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Principal Investigator: Xiaofeng Li
Organization: ABBRATECH, INC.
Fiscal Year: 2024
Award: $995,774
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Current strategies for developing neutralizing Abs are not effective and typically involve screening IgGs from
recovered patients. Pandemic viruses evolve for mutations that can shield their epitopes from host immune
surveillance system, so a lot of important epitopes will be missed. Even after neutralizing Abs isolated are
from human sample, they still need further characterization using epitope binning and determination of
specificities to avoid off target effect. A systematic method for exploring the entire protein surface of a virus
that can identify all potential sites on the virus which can affect its life cycle would have significant impact and
is needed. We propose a structure-guided systematic Ab development pipeline to discover Abs that
can fight infectious diseases. We propose using our novel site-directed Ab development technology,
‘EpiVolve’ (short for Epitope Evolution). EpiVolve will be used to develop site-specific Abs to solvent-exposed
residues and the adjacent ‘context’ sequences. These Abs will be used for fighting infectious disease. The
advantages of EpiVolve are a) overcoming immune tolerance and targeting virus’ human proteome-mimicking
epitopes, b) precisely targeting any antigenic epitopes regardless of its immunogenicity, c) taking advantage
of B cell expansion and somatic hypermutation to generate IgG clonotypes against one targeted residue,
which allows an ability to generate both pan-variants Abs and polymorphism-specific Abs, and d) an ability
for generating a neutralizing Ab discovery pipeline. We will model this on SARS-cov-2 virus in Phase I and
Influenza A in Phase II. EpiVolve developed site-specific antibodies will target solvent-exposed residues on
the protein surface. Structure-guided Ag design will empower the EpiVolve technology in this systematic
analysis. For this proposal, we will present the current preliminary data on the pilot EpiVolve study on SARS-
cov-2 Receptor Binding Domain (RBD), focused mainly on the host cell receptor ACE2 binding interface. For
Phase I studies, we propose to complete the pilot study and extend the study to the whole protein surface of
the RBD domain. Characterizing each Ab by its binding affinity and ability to neutralize SARS-cov-2 virus will
be included in Phase I studies. For Phase II, we propose to apply the learnings from this Phase I study on
another virus model of great importance, the Influenza A virus. Specifically targeting the solvent-accessible
residues of the conserved Stem/Stalk region of the Hemagglutinin (HA) protein
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><7S Gamma Globulin><ACE2><Affect><Affinity><Amino Acids><Animals><Antibodies><Antigenic Determinants><Antigens><Assay><Autoantigens><Autologous Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Binding Sites><Bioassay><Biological Assay><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 virus><Cell Body><Cells><CoV-2><CoV2><Combining Site><Communicable Diseases><Data><Development><Epitopes><Evolution><Generations><Genetic Alteration><Genetic Change><Genetic Polymorphism><Genetic defect><Grippe><Hemagglutinin><Human><Ig Somatic Hypermutation><IgG><Immune Surveillance><Immune Targeting><Immune Tolerance><Immunization><Immunize><Immunoglobulin G><Immunoglobulin Somatic Hypermutation><Immunologic Surveillance><Immunologic Surveillances><Immunologic Tolerance><Immunological Surveillance><Immunological Surveillances><Immunosurveillance><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Life Cycle><Life Cycle Stages><Measurement><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methods><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><Orthomyxovirus Type A><Patients><Phase><Phase I Study><Pilot Projects><Protein Binding Domain><Protein Binding Motif><Protein-Protein Interaction Domain><Proteins><Proteome><Protomer><Reactive Site><Receptor Cell><Rest><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><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><Sampling><Self-Antigens><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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 pandemic><Severe acute respiratory syndrome related corona virus 2><Site><Solvents><Specificity><Structure><Surface><Surface Proteins><System><Technology><Type A Influenza><Vaccines><Validation><Variant><Variation><Virus><Wuhan coronavirus><aminoacid><angiotensin converting enzyme 2><angiotensin converting enzyme II><applied learning><conformation><conformational><conformational state><conformationally><conformations><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 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><design><designing><developmental><empowerment><fighting><genome mutation><hCoV19><hands-on learning><immune system tolerance><immune unresponsiveness><immunization strategy><immunogen><immunogenicity><immunological paralysis><influenzavirus><innovate><innovation><innovative><interactive engagement><interactive learning><life course><nCoV2><neutralizing antibody><novel><pandemic virus><phase 1 study><pilot study><polymorphism><receptor binding><receptor bound><screening><screenings><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><somatic hypermutation><stem><tech development><technology development><three dimensional><vaccination strategy><validations>