A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

Abstract

Neutralizing antibodies could be antivirals against COVID-19 pandemics. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. B38 and H4 block the binding between virus S-protein RBD and cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD, making them a potential virus-targeting MAb-pair to avoid immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibodybased therapeutics and provide a structural basis for rational vaccine design.

Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies

“…The C105 epitope overlaps with the COV21 epitope defined by nsEMPEM, which also rests against the receptor-binding ridge in the RBD, although the Fab(s) in the COV21 reconstruction are predicted to adopt a different angle of approach ( Figure 5D). Interestingly, the C105-RBD interaction closely resembles the RBD interaction of another COVID-19 donorderived neutralizing mAb, B38 ( Figure 5E), as reported in a recent Fab-RBD crystal structure (Wu et al, 2020c). The heavy chains of both B38 and C105 are derived from the VH3-53 gene segment, whereas the light chain gene segments differ: KV1-9 for B38 (Wu et al, 2020c) and LV2-8 for C105 .…”

“…Interestingly, the C105-RBD interaction closely resembles the RBD interaction of another COVID-19 donorderived neutralizing mAb, B38 ( Figure 5E), as reported in a recent Fab-RBD crystal structure (Wu et al, 2020c). The heavy chains of both B38 and C105 are derived from the VH3-53 gene segment, whereas the light chain gene segments differ: KV1-9 for B38 (Wu et al, 2020c) and LV2-8 for C105 . Accordingly, the CDRH1 and CDRH2 loops of both neutralizing antibodies share similar conformations and contribute more to the antibody-RBD interface than their CDRH3 loops ( Figure 5B,E).…”

“…The common epitope of C105 and B38 overlaps with the binding site for ACE2 ( Figure 5F), rationalizing their potent neutralizing activities Wu et al, 2020c). Given that COV21 was one of the more potent neutralizing plasmas of the 149 that were collected , the overlap in the C105/B38 neutralizing epitope with the nsEMPEMdefined predominant COV21 epitope suggests that recognition of the COV21 epitope by S230like antibodies would also be neutralizing.…”

“…were over-represented . Other studies have also reported anti-SARS-CoV-2 mAbs derived from these genes (Brouwer et al, 2020;Cao et al, 2020;Chi et al, 2020;Ju et al, 2020;Rogers et al, 2020;Seydoux et al, 2020;Wu et al, 2020c;Zost et al, 2020).…”

Tiger team: a panel of human neutralizing mAbs targeting SARS-CoV-2 spike at multiple epitopes

“…For designing optimal therapeutic strategies, there is an urgent need for the identification of neutralizing monoclonal antibodies that specifically target SARS-CoV-2 (such antibodies may be identified either in humans in the course of illness/recovery, or in immunized animals). Recently, first two mAbs, elicited against the SARS-CoV-2, were reported 16 . Furthermore, efficient post-exposure therapy in humans, may require integration of several noncompeting mAbs, ideally neutralizing the virus infectivity by different mechanisms.…”