Recognition of the SARS-CoV-2 receptor binding domain by neutralizing antibodies


 Immediately from the outset of the COVID-19 pandemic, researchers from diverse biomedical and biological disciplines have united to study the novel pandemic virus, SARS-CoV-2. The antibody response to SARS-CoV-2 has been a major focus of COVID-19 research due to its clinical relevance and importance in vaccine and therapeutic development. Isolation and characterization of antibodies to SARS-CoV-2 have been accumulating at an unprecedented pace. Most of the SARS-CoV-2 neutralizing antibodies to date target the S protein receptor binding domain (RBD), which engages the host receptor ACE2 for viral entry. Here we review the binding sites and molecular features of monoclonal antibodies that target the SARS-CoV-2 RBD, including a few that also cross-neutralize SARS-CoV.


6 respect to their angle of approach to the RBD and their relative disposition with respect 120 to the ridge on the RBS. These antibodies vary considerably in their epitope size ranging 121 from 626 Å 2 to 1248 Å 2 122 in buried surface area (BSA) ( Table 1) common IGHV gene, different light-chain genes have been paired with IGHV3-53/3-66   199 and include IGKV1-9, IGKV3-20, IGKV1-39, and IGLV2-8 (Fig. 3C)   245 the proteoglycan site that involves an N-glycan at N343 has been found to be 246 recognized by a different cross-neutralizing antibody S309 [33]. It is nevertheless too 247 11 early to evaluate the relative frequency of targeting these two different cross-neutralizing 248 sites given the small number of antibodies characterized to these epitopes so far.

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The CR3022 site has now been found to be a target of cross-neutralizing antibodies

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Another cross-neutralizing antibody H014 is a humanized antibody that originally 266 isolated from a mouse immunized with recombinant SARS-CoV-2 RBD using phage 267 display [45]. With strong binding affinity to both SARS-CoV-2 and SARS-CoV RBDs and

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Structural analysis revealed that EY6A also binds to this cryptic epitope, but has no 278 steric hindrance to ACE2 binding except for a potential clash with glycans at N322 and 279 N546 of ACE2, as suggested [14]. Although this potential clash with EY6A could not 280 prevent receptor binding to the RBD, EY6A substantially increased the dissociation rate 281 between ACE2 and RBD, which may in part explain its moderate neutralization activity 282 (Table 2).

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Although the CR3022 cryptic site is not accessible when RBD is in the "down" state, a   regardless of the "up" or "down" state of the RBD (Fig. 6C). S309 is a cross-neutralizing 311 antibody that was isolated from a preserved blood sample of a patient who survived 312 SARS-CoV infection 17 years ago, and is the first antibody that was identified to bind to 313 this site [33]. Structural analysis showed that most of S309 epitope residues are 314 nevertheless conserved within sarbecoviruses. The N343 glycan is unusual for SARS-

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.