A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Guillaume Beaudoin-Bussières, Yaozong Chen, Irfan Ullah, Jérémie Prévost, William D. Tolbert, Kelly Symmes, Shilei Ding, Mehdi Benlarbi, Shang Yu Gong, Alexandra Tauzin, Romain Gasser, Debashree Chatterjee, Dani Vézina, Guillaume Goyette, Jonathan Richard, Fei Zhou, Leonidas Stamatatos, Andrew T. McGuire, Hughes Charest, Michel RogerEdwin Pozharski, Priti Kumar, Walther Mothes, Pradeep D. Uchil*, Marzena Pazgier*, Andrés Finzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.

Original languageEnglish
Article number110368
JournalCell Reports
Volume38
Issue number7
DOIs
StatePublished - 15 Feb 2022
Externally publishedYes

Keywords

  • ADCC
  • COVID-19
  • Fc-effector functions
  • K18-hACE2 mice
  • SARS-CoV-2
  • coronavirus
  • non-neutralizing antibodies
  • spike
  • synergy

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