A research plan is proposed to produce potent human polyclonal antibodies against influenza viruses by immunizing genetically modified bovines with seasonal influenza vaccine in combination with a strong adjuvant and immune stimulator. Previous studies have demonstrated that genetically engineered bovines are capable of producing large amounts of human polyclonal antibodies with extremely high titers and neutralization antibody activities against various antigens, including influenza viruses, following multiple immunizations. In this study, SAB Biotherapeutics, Inc. (SAB) and University of South Dakota intend to expand our earlier proof- of-concept study to produce a human anti-influenza polyclonal antibody product at pilot scale under current Good Manufacturing Practices (cGMP) using SAB's innovative human antibody production platform technology (diversitAb(tm)) and evaluate the antibodies in pre-clinical studies. There are five specific aims in this project: (1) o immunize genetically engineered bovines with tetravalent 2015-2016 seasonal inactivated influenza virus vaccine to generate fully human polyclonal antibodies against influenza and collect hyperimmune plasma; (2) to perform in vitro antibody characterization of anti-influenza serum generated in Aim 1; (3) to manufacture purified fully human anti-influenza antibody product at pilot scale under cGMP using plasma collected in Aim 1 and conduct a validation study of viral clearance; (4) to perform quality control tests for the release of purified anti-influenza antibody product and conduct stability testing; and (5) to conduct Investigational New Drug (IND)-enabling pre-clinical studies, including: (a) in vivo efficacy studies using a ferret model; and (b) in vitro human tissue cross reactivity study of manufactured anti-influenza product. Toxicity and pharmacokinetics studies in non-human primates will be performed following these studies although not as a part of this grant. Data generated from this grant will enable SAB to prepare and file an IND application for a human Phase 1 clinical trial. It is expected that fully human antibodies against influenza viruses produced in Tc bovines will have high potency and can be used to treat immunocompromised individuals who do not produce a response to the seasonal influenza vaccine. The success of this project would also provide validation for SAB's genetically engineered bovine platform technology as a novel approach to producing safe and potent human antibody therapeutics to treat a wide range of diseases caused by emerging pathogens in the future.
Public Health Relevance Statement: Public Health Relevance: Genetically modified bovines that express human polyclonal antibodies will be hyperimmunized with four strains of 2015-2016 seasonal influenza virus vaccine. Antibody titers against influenza viruses will be evaluated using in vitro assays during the immunization process. Fully human polyclonal antibodies against influenza viruses will be purified from hyperimmune bovine plasma at pilot scale under current Good Manufacturing Practices and evaluated in Investigational New Drug-enabling preclinical studies intended for approval of a therapeutic product for influenza treatment in immunocompromised individuals.
Project Terms: anti-influenza; Antibodies; Antibody Formation; Antibody Response; Antigens; Biological Assay; Biological Response Modifier Therapy; Cattle; Clinical Research; Collection; Communicable Diseases; cross reactivity; Data; Disease; Drug Kinetics; Ensure; Evaluation; Ferrets; Future; Genetic Engineering; Grant; Health; Hemagglutination; Hemagglutination Inhibition Tests; high risk; Human; human tissue; hyperimmunization; Immunization; Immunocompromised Host; Immunologic Adjuvants; In Vitro; in vitro Assay; in vivo; Individual; Influenza; Influenza virus vaccine; influenzavirus; innovation; Investigational Drugs; Investigational New Drug Application; Methods; Modeling; nonhuman primate; novel strategies; novel therapeutics; pathogen; Phase I Clinical Trials; Plasma; polyclonal antibody; polyclonal human antibody; preclinical study; Preparation; Procedures; Process; Production; public health relevance; Qualifying; Quality Control; Reporting; Research; response; Sampling; seasonal influenza; Seasons; Serum; South Dakota; stability testing; success; Technology; Temperature; Testing; Therapeutic; Therapeutic antibodies; Time; Tissues; Toxic effect; Universities; Validation; validation studies; Viral; Writing
