Journal: J Infect / Year: 2023 Title: Broadly potent anti-SARS-CoV-2 antibody shares 93% of epitope with ACE2 and provides full protection in monkeys. Authors: Craig Fenwick / Priscilla Turelli / Yoan Duhoo / Kelvin Lau / Cécile Herate / Romain Marlin / Myriam Lamrayah / Jérémy Campos / Line Esteves-Leuenberger / Alex Farina / Charlène Raclot / ...Authors: Craig Fenwick / Priscilla Turelli / Yoan Duhoo / Kelvin Lau / Cécile Herate / Romain Marlin / Myriam Lamrayah / Jérémy Campos / Line Esteves-Leuenberger / Alex Farina / Charlène Raclot / Vanessa Genet / Flurin Fiscalini / Julien Cesborn / Laurent Perez / Nathalie Dereuddre-Bosquet / Vanessa Contreras / Kyllian Lheureux / Francis Relouzat / Rana Abdelnabi / Pieter Leyssen / Yves Lévy / Florence Pojer / Roger Le Grand / Didier Trono / Giuseppe Pantaleo / Abstract: OBJECTIVES: Due to the rapid evolution of SARS-CoV-2 to variants with reduced sensitivity to vaccine-induced humoral immunity and the near complete loss of protective efficacy of licensed therapeutic ...OBJECTIVES: Due to the rapid evolution of SARS-CoV-2 to variants with reduced sensitivity to vaccine-induced humoral immunity and the near complete loss of protective efficacy of licensed therapeutic monoclonal antibodies, we isolated a potent, broad-spectrum neutralizing antibody that could potentially provide prophylactic protection to immunocompromised patient populations. METHODS: Spike-specific B-cell clones isolated from a vaccinated post-infected donor were profiled for those producing potent neutralizing antibodies against a panel of SARS-CoV-2 variants. The P4J15 ...METHODS: Spike-specific B-cell clones isolated from a vaccinated post-infected donor were profiled for those producing potent neutralizing antibodies against a panel of SARS-CoV-2 variants. The P4J15 antibody was further characterized to define the structural binding epitope, viral resistance, and in vivo efficacy. RESULTS: The P4J15 mAb shows <20 ng/ml neutralizing activity against all variants including the latest XBB.2.3 and EG.5.1 sub-lineages. Structural studies of P4J15 in complex with Omicron XBB.1 Spike show that the P4J15 epitope shares ∼93% of its buried surface area with the ACE2 contact region, consistent with an ACE2 mimetic antibody. In vitro selection of SARS-CoV-2 mutants escaping P4J15 neutralization showed reduced infectivity, poor ACE2 binding, and mutations are rare in public sequence databases. Using a SARS-CoV-2 XBB.1.5 monkey challenge model, P4J15-LS confers complete prophylactic protection with an exceptionally long in vivo half-life of 43 days. CONCLUSIONS: The P4J15 mAb has potential as a broad-spectrum anti-SARS-CoV-2 drug for prophylactic protection of at-risk patient populations.
Supramolecule #1: Spike XBB.1 RBD up - P4J15 Fab (Global)
Supramolecule
Name: Spike XBB.1 RBD up - P4J15 Fab (Global) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 Details: Full XBB.1 spike and P4J15-FAB complex. One RBD is up position and 1 FAB is bound to it.
Source (natural)
Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weight
Theoretical: 490 kDa/nm
-
Experimental details
-
Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
-
Sample preparation
Concentration
2 mg/mL
Buffer
pH: 7.4 Component:
Concentration
Formula
Name
0.137 M
NaCLSodium chloride
Sodium Chloride
0.0027 M
KCl
Potassium Chloride
0.01 M
Na2HPO4
Sodium Phosphate Dibasic
0.0018 M
KH2PO4
Potassium Phophate Monobasic
Vitrification
Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
FEI TITAN KRIOS
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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