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

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

Shmuel Yitzhaki, Jonathan D Edgeworth, Hagit Achdout, 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, Raghavendra Kikkeri, Hai Yu, Xi Chen, Shmuel C Shapira, Vered Padler-Karavani, Ohad Mazor, Ronit Rosenfeld

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.

2021

virology, molecular biology, Immunology

10.1016/j.isci.2021.102479

iScience