Currently available anti-thymocyte globulin (ATG) products are polyclonal animal antibodies (ATGAM equine polyclonal ATG, Thymoglobulin rabbit polyclonal ATG) and have found broad use as immune tolerizing agents, particularly for induction therapy in a majority of tissue transplants, for acute transplant rejection, and as treatment for graft vs. host disease following bone marrow transplants. Early clinical trials also suggest ATG may have a role in immunomodulation to treat the underlying autoimmunity of type 1 diabetes (T1D). However, animal-derived ATG products can result in serum sickness 5-15 days after administration as the recipient's immune system reacts to these xenobiotic immunoglobulins, rendering any subsequent redosing particularly problematic. An agent that could combine the beneficial effects of the current animal ATG products but avoid the xenobiotic responses would bring significant advantages to each of these therapeutic areas. This proposal seeks to produce potent fully human ATG polyclonal antibodies by immunizing transchromosomal bovines (TcBs) with human thymocytes in combination with a strong adjuvant and immune stimulator. TcB-derived fully human polyclonal ATG antibodies (SAB-142) will have potent activity and would eliminate the risk of anaphylaxis and serum sickness associated with xenobiotic IgG products. Success of this proposal will result in an IND filing that will facilitate a Phase 2 clinical trial to evaluate safety, tolerability, and efficacy. Previous studies have demonstrated that TcBs can produce large amounts of human polyclonal antibodies with extremely high titers and neutralizing activity against various antigens, including viruses, proteins, bacteria, and whole cell antigens following multiple immunizations. A phase I clinical trial has shown that the human antibody products produced by TcBs are safe and well-tolerated in healthy subjects (ClinicalTrials.gov NCT02508584). In this proposal, SAB Biotherapeutics, Inc. (SAB) and Sanford Research intend to expand our earlier proof-of- concept studies to produce a human ATG polyclonal antibody product (SAB-142) using SAB's innovative human antibody production platform technology (diversitAb) and evaluate the antibodies in pre-clinical studies. There are two phases in this project: Phase 1 (1) Evaluate and compare SAB-142 with ATGAM and Thymoglobulin for direct cytotoxicity toward conventional T cells, (2) Examine SAB-142 affinity toward red blood cells (RBCs), and evaluate the effects of RBC adsorption on SAB-142 binding to peripheral blood mononuclear cells, and (3) Evaluate and compare SAB-142 with ATGAM and Thymoglobulin for binding affinity to multiple subsets of PBMCs. Phase 2 (1) Production of two naïve TcBs for SAB-142 production, (2) Immunization and plasma collection from TcBs for SAB-142 production, (3) Purification of a pre-clinical lot and a clinical lot (cGMP) of SAB- 142 for use in Aims 4 and 5, (4) Develop and qualify a target-specific potency assay based on the results of the phase I aims, and (5) Complete IND-enabling pre-clinical evaluation of SAB-142.
Public Health Relevance Statement: Project Narrative The research proposed in this application seeks to produce a fully human anti-thymocyte globulin (ATG) product (SAB-142) in transchromosomal bovines that express human polyclonal antibodies for transplant induction/acute rejection therapy and potential immunomodulation therapy to treat the underlying autoimmunity of type 1 diabetes, as suggested by early clinical trial results. SAB-142 will combine the beneficial effects of current animal derived ATG products, while eliminating the risk of anaphylaxis and serum sickness associated with xenobiotic IgG administration. Development of SAB-142 will bring significant advantages to each of the established ATG therapeutic areas, while advancing our understanding of the underlying autoimmunity of T1D.
Project Terms: Acute; Adjuvant; Adsorption; Affinity; Anaphylaxis; animal efficacy; Animals; Antibodies; Antibody Formation; Antigens; Antithymoglobulin; Area; Autoimmunity; B-Lymphocytes; Bacteria; base; Binding; Biological Assay; Biological Response Modifier Therapy; Birth; Blood Cells; Bone Marrow Transplantation; Cattle; CD8B1 gene; Cells; Chromatin; clinical lot; Clinical Trials; Collection; cross reactivity; Cyclic GMP; cytotoxicity; Data; Data Analyses; Development; diabetes mellitus therapy; efficacy study; Embryo; Ensure; Equus caballus; Erythrocytes; Evaluation; FDA approved; Foundations; Funding; Goals; Graft Rejection; graft vs host disease; Hand; Hemagglutination; Hemolysis; Human; hyperimmunization; IL2RA gene; Immune; Immune system; Immunization; Immunize; Immunoglobulin G; Immunoglobulins; immunoregulation; Implant; innovation; insulin dependent diabetes mellitus onset; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Neoadjuvant Therapy; neutrophil; Oryctolagus cuniculus; Peripheral Blood Mononuclear Cell; Phase; phase 1 study; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; polyclonal antibody; polyclonal human antibody; pre-clinical; preclinical evaluation; preclinical study; Preparation; Production; Quality Control; Regulatory T-Lymphocyte; Research; Research Contracts; response; Risk; Role; Safety; Sampling; Serum; Serum Sickness; Source; stability testing; success; T-Lymphocyte; Technology; Testing; Therapeutic; thymocyte; Tissue Transplantation; Tissues; Toxicology; Transplantation; Transplanted tissue; Viral Proteins; Xenobiotics
