The Specific Aim of this SBIR direct-to-Phase II project is to develop natural repertoire recombinant intravenous immunoglobulin (rIVIg) "hyperimmunes" against common pathogens for patients with primary immune deficiency (PID). PID is a diverse family of congenital disorders, including common variable immune deficiency (CVID) and X- linked agammaglobulinemia (XLA), which are characterized by significantly reduced antibody titers. Immunologists treat humoral PID with prophylactic intravenous immunoglobulin (IVIg), which is a pool of proteins isolated from the plasma of thousands of donors. Still, 40% of patients suffer recurrent pneumonia, and 36% die from lung failure due to chronic lung disease. Most PID patients with recurrent infections receive prophylactic antibiotics to address chronic infection. Hyperimmunes are plasma-derived gammaglobulins that are enriched for activity against a particular pathogen. Unfortunately, the nine FDA-approved hyperimmunes do not address the pathogens that are most responsible for morbidity and mortality in PID patients. Previously, we developed GigaLink(tm), which uses microfluidics and multiplexed PCR to build massively polyclonal DNA libraries from antibody repertoires, with native heavy and light chain immunoglobulin (Ig) pairing intact. In our preliminary work, we leveraged GigaLink(tm) to produce and characterize hyperimmune influenza rIVIg with >40× enriched binding activity. In this SBIR direct-to-Phase II project, we will add hyperimmunes for two more pathogens of critical importance to PID outcomes, manufacture several test batches of rIVIg, and perform toxicology, pharmacokinetic, and pathogen binding studies. Though PID is the primary clinical indication, these drugs could be used for other kinds of immunocompromised patients, such as transplant recipients. Finally, our therapeutic approach will be useful to combat emerging pathogens, i.e., for West Nile rapid response.
Public Health Relevance Statement: Public Health Relevance: Intravenous immunoglobulin is used to treat many kinds of immune disorders and is currently derived from pools of sera from thousands of donors. We are building new technology that will allow us to manufacture intravenous immunoglobulin with special activity against bacteria and viruses and with less reliance on donors.
Project Terms: Address; Adult; Affect; American; Antibiotics; Antibodies; antibody libraries; Antibody Repertoire; Antigens; Bacteria; Binding; Biochemistry; Biological Assay; Capital; Cells; Chronic; Chronic lung disease; CLIA certified; Clinical; Cohort Studies; combat; Congenital Disorders; congenital immunodeficiency; Cytomegalovirus; Data; Diagnostic; Diagnostic tests; DNA Library; Doctor of Philosophy; Drug Kinetics; Europe; Exclusion; Failure; Family; FDA approved; Flow Cytometry; Genomics; Hemophilus; High Pressure Liquid Chromatography; Immune; Immune System Diseases; Immunocompromised Host; Immunologist; improved; In Vitro; Infection; Influenza; Intravenous Immunoglobulins; Ion Exchange; Libraries; Light-Chain Immunoglobulins; Lung; meetings; Methods; Microfluidics; monomer; Morbidity - disease rate; mortality; new technology; novel strategies; Outcome; pathogen; Patients; Pharmaceutical Preparations; Phase; Plasma; Pneumonia; polyclonal antibody; preclinical efficacy; product development; prophylactic; Prophylactic treatment; Proteins; public health relevance; Recombinants; Recurrence; response; Rodent; Scientist; Sequoia; seropositive; Serum; Small Business Innovation Research Grant; Specialist; Streptococcus; Testing; Therapeutic; Time; Toxicology; transcriptome sequencing; Transplant Recipients; United States National Institutes of Health; Vaccinated; Virus; West Nile virus; Work; X-Linked Agammaglobulinemia
