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
Public Health Relevance Statement: Narrative Current strategies for developing neutralizing Abs are not effective and typically involve screening IgGs from recovered patients. The challenges of this include immunogenicity limitation, long-term infection in patients, broad neutralizing capabilities depend on rare natural occurring chances. 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. Therefore, a systematic method for exploring the entire solvent-exposed surface of a virus that can identify all potential sites on the virus which can affect its life cycle would have significant impact and it is innovative. Our 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 is proactive, innovative, and significant.
Project Terms: Affect; aminoacid; Amino Acids; Animals; Antibodies; Antigenic Determinants; Binding Determinants; Epitopes; immunogen; Antigens; Autoantigens; Autologous Antigens; Self-Antigens; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Binding Sites; Combining Site; Reactive Site; Biological Assay; Assay; Bioassay; Biologic Assays; Cells; Cell Body; Communicable Diseases; Infectious Disease Pathway; Infectious Diseases; Infectious Disorder; Evolution; Hemagglutinin; Human; Modern Man; Immunoglobulin G; 7S Gamma Globulin; IgG; Immune Tolerance; Immunologic Tolerance; immune system tolerance; immune unresponsiveness; immunological paralysis; Immunization; Immunologic Surveillance; Immune Surveillance; Immunologic Surveillances; Immunological Surveillance; Immunological Surveillances; Immunosurveillance; Infection; Influenza; Grippe; Life Cycle Stages; Life Cycle; life course; Membrane Proteins; Membrane Protein Gene; Membrane-Associated Proteins; Surface Proteins; Methods; Molecular Conformation; Molecular Configuration; Molecular Stereochemistry; conformation; conformational; conformational state; conformationally; conformations; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Patients; Pilot Projects; pilot study; Genetic Polymorphism; polymorphism; Proteins; Rest; Solvents; Specificity; Technology; Vaccines; Virus; Generations; Site; Surface; Phase; Variation; Variant; Measurement; fighting; System; 3-Dimensional; 3-D; 3D; three dimensional; neutralizing antibody; receptor binding; receptor bound; technology development; tech development; Structure; novel; empowerment; Proteome; Modeling; Sampling; Immunoglobulin Somatic Hypermutation; Ig Somatic Hypermutation; somatic hypermutation; Influenza A virus; Influenza A; Influenza Viruses Type A; Influenzavirus A; Orthomyxovirus Type A; Type A Influenza; Protomer; Molecular Interaction; Binding; SARS; SARS coronavirus disease; SARS-CoV disease; Severe Acute Respiratory Syndrome CoV disease; Severe Acute Respiratory Syndrome coronavirus disease; Severe Acute Respiratory Syndrome; influenzavirus; Influenza Virus; Affinity; Data; Immune Targeting; Protein Binding Domain; Protein Binding Motif; Protein-Protein Interaction Domain; Receptor Cell; Validation; validations; Development; developmental; immunogenicity; designing; design; immunization strategy; vaccination strategy; innovate; innovative; innovation; stem; Phase I Study; phase 1 study; screenings; screening; applied learning; interactive engagement; interactive learning; hands-on learning; Immunize; 2019 novel corona virus; 2019 novel coronavirus; COVID-19 virus; COVID19 virus; CoV-2; CoV2; SARS corona virus 2; SARS-CO-V2; SARS-COVID-2; SARS-CoV-2; SARS-CoV2; 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 coronavirus 2; Severe acute respiratory syndrome related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; 2019-nCoV; COVID crisis; COVID epidemic; COVID pandemic; COVID-19 crisis; COVID-19 epidemic; COVID-19 global health crisis; COVID-19 global pandemic; COVID-19 health crisis; COVID-19 public health crisis; COVID19 crisis; COVID19 epidemic; COVID19 global health crisis; COVID19 global pandemic; COVID19 health crisis; COVID19 pandemic; COVID19 public health crisis; SARS-CoV-2 epidemic; SARS-CoV-2 global health crisis; SARS-CoV-2 global pandemic; SARS-CoV-2 pandemic; SARS-CoV2 epidemic; SARS-CoV2 pandemic; SARS-coronavirus-2 epidemic; SARS-coronavirus-2 pandemic; Severe Acute Respiratory Syndrome CoV 2 epidemic; Severe Acute Respiratory Syndrome CoV 2 pandemic; Severe acute respiratory syndrome coronavirus 2 epidemic; Severe acute respiratory syndrome coronavirus 2 pandemic; corona virus disease 2019 epidemic; corona virus disease 2019 pandemic; 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 crisis; coronavirus disease epidemic; coronavirus disease pandemic; coronavirus disease-19 global pandemic; coronavirus disease-19 pandemic; severe acute respiratory syndrome coronavirus 2 global health crisis; severe acute respiratory syndrome coronavirus 2 global pandemic; COVID-19 pandemic; angiotensin converting enzyme 2; angiotensin converting enzyme II; ACE2; pandemic virus
