Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Rajeshwer S. Sankhala; Vincent Dussupt; Wei Hung Chen; Hongjun Bai; Elizabeth J. Martinez; Jaime L. Jensen; Phyllis A. Rees; Agnes Hajduczki; William C. Chang; Misook Choe; Lianying Yan; Spencer L. Sterling; Isabella Swafford; Caitlin Kuklis; Sandrine Soman; Jocelyn King; Courtney Corbitt; Michelle Zemil; Caroline E. Peterson; Letzibeth Mendez-Rivera; Samantha M. Townsley; Gina C. Donofrio; Kerri G. Lal; Ursula Tran; Ethan C. Green; Clayton Smith; Natalia de Val; Eric D. Laing; Christopher C. Broder; Jeffrey R. Currier; Gregory D. Gromowski; Lindsay Wieczorek; Morgane Rolland; Dominic Paquin-Proulx; Dewald van Dyk; Zachary Britton; Saravanan Rajan; Yueh Ming Loo; Patrick M. McTamney; Mark T. Esser; Victoria R. Polonis; Nelson L. Michael; Shelly J. Krebs; Kayvon Modjarrad; M. Gordon Joyce

doi:10.1016/j.str.2023.11.015

Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Rajeshwer S. Sankhala, Vincent Dussupt, Wei Hung Chen, Hongjun Bai, Elizabeth J. Martinez, Jaime L. Jensen, Phyllis A. Rees, Agnes Hajduczki, William C. Chang, Misook Choe, Lianying Yan, Spencer L. Sterling, Isabella Swafford, Caitlin Kuklis, Sandrine Soman, Jocelyn King, Courtney Corbitt, Michelle Zemil, Caroline E. Peterson, Letzibeth Mendez-RiveraSamantha M. Townsley, Gina C. Donofrio, Kerri G. Lal, Ursula Tran, Ethan C. Green, Clayton Smith, Natalia de Val, Eric D. Laing, Christopher C. Broder, Jeffrey R. Currier, Gregory D. Gromowski, Lindsay Wieczorek, Morgane Rolland, Dominic Paquin-Proulx, Dewald van Dyk, Zachary Britton, Saravanan Rajan, Yueh Ming Loo, Patrick M. McTamney, Mark T. Esser, Victoria R. Polonis, Nelson L. Michael, Shelly J. Krebs^*, Kayvon Modjarrad, M. Gordon Joyce^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

Original language	English
Pages (from-to)	131-147.e7
Journal	Structure
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.str.2023.11.015
State	Published - 1 Feb 2024
Externally published	Yes

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Sankhala, R. S., Dussupt, V., Chen, W. H., Bai, H., Martinez, E. J., Jensen, J. L., Rees, P. A., Hajduczki, A., Chang, W. C., Choe, M., Yan, L., Sterling, S. L., Swafford, I., Kuklis, C., Soman, S., King, J., Corbitt, C., Zemil, M., Peterson, C. E., ... Joyce, M. G. (2024). Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain. Structure, 32(2), 131-147.e7. https://doi.org/10.1016/j.str.2023.11.015

@article{eadcb679594640f298c1da6d15d93fe6,

title = "Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain",

abstract = "Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 {\AA} and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.",

author = "Sankhala, {Rajeshwer S.} and Vincent Dussupt and Chen, {Wei Hung} and Hongjun Bai and Martinez, {Elizabeth J.} and Jensen, {Jaime L.} and Rees, {Phyllis A.} and Agnes Hajduczki and Chang, {William C.} and Misook Choe and Lianying Yan and Sterling, {Spencer L.} and Isabella Swafford and Caitlin Kuklis and Sandrine Soman and Jocelyn King and Courtney Corbitt and Michelle Zemil and Peterson, {Caroline E.} and Letzibeth Mendez-Rivera and Townsley, {Samantha M.} and Donofrio, {Gina C.} and Lal, {Kerri G.} and Ursula Tran and Green, {Ethan C.} and Clayton Smith and {de Val}, Natalia and Laing, {Eric D.} and Broder, {Christopher C.} and Currier, {Jeffrey R.} and Gromowski, {Gregory D.} and Lindsay Wieczorek and Morgane Rolland and Dominic Paquin-Proulx and {van Dyk}, Dewald and Zachary Britton and Saravanan Rajan and Loo, {Yueh Ming} and McTamney, {Patrick M.} and Esser, {Mark T.} and Polonis, {Victoria R.} and Michael, {Nelson L.} and Krebs, {Shelly J.} and Kayvon Modjarrad and Joyce, {M. Gordon}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2024",

month = feb,

day = "1",

doi = "10.1016/j.str.2023.11.015",

language = "English",

volume = "32",

pages = "131--147.e7",

journal = "Structure",

issn = "0969-2126",

number = "2",

}

Sankhala, RS, Dussupt, V, Chen, WH, Bai, H, Martinez, EJ, Jensen, JL, Rees, PA, Hajduczki, A, Chang, WC, Choe, M, Yan, L, Sterling, SL, Swafford, I, Kuklis, C, Soman, S, King, J, Corbitt, C, Zemil, M, Peterson, CE, Mendez-Rivera, L, Townsley, SM, Donofrio, GC, Lal, KG, Tran, U, Green, EC, Smith, C, de Val, N, Laing, ED , Broder, CC, Currier, JR, Gromowski, GD, Wieczorek, L, Rolland, M, Paquin-Proulx, D, van Dyk, D, Britton, Z, Rajan, S, Loo, YM, McTamney, PM, Esser, MT, Polonis, VR, Michael, NL, Krebs, SJ, Modjarrad, K & Joyce, MG 2024, 'Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain', Structure, vol. 32, no. 2, pp. 131-147.e7. https://doi.org/10.1016/j.str.2023.11.015

TY - JOUR

T1 - Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

AU - Sankhala, Rajeshwer S.

AU - Dussupt, Vincent

AU - Chen, Wei Hung

AU - Bai, Hongjun

AU - Martinez, Elizabeth J.

AU - Jensen, Jaime L.

AU - Rees, Phyllis A.

AU - Hajduczki, Agnes

AU - Chang, William C.

AU - Choe, Misook

AU - Yan, Lianying

AU - Sterling, Spencer L.

AU - Swafford, Isabella

AU - Kuklis, Caitlin

AU - Soman, Sandrine

AU - King, Jocelyn

AU - Corbitt, Courtney

AU - Zemil, Michelle

AU - Peterson, Caroline E.

AU - Mendez-Rivera, Letzibeth

AU - Townsley, Samantha M.

AU - Donofrio, Gina C.

AU - Lal, Kerri G.

AU - Tran, Ursula

AU - Green, Ethan C.

AU - Smith, Clayton

AU - de Val, Natalia

AU - Laing, Eric D.

AU - Broder, Christopher C.

AU - Currier, Jeffrey R.

AU - Gromowski, Gregory D.

AU - Wieczorek, Lindsay

AU - Rolland, Morgane

AU - Paquin-Proulx, Dominic

AU - van Dyk, Dewald

AU - Britton, Zachary

AU - Rajan, Saravanan

AU - Loo, Yueh Ming

AU - McTamney, Patrick M.

AU - Esser, Mark T.

AU - Polonis, Victoria R.

AU - Michael, Nelson L.

AU - Krebs, Shelly J.

AU - Modjarrad, Kayvon

AU - Joyce, M. Gordon

PY - 2024/2/1

Y1 - 2024/2/1

N2 - Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

AB - Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

UR - http://www.scopus.com/inward/record.url?scp=85182905679&partnerID=8YFLogxK

U2 - 10.1016/j.str.2023.11.015

DO - 10.1016/j.str.2023.11.015

M3 - Article

C2 - 38157856

AN - SCOPUS:85182905679

SN - 0969-2126

VL - 32

SP - 131-147.e7

JO - Structure

JF - Structure

IS - 2

ER -

Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Abstract

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