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 journalArticlepeer-review

35 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 languageEnglish
Pages (from-to)1503-1514
Number of pages12
JournalNature Immunology
Volume22
Issue number12
DOIs
StatePublished - Dec 2021
Externally publishedYes

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