A Highly Potent Antibody Effective Against SARS-CoV-2 Variants of Concern

Fenwick, Craig; Turelli, Priscilla; Perez, Laurent; Pellaton, Céline; Esteves-Leuenberger, Line; Farina, A.; Campos, Jérémy; Lana, Erica; Fiscalini, Flurin; Raclot, Charlène; Pojer, Florence; Lau, Kelvin; Demurtas, Davide; Descatoire, Marc; Joo, Victor; Foglierini, Mathilde; Noto, Alessandra; Abdelnabi, Rana; Foo, Caroline Shi-Yan; Vangeel, Laura; Neyts, Johan; Du, Wenjuan; Bosch, Berend-Jan; Veldman, Geertruida M.; Leyssen, Pieter; Thiel, Volker; Grand, Roger Le; Lévy, Yves; Trono, Didier; Pantaleo, Giuseppe

doi:10.2139/ssrn.3844718

Cited by 10 publications

(27 citation statements)

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“…The region of the Omicron RBD interacting with the Class 1 P5C3 mAb is identical to that previously described for the D614G Spike (Extended Data Fig. 5-7) 21 . P2G3 binds a surface area of around 700 Å 2 as a Class 3 neutralizing mAb 4 , recognizing an epitope on the SARS-CoV-2 RBD distinct from the receptor-binding motif, with the two mAbs covering together a surface of greater than 1200 Å 2 (Fig.…”

Section: Structural Analysis Of P2g3 and P5c3 Fab Bound To Omicron Sp...supporting

confidence: 72%

“…1a) . Cross-competitive Spike RBD binding studies performed with a panel of authorized or clinically advanced anti-SARS-CoV-2 mAbs (REGN10933 and REGN10987 from Regeneron 17 , AZD8895 and AZD1061 from AstraZeneca 18 , ADG-2 from Adagio 19 , S309/Sotrovimab from Vir/GSK 20 ) and mAbs previously described by our group 21 , demonstrate that P2G3 binds an unique albeit overlapping epitope with those recognized by both AZD1061 and S309/Sotrovimab, the latter of which acts by a mechanism distinct from blocking the RBD/ACE2 interaction 20 ( Extended Data Fig. 1b) .…”

Section: Resultsmentioning

confidence: 99%

“…SARS-Cov2 Spike mutations are similar for all the cloned Spike variants and the corresponding viral isolates and are listed in Table 2. Production of 2019-nCoV (D614G), B.1.17, B.1.351 and P.1 variants has already been described 21 . RNA isolated from an anonymized leftover sample of an individual suspected to be SARS-CoV-2 Omicron strain infected was reverse transcribed into cDNA.…”

Section: Methodsmentioning

confidence: 98%

“…All the biosafety level 3 procedures were approved by the Swiss Federal Office of Public Health. The SARS-Cov2 D614G isolate and B.1.1.7 clone have previously been described 21 . Beta (EPI_ISL_981782), Gamma (EPI_ISL_981707), Delta B1.617.2 (EPI_ISL_1811202) and Omicron B.1.1.529.1 (EPI_ISL_7605546) early isolates were a kind gift from I. Eckerle, Geneva University Hospitals.…”

Section: Methodsmentioning

confidence: 99%

“…Freshly isolated cells were stained with the cocktail of fluorescent conjugated antibodies containing anti-CD19 APC-Cy7, anti-CD3-BV510, anti-IgM-FITC, anti-IgD PE-CF594, anti-CD27-APC, anti-CD38-V450 (BD Biosciences) along with the pre-complexed Beta variant Spike tetramer (2 µg in 100µl) coupled to PE-streptavidin (BD Biosciences). All other aspects with cell sorting, immortalization and cloning were as described in Fenwick et al 21 .…”

Section: Anti-spike B Cell Sorting Immortalization and Cloningmentioning

confidence: 99%

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SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties

Fenwick

Turelli

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant exhibits very high levels of transmission, pronounced resistance to authorized therapeutic human monoclonal antibodies and reduced sensitivity to vaccine-induced immunity. Here we describe P2G3, a human monoclonal antibody (mAb) isolated from a previously infected and vaccinated donor, which displays picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other current variants, and is thus markedly more potent than all authorized or clinically advanced anti-SARS-CoV-2 mAbs. Structural characterization of P2G3 Fab in complex with the Omicron Spike demonstrates unique binding properties to both down and up spike trimer conformations at an epitope that partially overlaps with the receptor-binding domain (RBD), yet is distinct from those bound by all other characterized mAbs. This distinct epitope and angle of attack allows P2G3 to overcome all the Omicron mutations abolishing or impairing neutralization by other anti-SARS-COV-2 mAbs, and P2G3 accordingly confers complete prophylactic protection in the SARS-CoV-2 Omicron monkey challenge model. Finally, although we could isolate in vitro SARS-CoV2 mutants escaping neutralization by P2G3 or by P5C3, a previously described broadly active Class 1 mAb, we found these viruses to be lowly infectious and their key mutations extremely rare in the wild, and we could demonstrate that P2G3/P5C3 efficiently cross-neutralized one another's escapees. We conclude that this combination of mAbs has great prospects in both the prophylactic and therapeutic settings to protect from Omicron and other VOCs.

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Section: Structural Analysis Of P2g3 and P5c3 Fab Bound To Omicron Sp...supporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Anti-spike B Cell Sorting Immortalization and Cloningmentioning

confidence: 99%

See 3 more Smart Citations

SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties

Fenwick

Turelli

et al. 2022

Preprint

Self Cite

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Patient-derived monoclonal antibody neutralizes SARS-CoV-2 Omicron variants and confers full protection in monkeys

Fenwick

Turelli

et al. 2022

Nat Microbiol

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The SARS-CoV-2 Omicron variant has very high levels of transmission, is resistant to neutralization by authorized therapeutic human monoclonal antibodies (mAb) and is less sensitive to vaccine-mediated immunity. To provide additional therapies against Omicron, we isolated a mAb named P2G3 from a previously infected vaccinated donor and showed that it has picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other variants tested. We solved the structure of P2G3 Fab in complex with the Omicron spike using cryo-electron microscopy at 3.04 Å resolution to identify the P2G3 epitope as a Class 3 mAb that is different from mAb-binding spike epitopes reported previously. Using a SARS-CoV-2 Omicron monkey challenge model, we show that P2G3 alone, or in combination with P5C3 (a broadly active Class 1 mAb previously identified), confers complete prophylactic or therapeutic protection. Although we could select for SARS-CoV-2 mutants escaping neutralization by P2G3 or by P5C3 in vitro, they had low infectivity and ‘escape’ mutations are extremely rare in public sequence databases. We conclude that this combination of mAbs has potential as an anti-Omicron drug.

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Outpatient treatment options to address the SARS-CoV-2 variant Omicron

McCarthy

2022

Expert Review of Anti-infective Therapy

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A Highly Potent Antibody Effective Against SARS-CoV-2 Variants of Concern

Cited by 10 publications

References 0 publications

SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties

SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties

Patient-derived monoclonal antibody neutralizes SARS-CoV-2 Omicron variants and confers full protection in monkeys

Outpatient treatment options to address the SARS-CoV-2 variant Omicron

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