A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

Abstract

SUMMARYWith the emergence of SARS-CoV-2 variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here we developed a panel of neutralizing anti-SARS-CoV-2 mAbs that bind the receptor binding domain of the spike protein at distinct epitopes and block virus attachment to cells and its receptor, human angiotensin converting enzyme-2 (hACE2). While several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by historical SARS-CoV-2 strains, others induced escape variantsin vivoand lost activity against emerging strains. We identified one mAb, SARS2-38, that potently neutralizes all SARS-CoV-2 variants of concern tested and protects mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engages a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of inhibitory antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.

Current status of therapeutic monoclonal antibodies against SARS-CoV-2

“…Currently, combination therapies comprising a cocktail of NAbs targeting distinct nonoverlapping epitopes on RBD have demonstrated exceptional potency and promising correlates of protection against SARS-CoV-2 and its variants (Fig 2B) [36,38]. Additionally, newly identified RBD core-binding NAbs SARS2-38 [39] and LY-CoV1404 [40] as monotherapy potently neutralize all SARS-CoV-2 VOCs. Therefore, several options of NAbs targeting conserved RBD epitopes are emerging as promising and attractive therapeutic candidates to tackle the disease burden caused by SARS-CoV-2 or its variants.…”

Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease

“…Plates were harvested 24-30 h later by removing overlays and fixed with 4% PFA in PBS for 20 min at room temperature. Plates were washed and sequentially incubated with an oligoclonal pool of SARS2-2, SARS2-11, SARS2-16, SARS2-31, SARS2-38, SARS2-57, and SARS2-71 anti-spike protein antibodies (VanBlargan et al, 2021) and HRP-conjugated goat anti-mouse IgG in PBS supplemented with 0.1% saponin and 0.1% bovine serum albumin. SARS-CoV-2-infected cell foci were visualized using TrueBlue peroxidase substrate (KPL) and quantitated on an ImmunoSpot microanalyzer (Cellular Technologies).…”

Preclinical Efficacy of IMM-BCP-01, a Highly Active Patient-Derived Anti-SARS-CoV-2 Antibody Cocktail

“…While both residues appear to be moderately available in the "Up" confirmation of Trimer (Figure 5D) the activity associated with IMM20253 points to the availability of its epitope to antibody-based targeting both in vitro and in vivo. There are two reported antibodies (a nanobody derived from llama and a mouse-derived antibody) that appear to have somewhat overlapping epitopes with IMM20253 (36,37). However, both described antibodies bound to broader epitopes, i.e more sensitive to mutational drift; both were generated via animal immunizations and need to be tested for off-target binding to human tissues; and either need to be humanized (mouse-derived) or re-designed (llama-derived) prior to being considered for use as therapeutics.…”