.; Gallay, P. Science, Vol. 272, Issue 5259 https://doi.org/10.1126/science.272.5259.263	journal	April 1996
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S. Science, Vol. 367, Issue 6483 https://doi.org/10.1126/science.abb2507	journal	February 2020
Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability Brouwer, Philip J. M.; Caniels, Tom G.; van der Straten, Karlijn Science, Vol. 369, Issue 6504 https://doi.org/10.1126/science.abc5902	journal	June 2020
Broad neutralization of SARS-related viruses by human monoclonal antibodies Wec, Anna Z.; Wrapp, Daniel; Herbert, Andrew S. Science, Vol. 369, Issue 6504 https://doi.org/10.1126/science.abc7424	journal	June 2020
Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model Rogers, Thomas F.; Zhao, Fangzhu; Huang, Deli Science, Vol. 369, Issue 6506 https://doi.org/10.1126/science.abc7520	journal	June 2020
Structure-based design of prefusion-stabilized SARS-CoV-2 spikes Hsieh, Ching-Lin; Goldsmith, Jory A.; Schaub, Jeffrey M. Science, Vol. 369, Issue 6510 https://doi.org/10.1126/science.abd0826	journal	July 2020
Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants Wang, Lingshu; Zhou, Tongqing; Zhang, Yi Science, Vol. 373, Issue 6556 https://doi.org/10.1126/science.abh1766	journal	July 2021
Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study Hastie, Kathryn M.; Li, Haoyang; Bedinger, Daniel Science, Vol. 374, Issue 6566 https://doi.org/10.1126/science.abh2315	journal	October 2021
SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern McCallum, Matthew; Bassi, Jessica; De Marco, Anna Science https://doi.org/10.1126/science.abi7994	journal	July 2021
Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants McCallum, Matthew; Walls, Alexandra C.; Sprouse, Kaitlin R. Science, Vol. 374, Issue 6575 https://doi.org/10.1126/science.abl8506	journal	December 2021
Immune boosting by B.1.1.529 ( Omicron) depends on previous SARS-CoV-2 exposure Reynolds, Catherine J.; Pade, Corinna; Gibbons, Joseph M. Science, Vol. 377, Issue 6603 https://doi.org/10.1126/science.abq1841	journal	July 2022
A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates Joyce, M. Gordon; King, Hannah A. D.; Elakhal-Naouar, Ines Science Translational Medicine, Vol. 14, Issue 632 https://doi.org/10.1126/scitranslmed.abi5735	journal	February 2022
A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice Martinez, David R.; Schäfer, Alexandra; Gobeil, Sophie Science Translational Medicine, Vol. 14, Issue 629 https://doi.org/10.1126/scitranslmed.abj7125	journal	January 2022
Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape Wang, Lingshu; Shi, Wei; Chappell, James D. Journal of Virology, Vol. 92, Issue 10 https://doi.org/10.1128/JVI.02002-17	journal	March 2018
A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody Wu, Nicholas C.; Yuan, Meng; Bangaru, Sandhya PLOS Pathogens, Vol. 16, Issue 12 https://doi.org/10.1371/journal.ppat.1009089	journal	December 2020
Current status of therapeutic monoclonal antibodies against SARS-CoV-2 Kumar, Sanjeev; Chandele, Anmol; Sharma, Amit PLOS Pathogens, Vol. 17, Issue 9 https://doi.org/10.1371/journal.ppat.1009885	journal	September 2021
Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody Li, Tingting; Cai, Hongmin; Zhao, Yapei EMBO Molecular Medicine, Vol. 13, Issue 12 https://doi.org/10.15252/emmm.202114544	journal	November 2021
Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022 Thompson, Mark G.; Natarajan, Karthik; Irving, Stephanie A. MMWR. Morbidity and Mortality Weekly Report, Vol. 71, Issue 4 https://doi.org/10.15585/mmwr.mm7104e3	journal	January 2022
Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022 Ferdinands, Jill M.; Rao, Suchitra; Dixon, Brian E. MMWR. Morbidity and Mortality Weekly Report, Vol. 71, Issue 7 https://doi.org/10.15585/mmwr.mm7107e2	journal	February 2022
Cross-Reactive SARS-CoV-2 Neutralizing Antibodies From Deep Mining of Early Patient Responses Bullen, Georgia; Galson, Jacob D.; Hall, Gareth Frontiers in Immunology, Vol. 12 https://doi.org/10.3389/fimmu.2021.678570	journal	June 2021
Collaboration gets the most out of software Morin, Andrew; Eisenbraun, Ben; Key, Jason eLife, Vol. 2 https://doi.org/10.7554/eLife.01456	journal	September 2013

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60 APPLIED LIFE SCIENCES
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SARS-CoV-2
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neutralizing antibodies
receptor binding domain
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Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

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