Potently neutralizing and protective human antibodies against SARS-CoV-2

Zost, Seth J.; Gilchuk, Pavlo; Case, James Brett; Binshtein, Elad; Chen, Rita E.; Nkolola, Joseph P.; Schäfer, Alexandra; Reidy, Joseph X.; Trivette, Andrew; Nargi, Rachel S.; Sutton, Rachel E.; Suryadevara, Naveen Chandra; Martinez, David R.; Williamson, Lauren E.; Chen, Elaine C.; Jones, Taylor; Day, Samuel B.; Myers, Luke; Hassan, Ahmed O.; Kafai, Natasha M.; Winkler, Emma S.; Fox, Julie M.; Shrihari, Swathi; Mueller, Benjamin K.; Meiler, Jens; Chandrashekar, Abishek; Mercado, Noe B.; Steinhardt, James J.; Ren, Kuishu; Loo, Yueh–Ming; Kallewaard, Nicole L.; McCune, Broc T.; Keeler, Shamus P.; Holtzman, Michael J.; Barouch, Dan H.; Gralinski, Lisa E.; Baric, Ralph S.; Thackray, Larissa B.; Diamond, Michael S.; Carnahan, Robert H.; Crowe, James E.

doi:10.1038/s41586-020-2548-6

Cited by 998 publications

(1,138 citation statements)

References 59 publications

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“…Compared with conventional methods for screening neutralizing Abs 10,13,14,17,21 , a few strategically optimized details of our screening system were described as following ( Figure S1. The optimization of the screening platform).…”

Section: Resultsmentioning

confidence: 99%

“…Neutralizing antibodies were considered as an ideal medicine for prophylaxis and treatment of infectious diseases 33 . At present, several potent neutralizing Abs to SARS-CoV-2 have been promptly developed and being tested in clinical trials (clinicaltrials.gov NCT04497987, NCT04426695 and NCT04425629) for treating COVID-19 patients [12][13][14][15]17,[19][20][21]34,35 . These reports showed that even though neutralizing antibodies against SASR-CoV-2 could be obtained from convalescent patients, the success rate to discover potent neutralizing antibodies with therapeutic value remains unideal.…”

Section: Discussionmentioning

confidence: 99%

“…Its viral spike(S) containing the receptorbinding domain (RBD) is responsible for binding to the receptor angiotensin-converting enzyme-2(ACE2) receptor on the host cells 8,9 . To date, several teams have promptly developed some potent neutralizing mAbs to SARS-CoV-2 [10][11][12][13][14][15][16][17][18][19][20][21][22] . In these studies, different methodologies were employed for screening of neutralizing Abs.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies utilized SARS-CoV-2 S -or RBD-labeled memory B cells from convalescent patients with SASR-CoV-2 infection and directly amplified Ab genes by RT-PCR and nested PCR at a single-cell level 10,18 . In other studies, plasma cells were activated and expanded with stimulators and cytokines in vitro for selecting neutralizing Abs 14,19 . Humanized mice were also used to generate full human monoclonal antibodies against S protein 11,22 .…”

Section: Introductionmentioning

confidence: 99%

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A rapid and efficient screening system for neutralizing antibodies and its application for the discovery of potent neutralizing antibodies to SARS-CoV-2 S-RBD

Han

Wang

et al. 2020

Preprint

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Neutralizing antibodies (Abs) have been considered as promising therapeutics for the prevention and treatment of pathogens. After the outbreak of COVID-19, potent neutralizing Abs to SARS-CoV-2 were promptly developed, and a few of those neutralizing Abs are being tested in clinical studies. However, there were few methodologies detailly reported on how to rapidly and efficiently generate neutralizing Abs of interest. Here, we present a strategically optimized method for precisive screening of neutralizing monoclonal antibodies (mAbs), which enabled us to identify SARS-CoV-2 receptor-binding domain (RBD) specific Abs within 4 days, followed by another 2 days for neutralization activity evaluation. By applying the screening system, we obtained 198 Abs against the RBD of SARS-CoV-2. Excitingly, we found that approximately 50% (96/198) of them were candidate neutralizing Abs in a preliminary screening of SARS-CoV-2 pseudovirus and 20 of these 96 neutralizing Abs were confirmed with high potency. Furthermore, 2 mAbs with the highest neutralizing potency were identified to block authentic SARS-CoV-2 with the half-maximal inhibitory concentration (IC50) at concentrations of 9.88 ng/ml and 11.13 ng/ml. In this report, we demonstrated that the optimized neutralizing Abs screening system is useful for the rapid and efficient discovery of potent neutralizing Abs against SARS-CoV-2. Our study provides a methodology for the generation of preventive and therapeutic antibody drugs for emerging infectious diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A rapid and efficient screening system for neutralizing antibodies and its application for the discovery of potent neutralizing antibodies to SARS-CoV-2 S-RBD

Han

Wang

et al. 2020

Preprint

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“…Most recent strategies to prevent SARS-CoV-2 entry into the host cell aim at blocking the ACE2-RBD interaction. High-affinity monoclonal antibodies, many identified from convalescent patients, are leading the way as potential therapeutics (22)(23)(24)(25)(26)(27)(28)(29). While highly effective in vitro, these agents are expensive to produce by mammalian cell expression and need to be intravenously administered by healthcare professionals (30).…”

Section: Discussionmentioning

confidence: 99%

An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation

Schoof

Faust

Saunders

et al. 2020

Preprint

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Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

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