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Principal Investigator: Gaya K. Amarasinghe
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2023
Award: $638,713
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
This R01 entitled, “Development and characterization of engineered therapeutic antibodies against SARS-CoV-
2”, builds on our project infrastructure, expertise, and experience in characterizing viral-host factor interactions
in negative strand RNA viruses. Since originating in China, SARS-CoV-2 has since rapidly spread and is now a
global pandemic. Significant concerns are that humans are immunologically naïve, and there are no available
therapies. In the US, the disease has already overwhelmed the healthcare system in some states and have a
serious knock-on effect in exacerbating the standard of care for other diseases. At the time of writing, nearly 5
million cases and >160,000 deaths have been attributed to COVID-19. The virus replicates in the lungs and
causes a severe respiratory disease, COVID-19, which is fatal in >2% of cases. Neutralizing antibodies (nAbs)
generated by natural infection or vaccines is known to control many infections and early studies in the current
COVID-19 pandemic, including studies to test convalescent plasma treatments, are promising. These studies
highlight the potential significance of nAb-based therapy. While IgG format of nAbs have long been the most
extensively used format, early studies, including our own suggest that additional multivalent formats of nAbs may
be more effective. This provides an innovative method to develop nAbs while acquiring potential benefits from
effective neutralization at lower doses and lower likelihood of the emergence of resistance mutants. SARS-CoV-
2 is a single stranded, non-segmented, enveloped RNA virus. Viral infection requires interaction of the spike
glycoprotein receptor binding domain (RBD) to the host receptor ACE2. Here, we will build on newly developed
and established approaches that have been optimized through our work other systems to generate antibodies
targeting spike and spike RBD using phage display technology and characterize their physical properties. We
will engineer antibodies with increased valency and test for potency in in vitro neutralization assays and in vivo
efficacy in a mouse model. At the completion, we expect to provide innovative and unique multivalent nAb leads
with unique characteristics that will rival the best in class IgG drugs.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><ACE2><Address><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Therapy><Antigenic Determinants><Assay><Bats><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Biophysics><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 antibody><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cessation of life><Characteristics><China><Chiroptera><CoV-2><CoV2><Collaborations><Death><Development><Diamond><Disease><Disorder><Dose><Drug Combinations><Drugs><Engineering><Epitopes><Geometry><Glycoproteins><Health><Health Care Systems><Healthcare Systems><Host Factor><Host Factor Protein><Human><IgG><Immunochemical Immunologic><Immunoglobulin G><Immunologic><Immunological><Immunologically><Immunologics><In Vitro><Incidence><Incubated><Individual><Infection><Infrastructure><Integration Host Factors><Investigators><Lentivirinae><Lentivirus><Lightning><Lung><Lung Respiratory System><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Mainland China><Mammalia><Mammals><Marketing><Medication><Methods><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modern Man><Molecular Interaction><Persons><Phage Display><Pharmaceutic Preparations><Pharmaceutical Preparations><Protein Engineering><Proteins><RNA Viruses><Race><Races><Receptor Protein><Reporting><Research><Research Personnel><Researchers><Resistance><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 antibody><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 inhibitor><SARS-CoV-2 pandemic><SARS-CoV-2 pathogenesis><SARS-CoV2><SARS-CoV2 antibody><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Series><Severe Acute Respiratory Coronavirus><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Speed><System><Technology><Testing><Therapeutic antibodies><Time><Transmission><United States><VSV><Vaccines><Validation><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Diseases><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Work><Writing><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 based therapies><antibody engineering><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><antibody treatment><antibody-based therapeutics><antibody-based treatment><beta CoV><beta coronavirus><betaCoV><betacoronavirus><biophysical foundation><biophysical principles><biophysical sciences><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><convalescent plasma><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 antibody><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><current pandemic><developmental><drug/agent><early clinical trial><early phase clinical trial><experience><genetic protein engineering><hCoV19><in vivo><indexing><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><lead candidate><model of animal><mouse model><murine 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