Biparatopic antibody BA7208/7125 effectively neutralizes SARS-CoV-2 variants including Omicron BA.1-BA.5

Abstract

SARS-CoV-2 Omicron subvariants have demonstrated extensive evasion from monoclonal antibodies (mAbs) developed for clinical use, which raises an urgent need to develop new broad-spectrum mAbs. Here, we report the isolation and analysis of two anti-RBD neutralizing antibodies BA7208 and BA7125 from mice engineered to produce human antibodies. While BA7125 showed broadly neutralizing activity against all variants except the Omicron sublineages, BA7208 was potently neutralizing against all tested SARS-CoV-2 variants (including Omicron BA.1–BA.5) except Mu. By combining BA7208 and BA7125 through the knobs-into-holes technology, we generated a biparatopic antibody BA7208/7125 that was able to neutralize all tested circulating SARS-CoV-2 variants. Cryo-electron microscopy structure of these broad-spectrum antibodies in complex with trimeric Delta and Omicron spike indicated that the contact residues are highly conserved and had minimal interactions with mutational residues in RBD of current variants. In addition, we showed that administration of BA7208/7125 via the intraperitoneal, intranasal, or aerosol inhalation route showed potent therapeutic efficacy against Omicron BA.1 and BA.2 in hACE2-transgenic and wild-type mice and, separately, effective prophylaxis. BA7208/7125 thus has the potential to be an effective candidate as an intervention against COVID-19.

Identification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants

“…Here, we identified a conserved neutralizing epitope present on the RBD region targeted by a highly potent neutralizing mAb BA7535. In vitro, neutralizing potency of BA7535 used alone or in combination with previously reported BA7208 30 against over 30 previous and recently emerged SARS-CoV-2 variants performed well. Cryo-electron microscopy analysis elucidates the broad-spectrum mechanism of BA7535 and reveals the conserved antigenic epitope in SARS-CoV-2 RBD.…”

Electrical Detection Assay Based on Programmable Nucleic Acid Probe for Efficient Single-Nucleotide Polymorphism Identification

“…To investigate the detection ability of PNprobe-functionalized FET biosensors for different RNA mutations in SARS-CoV-2 variants, seven representative RNA mutations, including SNPs, such as K417N, K417T, and D614G mutations, as well as mutations with nucleotide deletion, such as LPPA24-27S, IHV68-70I, GVYY142-145D, and EFR156-158G were considered (Figures a and S12). ,− Figures b,c and S11 display the current responses of the PNprobe-functionalized FET biosensors toward D614G mutation and IHV68-70I mutation, respectively. Obviously, the current responses increase gradually with the concentration of mutated RNA.…”

Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

“…The transgenic hACE2 mouse model has been used previously in research to study SARS-CoV-2 infection and evaluate potential vaccines and therapeutic agents ( 32 , 45 ). Intranasal delivery of IgM (3.5 mg/kg) ( 38 ) and IgG (3 mg/kg) ( 62 ) antibodies after infection with SARS-CoV-2 (Beta or Omicron BA.2) was previously shown to reduce the viral load in the lungs of hACE2 expressing mice. We showed here, for the first time, that a therapeutic or prophylactic intranasal administration of dIgA1, confers significant protection against Omicron BA.5 in the hACE2 transgenic mouse model and considerably reduces the viral load in both the lung and trachea.…”