Development of neutralizing nanobodies against SARS-CoV-2

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

↗ Live URL (may be dead)

Document text

Principal Investigator: Mitchell  Ho
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2022
Award: $45,270
Funding agency: National Cancer Institute

During the pandemic, Dr Ho has evaluated the challenges for developing antibody      therapeutics targeting SARS-Cov-2 and wrote a review/perspective article [Ho Antibody      Therapeutics 2020; PMID: 32566896]. SARS-CoV-2 gains entry to human cells through its spike      (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the S protein is the      primary target for neutralizing antibodies. In FY2022, we summarized our work on isolation of      dromedary camel nanobodies against SARS-CoV-2 and published the data in PNAS [Hong et al. Proc      Natl Acad Sci U S A. 2022]. With the emergence of SARS-CoV-2 variants, there is an urgent need      to develop broadly neutralizing antibodies. We isolated two VHH nanobodies (7A3 and 8A2) from      dromedary camels by phage display, which have high affinity for the receptor-binding domain      (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants.      Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits      receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike      regardless of the RBD conformational state. 7A3 at a dose of 5 mg/kg efficiently protects      K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2, suggesting that      the nanobody has promising therapeutic potential to curb the COVID-19 surge with emerging      SARS-CoV-2 variants.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><Affinity><B.1.351><B.1.617.2><Bacteriophages><Binding Proteins><Biological><COVID-19><COVID-19 S protein><COVID-19 antibody><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Camels><Cell Body><Cells><CoV-2><CoV2><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Delta variant><Development><Dose><Dromedaries><Electron Cryomicroscopy><Human><K-18><K-18 conjugate><K18><K18 combination><Libraries><Ligand Binding Protein><Ligand Binding Protein Gene><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Nurses><Phage Display><Phages><Protein Binding><Proteins><Publishing><Research><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.351><SARS-CoV-2 B.1.617.2><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 beta><SARS-CoV-2 delta><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 antibody><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shark><Site><South Africa strain><South Africa variant><South African strain><South African variant><Structure><Surface><Therapeutic><Therapeutic antibodies><Transgenic Mice><Variant><Variation><Viral><Virus><Work><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to SARS-CoV2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><bacterial virus><biologic><bound protein><conformation><conformational state><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cryo-EM><cryoEM><developmental><global health><hCoV19><nCoV2><nanobodies><nanobody><neutralizing antibody><novel><nurse><pandemic><pandemic disease><receptor binding><receptor bound><sdAb><severe acute respiratory syndrome coronavirus 2 B.1.351><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><single domain antibodies><therapeutic target>