Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Vincent Dussupt; Rajeshwer S. Sankhala; Letzibeth Mendez-Rivera; Samantha M. Townsley; Fabian Schmidt; Lindsay Wieczorek; Kerri G. Lal; Gina C. Donofrio; Ursula Tran; Nathaniel D. Jackson; Weam I. Zaky; Michelle Zemil; Sarah R. Tritsch; Wei Hung Chen; Elizabeth J. Martinez; Aslaa Ahmed; Misook Choe; William C. Chang; Agnes Hajduczki; Ningbo Jian; Caroline E. Peterson; Phyllis A. Rees; Magdalena Rutkowska; Bonnie M. Slike; Christopher N. Selverian; Isabella Swafford; I. Ting Teng; Paul V. Thomas; Tongqing Zhou; Clayton J. Smith; Jeffrey R. Currier; Peter D. Kwong; Morgane Rolland; Edgar Davidson; Benjamin J. Doranz; Christopher N. Mores; Theodora Hatziioannou; William W. Reiley; Paul D. Bieniasz; Dominic Paquin-Proulx; Gregory D. Gromowski; Victoria R. Polonis; Nelson L. Michael; Kayvon Modjarrad; M. Gordon Joyce; Shelly J. Krebs

doi:10.1038/s41590-021-01068-z

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Vincent Dussupt, Rajeshwer S. Sankhala, Letzibeth Mendez-Rivera, Samantha M. Townsley, Fabian Schmidt, Lindsay Wieczorek, Kerri G. Lal, Gina C. Donofrio, Ursula Tran, Nathaniel D. Jackson, Weam I. Zaky, Michelle Zemil, Sarah R. Tritsch, Wei Hung Chen, Elizabeth J. Martinez, Aslaa Ahmed, Misook Choe, William C. Chang, Agnes Hajduczki, Ningbo JianCaroline E. Peterson, Phyllis A. Rees, Magdalena Rutkowska, Bonnie M. Slike, Christopher N. Selverian, Isabella Swafford, I. Ting Teng, Paul V. Thomas, Tongqing Zhou, Clayton J. Smith, Jeffrey R. Currier, Peter D. Kwong, Morgane Rolland, Edgar Davidson, Benjamin J. Doranz, Christopher N. Mores, Theodora Hatziioannou, William W. Reiley, Paul D. Bieniasz, Dominic Paquin-Proulx, Gregory D. Gromowski, Victoria R. Polonis, Nelson L. Michael, Kayvon Modjarrad, M. Gordon Joyce^*, Shelly J. Krebs^*

^*Corresponding author for this work

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

40 Scopus citations

Abstract

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

Original language	English
Pages (from-to)	1503-1514
Number of pages	12
Journal	Nature Immunology
Volume	22
Issue number	12
DOIs	https://doi.org/10.1038/s41590-021-01068-z
State	Published - Dec 2021
Externally published	Yes

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Dussupt, V., Sankhala, R. S., Mendez-Rivera, L., Townsley, S. M., Schmidt, F., Wieczorek, L., Lal, K. G., Donofrio, G. C., Tran, U., Jackson, N. D., Zaky, W. I., Zemil, M., Tritsch, S. R., Chen, W. H., Martinez, E. J., Ahmed, A., Choe, M., Chang, W. C., Hajduczki, A., ... Krebs, S. J. (2021). Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations. Nature Immunology, 22(12), 1503-1514. https://doi.org/10.1038/s41590-021-01068-z

@article{edf7837cbaad49da85865a0357a24441,

title = "Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations",

abstract = "Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.",

author = "Vincent Dussupt and Sankhala, {Rajeshwer S.} and Letzibeth Mendez-Rivera and Townsley, {Samantha M.} and Fabian Schmidt and Lindsay Wieczorek and Lal, {Kerri G.} and Donofrio, {Gina C.} and Ursula Tran and Jackson, {Nathaniel D.} and Zaky, {Weam I.} and Michelle Zemil and Tritsch, {Sarah R.} and Chen, {Wei Hung} and Martinez, {Elizabeth J.} and Aslaa Ahmed and Misook Choe and Chang, {William C.} and Agnes Hajduczki and Ningbo Jian and Peterson, {Caroline E.} and Rees, {Phyllis A.} and Magdalena Rutkowska and Slike, {Bonnie M.} and Selverian, {Christopher N.} and Isabella Swafford and Teng, {I. Ting} and Thomas, {Paul V.} and Tongqing Zhou and Smith, {Clayton J.} and Currier, {Jeffrey R.} and Kwong, {Peter D.} and Morgane Rolland and Edgar Davidson and Doranz, {Benjamin J.} and Mores, {Christopher N.} and Theodora Hatziioannou and Reiley, {William W.} and Bieniasz, {Paul D.} and Dominic Paquin-Proulx and Gromowski, {Gregory D.} and Polonis, {Victoria R.} and Michael, {Nelson L.} and Kayvon Modjarrad and Joyce, {M. Gordon} and Krebs, {Shelly J.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41590-021-01068-z",

language = "English",

volume = "22",

pages = "1503--1514",

journal = "Nature Immunology",

issn = "1529-2908",

number = "12",

}

Dussupt, V, Sankhala, RS, Mendez-Rivera, L, Townsley, SM, Schmidt, F, Wieczorek, L, Lal, KG, Donofrio, GC, Tran, U, Jackson, ND, Zaky, WI, Zemil, M, Tritsch, SR, Chen, WH, Martinez, EJ, Ahmed, A, Choe, M, Chang, WC, Hajduczki, A, Jian, N, Peterson, CE, Rees, PA, Rutkowska, M, Slike, BM, Selverian, CN, Swafford, I, Teng, IT, Thomas, PV, Zhou, T, Smith, CJ, Currier, JR, Kwong, PD, Rolland, M, Davidson, E, Doranz, BJ, Mores, CN, Hatziioannou, T, Reiley, WW, Bieniasz, PD, Paquin-Proulx, D, Gromowski, GD, Polonis, VR, Michael, NL, Modjarrad, K, Joyce, MG & Krebs, SJ 2021, 'Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations', Nature Immunology, vol. 22, no. 12, pp. 1503-1514. https://doi.org/10.1038/s41590-021-01068-z

TY - JOUR

T1 - Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

AU - Dussupt, Vincent

AU - Sankhala, Rajeshwer S.

AU - Mendez-Rivera, Letzibeth

AU - Townsley, Samantha M.

AU - Schmidt, Fabian

AU - Wieczorek, Lindsay

AU - Lal, Kerri G.

AU - Donofrio, Gina C.

AU - Tran, Ursula

AU - Jackson, Nathaniel D.

AU - Zaky, Weam I.

AU - Zemil, Michelle

AU - Tritsch, Sarah R.

AU - Chen, Wei Hung

AU - Martinez, Elizabeth J.

AU - Ahmed, Aslaa

AU - Choe, Misook

AU - Chang, William C.

AU - Hajduczki, Agnes

AU - Jian, Ningbo

AU - Peterson, Caroline E.

AU - Rees, Phyllis A.

AU - Rutkowska, Magdalena

AU - Slike, Bonnie M.

AU - Selverian, Christopher N.

AU - Swafford, Isabella

AU - Teng, I. Ting

AU - Thomas, Paul V.

AU - Zhou, Tongqing

AU - Smith, Clayton J.

AU - Currier, Jeffrey R.

AU - Kwong, Peter D.

AU - Rolland, Morgane

AU - Davidson, Edgar

AU - Doranz, Benjamin J.

AU - Mores, Christopher N.

AU - Hatziioannou, Theodora

AU - Reiley, William W.

AU - Bieniasz, Paul D.

AU - Paquin-Proulx, Dominic

AU - Gromowski, Gregory D.

AU - Polonis, Victoria R.

AU - Michael, Nelson L.

AU - Modjarrad, Kayvon

AU - Joyce, M. Gordon

AU - Krebs, Shelly J.

PY - 2021/12

Y1 - 2021/12

N2 - Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

AB - Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

UR - http://www.scopus.com/inward/record.url?scp=85118323133&partnerID=8YFLogxK

U2 - 10.1038/s41590-021-01068-z

DO - 10.1038/s41590-021-01068-z

M3 - Article

C2 - 34716452

AN - SCOPUS:85118323133

SN - 1529-2908

VL - 22

SP - 1503

EP - 1514

JO - Nature Immunology

JF - Nature Immunology

IS - 12

ER -

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

Abstract

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