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

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

doi:10.1128/jvi.01596-22

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

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

^*Corresponding author for this work

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

9 Scopus citations

Abstract

Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, 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.

Original language	English
Article number	e0159622
Journal	Journal of Virology
Volume	97
Issue number	7
DOIs	https://doi.org/10.1128/jvi.01596-22
State	Published - Jul 2023
Externally published	Yes

Keywords

COVID-19
SARS-CoV
SARS-CoV-2
X-ray crystallography
betacoronaviruses
convalescent
cryptic
epitope
neutralizing antibodies
receptor binding domain
sarbecoviruses
spike
structural biology
variants of concern

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10.1128/jvi.01596-22

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Jensen, J. L., Sankhala, R. S., Dussupt, V., Bai, H., Hajduczki, A., Lal, K. G., Chang, W. C., Martinez, E. J., Peterson, C. E., Golub, E. S., Rees, P. A., Mendez-Rivera, L., Zemil, M., Kavusak, E., Mayer, S. V., Wieczorek, L., Kannan, S., Doranz, B. J., Davidson, E., ... Joyce, M. G. (2023). Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity. Journal of Virology, 97(7), Article e0159622. https://doi.org/10.1128/jvi.01596-22

@article{a9d75c7b45d344cbb0faa05579b619ba,

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

abstract = "Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, 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.",

keywords = "COVID-19, SARS-CoV, SARS-CoV-2, X-ray crystallography, betacoronaviruses, convalescent, cryptic, epitope, neutralizing antibodies, receptor binding domain, sarbecoviruses, spike, structural biology, variants of concern",

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

year = "2023",

month = jul,

doi = "10.1128/jvi.01596-22",

language = "English",

volume = "97",

journal = "Journal of Virology",

issn = "0022-538X",

number = "7",

}

Jensen, JL, Sankhala, RS, Dussupt, V, Bai, H, Hajduczki, A, Lal, KG, Chang, WC, Martinez, EJ, Peterson, CE, Golub, ES, Rees, PA, Mendez-Rivera, L, Zemil, M, Kavusak, E, Mayer, SV, Wieczorek, L, Kannan, S, Doranz, BJ, Davidson, E, Yang, ES, Zhang, Y, Chen, M, Choe, M, Wang, L, Gromowski, GD, Koup, RA, Michael, NL, Polonis, VR, Rolland, M, Modjarrad, K, Krebs, SJ & Joyce, MG 2023, 'Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity', Journal of Virology, vol. 97, no. 7, e0159622. https://doi.org/10.1128/jvi.01596-22

TY - JOUR

T1 - Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

AU - Jensen, Jaime L.

AU - Sankhala, Rajeshwer S.

AU - Dussupt, Vincent

AU - Bai, Hongjun

AU - Hajduczki, Agnes

AU - Lal, Kerri G.

AU - Chang, William C.

AU - Martinez, Elizabeth J.

AU - Peterson, Caroline E.

AU - Golub, Emily S.

AU - Rees, Phyllis A.

AU - Mendez-Rivera, Letzibeth

AU - Zemil, Michelle

AU - Kavusak, Erin

AU - Mayer, Sandra V.

AU - Wieczorek, Lindsay

AU - Kannan, Shruthi

AU - Doranz, Benjamin J.

AU - Davidson, Edgar

AU - Yang, Eun Sung

AU - Zhang, Yi

AU - Chen, Man

AU - Choe, Misook

AU - Wang, Lingshu

AU - Gromowski, Gregory D.

AU - Koup, Richard A.

AU - Michael, Nelson L.

AU - Polonis, Victoria R.

AU - Rolland, Morgane

AU - Modjarrad, Kayvon

AU - Krebs, Shelly J.

AU - Joyce, M. Gordon

PY - 2023/7

Y1 - 2023/7

N2 - Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, 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.

AB - Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, 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.

KW - COVID-19

KW - SARS-CoV

KW - SARS-CoV-2

KW - X-ray crystallography

KW - betacoronaviruses

KW - convalescent

KW - cryptic

KW - epitope

KW - neutralizing antibodies

KW - receptor binding domain

KW - sarbecoviruses

KW - spike

KW - structural biology

KW - variants of concern

UR - http://www.scopus.com/inward/record.url?scp=85166362433&partnerID=8YFLogxK

U2 - 10.1128/jvi.01596-22

DO - 10.1128/jvi.01596-22

M3 - Article

C2 - 37395646

AN - SCOPUS:85166362433

SN - 0022-538X

VL - 97

JO - Journal of Virology

JF - Journal of Virology

IS - 7

M1 - e0159622

ER -

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

Abstract

Keywords

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