Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2

Xiang, Yufei; Nambulli, Sham; Xiao, Zhengyun; Liu, Heng; Sang, Zhe; Duprex, W. Paul; Stroopinsky, Dina; Zhang, Cheng; Shi, Yi

doi:10.1126/science.abe4747

Cited by 344 publications

(471 citation statements)

References 63 publications

(36 reference statements)

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“…Overall, our analysis suggests that a loss in mAb efficacy by the mutations may be alleviated by combination treatments consisting of mAbs that bind alternative, non-overlapping epitopes and act via different neutralization mechanisms to block virus mutational escape (Baum, et al, 2020;Hansen, et al, 2020;Marovich, et al, 2020;Xiang, et al, 2020) . A potential approach to minimize the impact of mAb escape mutations is indeed to develop additional mAbs with epitopes that are highly resistant to viral escape, such as those that include epitopes outside of the RBD and epitopes that are cross-reactive across SARS-CoV and SARS-CoV-2, indicating conserved epitopes with low tolerance for mutation (Pinto, et al, 2020;Wec, et al, 2020).…”

Section: Discussionmentioning

confidence: 91%

“…Here, we examined 11 mAbs (Table 1) reported to have neutralizing effects on wt virus, including two Abs used in the Regeneron combination Ab therapy that has been granted emergency use authorization. Five mAb binding epitopes (Epitope I to V) on the SARS-CoV-2 RBD have been identified, residues E484 and K417 contributing to Epitopes I and II (Xiang, et al, 2020). These two charged residues play an essential role in binding many mAbs by forming interfacial salt bridges with oppositely charged spike residues.…”

Section: Discussionmentioning

confidence: 99%

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Impact of South African 501.V2 Variant on SARS-CoV-2 Spike Infectivity and Neutralization: A Structure-based Computational Assessment

Cheng

Krieger

Kaynak

et al. 2021

Preprint

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MotivationThe SARS-CoV-2 variants emerging from South Africa (501.V2) and the UK (B.1.1.7) necessitate rapid assessment of the effects of the corresponding amino acid substitutions in the spike (S) receptor-binding domain (RBD) of the variants on the interactions with the human ACE2 receptor and monoclonal antibodies (mAbs) reported earlier to neutralize the spike.ResultsMolecular modeling and simulations reveal that N501Y, shared by both variants, increases ACE2 binding affinity, and may impact the collective dynamics of the ACE2-RBD complex, occupying a central hinge site that modulates the overall dynamics of the complex. In contrast, the substitutions K417N and E484K in the South African variant 501.V2 would reduce the ACE2-binding affinity by abolishing two interfacial salt bridges that facilitate RBD binding to ACE2, K417(S)-D30(ACE2) and E484 (S)-K31(ACE2). These two mutations may thus be more than compensating the attractive effect induced by N501Y, overall resulting in an ACE2-binding affinity comparable to that of the wildtype RBD. Further analysis of the impact of these mutations on the interactions with mAbs targeting the spike indicate that the substitutions K417N and E484K may also abolish the salt bridges between the spike and selected mAbs, such as REGN10933, BD23, H11_H4, and C105, thus reducing the binding affinity and effectiveness of these mAbs.Contactbahar@pitt.eduSupplementary informationSupplementary data are available at Bioinformatics online.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Impact of South African 501.V2 Variant on SARS-CoV-2 Spike Infectivity and Neutralization: A Structure-based Computational Assessment

Cheng

Krieger

Kaynak

et al. 2021

Preprint

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“…Furthermore, most of these neutralizing antibodies bind to epitopes in the RBD; several also bind to the NTD (Table 2). Epitope mapping and crystal structure studies of the antibodies revealed various binding sites in the RBD (Brouwer et al, 2020;Hansen et al, 2020;Huo et al, 2020;Ju et al, 2020;Pinto et al, 2020;Robbiani et al, 2020;Rogers et al, 2020;Seydoux et al, 2020;Shi et al, 2020;Wan et al, 2020a;Wu et al, 2020c;Xiang et al, 2020;Zost et al, 2020). Some neutralizing antibodies bind to the ACE2 interaction sites on RBD, therefore sterically hindering viral engagement, while others bind to non-ACE2 interacting areas on RBD.…”

Section: Neutralizing Monoclonal Antibodies To Sars-cov-2mentioning

confidence: 99%

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

Zhang

Zhan

et al. 2020

Sci. China Life Sci.

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The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients’ outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

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“…Although they can use a more diverse VH-gene pool, class 2 antibodies include VH1-2 germline restricted antibodies that form a second commonly elicited multi-donor class of public antibodies 17 . The RBD is also the target of several nanobodies/sybodies that are being considered for clinical development 18,19 .…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

Wibmer

Ayres

Hermanus

et al. 2021

Preprint

403

318

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SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein. Here we show that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.

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Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2

Cited by 344 publications

References 63 publications

Impact of South African 501.V2 Variant on SARS-CoV-2 Spike Infectivity and Neutralization: A Structure-based Computational Assessment

Impact of South African 501.V2 Variant on SARS-CoV-2 Spike Infectivity and Neutralization: A Structure-based Computational Assessment

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

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