SBIR-STTR Award

The natural immune response to foreign pathogens involves a complex coordination of cells, including an adaptive response to select and secrete antibodies into circulation. Individuals who have recovered from a pathogenic infection retain immune memory and continue to circulate pathogen-specific antibodies. For many infectious diseases like respiratory syncytial virus, Ebola, and poxviruses, antibodies with neutralizing activity to multiple viral strains have been discovered from human survivors. The discovered antibodies are highly valuable as potential biologic therapeutics for the broader population, as the antibodies have been naturally optimized to defend against human pathogens.Efforts to discover antibodies from humans recovering from coronavirus infection are underway, SARS-CoV-2 in particular, but are hampered by the limitations of existing antibody discovery platforms. Current approaches require screening for live B cells actively producing pathogen-specific antibodies, which are sensitive to cell death and rarely found in blood. In contrast, antibody protein is stable and pathogen-reactive antibodies are abundant in serum. While protein is the ideal material to start with, characterization of polyclonal antibody (pAb) protein presents new challenges.Recent advances in mass spectrometry and analysis have shown individual antibody candidates can be derived from affinity-purified pAb proteins when a sufficiently matched B-cell genetic antibody repertoire is provided. We aim to develop algorithms to supplant the need of a genetic antibody repertoire, and de novo identify antibody candidates from limited complexity pAb samples. This is achieved by improvements to de novo peptide sequencing using machine learning, and targeted assembly of specificity determining regions (CDR3s) and antibody frameworks using de Bruijn graphs. The proposed software will provide estimates of clonal diversity and candidate sequences that can be synthesized and tested for reactivity. In addition to addressing needs for infectious diseases, as demonstrated with an urgent unmet need to stop the COVID-19 pandemic, the software also applies to clinical and biomedical research needs in autoimmune disease, and commercial interests in replacing polyclonal antibody reagents with highly reproducible monoclonal antibody equivalents. Public Health Relevance Statement The antibody repertoire circulating in serum is the most active component to an immune response, yet is unable to be directly queried without aid from the genetic antibody repertoire from cells. Our innovative algorithms enable querying and sequencing of antibodies directly from protein - opening the door to previously inaccessible autoimmune and infectious disease research and therapeutic antibody discovery.

Project Terms:
Algorithms ; Amino Acid Sequence ; Primary Protein Structure ; protein sequence ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Antibody Affinity ; antigen antibody affinity ; Antigens ; immunogen ; Autoantibodies ; autoimmune antibody ; autoreactive antibody ; self reactive antibody ; Autoimmune Diseases ; autoimmune condition ; autoimmune disorder ; B-Lymphocytes ; B blood cells ; B cell ; B cells ; B-Cells ; B-cell ; Biocompatible Materials ; Biomaterials ; biological material ; Biological Response Modifier Therapy ; Biologic Therapy ; Biological Therapy ; biological therapeutic ; biological treatment ; biotherapeutics ; biotherapy ; Biomedical Research ; Blood ; Blood Reticuloendothelial System ; Blood Cells ; Peripheral Blood Cell ; Blood Circulation ; Bloodstream ; Circulation ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Clinical Research ; Clinical Study ; Color ; Communicable Diseases ; Infectious Disease Pathway ; Infectious Diseases ; Infectious Disorder ; Decision Making ; Fingerprint ; HIV ; AIDS Virus ; Acquired Immune Deficiency Syndrome Virus ; Acquired Immunodeficiency Syndrome Virus ; Human Immunodeficiency Viruses ; LAV-HTLV-III ; Lymphadenopathy-Associated Virus ; Virus-HIV ; HIV Infections ; HTLV-III Infections ; HTLV-III-LAV Infections ; Human T-Lymphotropic Virus Type III Infections ; Human ; Modern Man ; Hybrids ; Complementarity Determining Regions ; Complimentarity Determining Region ; Hypervariable Loop ; Hypervariable Regions ; Immunoglobulin Hypervariable Region ; Immunologic Memory ; Immune memory ; Immunological Memory ; anamnestic reaction ; secondary immune response ; Infection ; instrumentation ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Patients ; Peptides ; Poxviridae ; Poxviruses ; pox virus ; Proteins ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Reagent ; Respiratory syncytial virus ; Salvelinus ; Chars ; Computer software ; Software ; Specificity ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Testing ; analytical method ; improved ; sample collection ; specimen collection ; Clinical ; Survivors ; Coronavirus ; Coronaviridae ; corona virus ; Coronavirus Infections ; Coronaviridae Infections ; Serum ; Blood Serum ; Individual ; Databases ; Data Bases ; data base ; Oncology ; Oncology Cancer ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; polyclonal antibody ; Genetic ; Exposure to ; machine learned ; Machine Learning ; Complex ; Viral ; interest ; Services ; infectious disease diagnosis ; communicable disease diagnosis ; Tumor Cell ; neoplastic cell ; novel ; member ; Graph ; Amino Acid Sequence Determinations ; Protein Sequence Determinations ; Protein Sequencing ; Protein Sequencing Molecular Biology ; Peptide Sequence Determination ; Modeling ; Sampling ; response ; Proteomics ; Genomics ; Pathogenicity ; Bio-Informatics ; Bioinformatics ; Address ; Length ; Affinity ; Data ; Infectious Diseases / Laboratory ; Infectious Diseases Research ; Reproducibility ; Antibody Repertoire ; Transcript ; Vaccine Design ; cost ; digital ; pathogen ; Population ; innovation ; innovate ; innovative ; transcriptomics ; Therapeutic antibodies ; next generation sequencing ; NGS Method ; NGS system ; next gen sequencing ; nextgen sequencing ; screening ; Antibody Response ; proteogenomics ; experimental study ; experiment ; experimental research ; adaptive immune response ; human pathogen ; 2019-nCoV ; 2019 novel corona virus ; 2019 novel coronavirus ; COVID-19 virus ; COVID19 virus ; CoV-2 ; CoV2 ; SARS corona virus 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 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 related corona virus 2 ; Wuhan coronavirus ; coronavirus disease 2019 virus ; hCoV19 ; nCoV2 ; Ebola ; COVID-19 pandemic ; 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 ; severe acute respiratory syndrome coronavirus 2 global health crisis ; severe acute respiratory syndrome coronavirus 2 global pandemic ;

The natural immune response to foreign pathogens involves a complex coordination of cells, including an adaptive response to select and secrete antibodies into circulation. Individuals who have recovered from a pathogenic infection retain immune memory and continue to circulate pathogen-specific antibodies. For many infectious diseases like respiratory syncytial virus, Ebola, and poxviruses, antibodies with neutralizing activity to multiple viral strains have been discovered from human survivors. The discovered antibodies are highly valuable as potential biologic therapeutics for the broader population, as the antibodies have been naturally optimized to defend against human pathogens.Efforts to discover antibodies from humans recovering from coronavirus infection are underway, SARS-CoV-2 in particular, but are hampered by the limitations of existing antibody discovery platforms. Current approaches require screening for live B cells actively producing pathogen-specific antibodies, which are sensitive to cell death and rarely found in blood. In contrast, antibody protein is stable and pathogen-reactive antibodies are abundant in serum. While protein is the ideal material to start with, characterization of polyclonal antibody (pAb) protein presents new challenges.Recent advances in mass spectrometry and analysis have shown individual antibody candidates can be derived from affinity-purified pAb proteins when a sufficiently matched B-cell genetic antibody repertoire is provided. We aim to develop algorithms to supplant the need of a genetic antibody repertoire, and de novo identify antibody candidates from limited complexity pAb samples. This is achieved by improvements to de novo peptide sequencing using machine learning, and targeted assembly of specificity determining regions (CDR3s) and antibody frameworks using de Bruijn graphs. The proposed software will provide estimates of clonal diversity and candidate sequences that can be synthesized and tested for reactivity. In addition to addressing needs for infectious diseases, as demonstrated with an urgent unmet need to stop the COVID-19 pandemic, the software also applies to clinical and biomedical research needs in autoimmune disease, and commercial interests in replacing polyclonal antibody reagents with highly reproducible monoclonal antibody equivalents. Public Health Relevance Statement The antibody repertoire circulating in serum is the most active component to an immune response, yet is unable to be directly queried without aid from the genetic antibody repertoire from cells. Our innovative algorithms enable querying and sequencing of antibodies directly from protein - opening the door to previously inaccessible autoimmune and infectious disease research and therapeutic antibody discovery.

Project Terms:
Algorithms ; Amino Acid Sequence ; Primary Protein Structure ; protein sequence ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Antibody Affinity ; antigen antibody affinity ; Antigens ; immunogen ; Autoantibodies ; autoimmune antibody ; autoreactive antibody ; self reactive antibody ; Autoimmune Diseases ; autoimmune condition ; autoimmune disorder ; B-Lymphocytes ; B blood cells ; B cell ; B cells ; B-Cells ; B-cell ; Biocompatible Materials ; Biomaterials ; biological material ; Biological Response Modifier Therapy ; Biologic Therapy ; Biological Therapy ; biological therapeutic ; biological treatment ; biotherapeutics ; biotherapy ; Biomedical Research ; Blood ; Blood Reticuloendothelial System ; Blood Cells ; Peripheral Blood Cell ; Blood Circulation ; Bloodstream ; Circulation ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Clinical Research ; Clinical Study ; Color ; Communicable Diseases ; Infectious Disease Pathway ; Infectious Diseases ; Infectious Disorder ; Decision Making ; Fingerprint ; HIV ; AIDS Virus ; Acquired Immune Deficiency Syndrome Virus ; Acquired Immunodeficiency Syndrome Virus ; Human Immunodeficiency Viruses ; LAV-HTLV-III ; Lymphadenopathy-Associated Virus ; Virus-HIV ; HIV Infections ; HTLV-III Infections ; HTLV-III-LAV Infections ; Human T-Lymphotropic Virus Type III Infections ; Human ; Modern Man ; Hybrids ; Complementarity Determining Regions ; Complimentarity Determining Region ; Hypervariable Loop ; Hypervariable Regions ; Immunoglobulin Hypervariable Region ; Immunologic Memory ; Immune memory ; Immunological Memory ; anamnestic reaction ; secondary immune response ; Infection ; instrumentation ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Patients ; Peptides ; Poxviridae ; Poxviruses ; pox virus ; Proteins ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Reagent ; Respiratory syncytial virus ; Salvelinus ; Chars ; Computer software ; Software ; Specificity ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Testing ; analytical method ; improved ; sample collection ; specimen collection ; Clinical ; Survivors ; Coronavirus ; Coronaviridae ; corona virus ; Coronavirus Infections ; Coronaviridae Infections ; Serum ; Blood Serum ; Individual ; Databases ; Data Bases ; data base ; Oncology ; Oncology Cancer ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; polyclonal antibody ; Genetic ; Exposure to ; machine learned ; Machine Learning ; Complex ; Viral ; interest ; Services ; infectious disease diagnosis ; communicable disease diagnosis ; Tumor Cell ; neoplastic cell ; novel ; member ; Graph ; Amino Acid Sequence Determinations ; Protein Sequence Determinations ; Protein Sequencing ; Protein Sequencing Molecular Biology ; Peptide Sequence Determination ; Modeling ; Sampling ; response ; Proteomics ; Genomics ; Pathogenicity ; Bio-Informatics ; Bioinformatics ; Address ; Length ; Affinity ; Data ; Infectious Diseases / Laboratory ; Infectious Diseases Research ; Reproducibility ; Antibody Repertoire ; Transcript ; Vaccine Design ; cost ; digital ; pathogen ; Population ; innovation ; innovate ; innovative ; transcriptomics ; Therapeutic antibodies ; next generation sequencing ; NGS Method ; NGS system ; next gen sequencing ; nextgen sequencing ; screening ; Antibody Response ; proteogenomics ; experimental study ; experiment ; experimental research ; adaptive immune response ; human pathogen ; 2019-nCoV ; 2019 novel corona virus ; 2019 novel coronavirus ; COVID-19 virus ; COVID19 virus ; CoV-2 ; CoV2 ; SARS corona virus 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 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 related corona virus 2 ; Wuhan coronavirus ; coronavirus disease 2019 virus ; hCoV19 ; nCoV2 ; Ebola ; COVID-19 pandemic ; 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 ; severe acute respiratory syndrome coronavirus 2 global health crisis ; severe acute respiratory syndrome coronavirus 2 global pandemic ;