Therapeutic antibodies, targeting the SARS-CoV-2 spike N-terminal domain, protect lethally infected K18-hACE2 mice

Tal Noy-Porat, Adva Mechaly, Yinon Levy, Efi Makdasi, Ron Alcalay, David Gur, Moshe Aftalion, Reut Falach, Shani Leviatan Ben-Arye, Shirley Lazar, Ayelet Zauberman, Eyal Epstein, Theodor Chitlaru, Shay Weiss, Hagit Achdout, Jonathan D. Edgeworth, Raghavendra Kikkeri, Hai Yu, Xi Chen, Shmuel YitzhakiShmuel C. Shapira, Vered Padler-Karavani, Ohad Mazor*, Ronit Rosenfeld*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Neutralizing antibodies represent a valuable therapeutic approach to countermeasure the current COVID-19 pandemic. Emergence of SARS-CoV-2 variants emphasizes the notion that antibody treatments need to rely on highly neutralizing monoclonal antibodies (mAbs), targeting several distinct epitopes for circumventing therapy escape mutants. Previously, we reported efficient human therapeutic mAbs recognizing epitopes on the spike receptor-binding domain (RBD) of SARS-CoV-2. Here we report the isolation, characterization, and recombinant production of 12 neutralizing human mAbs, targeting three distinct epitopes on the spike N-terminal domain of the virus. Neutralization mechanism of these antibodies involves receptors other than the canonical hACE2 on target cells, relying both on amino acid and N-glycan epitope recognition, suggesting alternative viral cellular portals. Two selected mAbs demonstrated full protection of K18-hACE2 transgenic mice when administered at low doses and late post-exposure, demonstrating the high potential of the mAbs for therapy of SARS-CoV-2 infection.

Original languageEnglish
Article number102479
JournaliScience
Volume24
Issue number5
DOIs
StatePublished - 21 May 2021

Funding

FundersFunder number
Institute of Virology
Charité – Universitätsmedizin Berlin
Israel Institute for Biological Research

    Keywords

    • Immunology
    • Molecular biology
    • Virology

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