Journal: bioRxiv / Year: 2020 Title: Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations. Authors: Shane Miersch / Zhijie Li / Reza Saberianfar / Mart Ustav / James Brett Case / Levi Blazer / Chao Chen / Wei Ye / Alevtina Pavlenco / Maryna Gorelik / Julia Garcia Perez / Suryasree ...Authors: Shane Miersch / Zhijie Li / Reza Saberianfar / Mart Ustav / James Brett Case / Levi Blazer / Chao Chen / Wei Ye / Alevtina Pavlenco / Maryna Gorelik / Julia Garcia Perez / Suryasree Subramania / Serena Singh / Lynda Ploder / Safder Ganaie / Rita E Chen / Daisy W Leung / Pier Paolo Pandolfi / Giuseppe Novelli / Giulia Matusali / Francesca Colavita / Maria R Capobianchi / Suresh Jain / J B Gupta / Gaya K Amarasinghe / Michael S Diamond / James Rini / Sachdev S Sidhu Abstract: Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of ...Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development.
History
Deposition
Nov 3, 2020
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Header (metadata) release
Feb 10, 2021
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Map release
Feb 10, 2021
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Update
Aug 25, 2021
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Current status
Aug 25, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: C-flat-2/2 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 20.0 nm / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.04 kPa / Details: current = 15 mA
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: blotting force = 1 blotting time = 2.5 s.
Details
The Fab and the spike protein was mixed at 3:1 molar ratio. The total concentration of the proteins was 0.4 mg/mL.
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 6431 / Average exposure time: 9.0 sec. / Average electron dose: 38.08 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
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