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 journalArticlepeer-review

6 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 languageEnglish
Article numbere0159622
JournalJournal of Virology
Volume97
Issue number7
DOIs
StatePublished - Jul 2023
Externally publishedYes

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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