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

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

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 (NTD) 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.