Broad-Spectrum Heavily Mutated Monoclonal Antibody Isolated from COVID-19 Convalescent Vaccinee with Capacity to Neutralize SARS-CoV2 Variants Ranging from B.1 to BQ.1.1

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/539267v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@f7dab8org.highwire.dtl.DTLVardef@388861org.highwire.dtl.DTLVardef@181a7c7org.highwire.dtl.DTLVardef@12e02cb_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG In briefChoudhary et al. have isolated and characterized Acovimab, a broadly neutralizing RBM-specific human monoclonal antibody with a relatively high level of somatic hypermutation, which potently neutralizes SARS-CoV2 variants ranging from WuhanB.1 to OmicronBQ.1.1, but not the XBB.1.5 variant. Acovimab also possesses strong synergistic neutralizing activity against some Omicron variants when combined with Sotrovimab. Polyclonal plasma antibodies from COVID-19 vaccinees who had recovered from SARS-CoV2 infection were shown to possess low neutralizing titers of antibodies against conserved RBD targets of CoV2 variants including XBB.1.5, which also synergistically neutralize with Sotrovimab against this variant. SummaryThe increasing prevalence of the highly antibody-evasive Omicron sublineages increases the risk of breakthrough infections and leaves high-risk and vulnerable immunocompromised individuals with no effective options for prophylactic or therapeutic antibody treatments. Here, we report a heavily mutated anti-RBD monoclonal antibody, Acovimab, directed against a site in the receptor-binding motif (RBM) region of the CoV2 receptor-binding domain (RBD), that possesses very broad and highly potent neutralizing activity against CoV2 variants, including many Omicron variants. This antibody is derived from the IGHV1-58*01 germline sequence and possesses a relatively high level of mutation (15.5% of the VH aa sequence), which is unusual for anti-RBD antibodies. Neutralizing activity was very potent (IC50s range of 1-9 ng/ml) for early Omicron subvariants that possess an unmutated F486 residue and is retained but less potent (IC50s of 200-650 ng/ml) for more resistant Omicron subvariants which contain the F486V mutation (BA4/5, BA4.6, and BQ1.1), but is lost for the later ultra-resistant variants that contain F486S (XBB) or F486P (XBB.1.5) mutations. Based on these specificities, it is predicted that Acovimab by itself should protect against CoV2 infections other than those caused by the XBB/XBB.1.5 family. Acovimab also shows strong synergy in neutralization when combined with Sotrovimab, which neutralizes all Omicron variants, including XBB.1.5. Plasma from subjects with hybrid immunity (induced by vaccination + infection) possessed low levels of XBB.1.5 RBM-targeting plasma-neutralizing antibodies, and these also neutralized synergistically when combined with Sotrovimab. These results suggest potentially novel immunotherapeutic options for treating most of the CoV2 variants responsible for current infections.