The goal of this new SBIR program is to produce a combined clotting Factor VIII replacement and immunomodulatory therapy that will provide FVIII-specific tolerance induction at therapeutic doses for Hemophilia A patients. Hemophiliacs with <1% functional FVIII are classified as severe and must receive regular doses of replacement factor. A major issue with successful FVIII replacement therapy for Hemophilia A is overcoming the neutralizing antibody response against FVIII that is seen in up to 30% of hemophiliacs and 50% of patients with severe disease. These "inhibitors" delay or inhibit clotting by interfering with FVIII binding to its ligands. A number of treatments for inhibitors exist but these approaches are either not fully successful or still experimental and present a large health risk for the patient. There is an urgent need for a safe, biologically rational and cost effective approach to induce long-term immune tolerance to FVIII. "Tregitopes" are immunoglobulin-derived natural regulatory T-cell (nTreg) epitopes that expand a subset of circulating nTregs, leading to suppression of inflammation and, when administered with a target antigen, adaptive tolerance. Since publication of this discovery in 2008, we have shown that presentation of Tregitopes at the surface of antigen presentation cells (APCs) to nTregs drives tolerogenic pathways in both APCs and nTregs, and induces target-antigen specific adaptive Tregs that interface with the same APC. Thus, as a natural immune system 'off switch,' Tregitopes have great potential as therapeutics to induce immunological tolerance to co-administered proteins. We therefore propose to couple Tregitopes to FVIII to produce a novel combined replacement and tolerance induction therapy. In this Phase I proof-of concept application, we propose to (i) demonstrate that FVIII-Tregitope modulates human T cell responses and establish correlates of tolerance induction that may be used in clinical trial design and (ii) demonstrate FVIII-Tregitope-mediated tolerance induction in an in vivo hemophilia model, which enables evaluation of Tregitope efficacy on the key outcome - elimination of inhibitors. In future Phase II studies, we will transition to recombinant production of FVIII-Tregitope, a process too complex and costly for proof-of-concept studies. ProBioGen, our Phase II collaborator, is a leading company with expertise in activities central to the manufacture of recombinant human FVIII, including cell line engineering, upstream fermentation, downstream purification, liquid pre-formulation of bulk drug substance and in-process analytics including titer determination and chromogenic determination of FVIII bioactivity. In addition, we have established a strong collaboration with a large Pharma that has experience in the regulatory and clinical trial aspects of FVIII drug development and anticipate that FVIII-Tregitope will move into clinical studies once we achieve the goals of the SBIR program.
Public Health Relevance: Hemophilia A patients do not develop immune tolerance to the very treatment they require, replacement clotting Factor VIII. This research program aims to demonstrate that Factor VIII, when linked to immunosuppressive segments of immunoglobulin, is tolerogenic at normal therapeutic dosing levels.
Public Health Relevance Statement: Hemophilia A patients do not develop immune tolerance to the very treatment they require, replacement clotting Factor VIII. This research program aims to demonstrate that Factor VIII, when linked to immunosuppressive segments of immunoglobulin, is tolerogenic at normal therapeutic dosing levels.
NIH Spending Category: Hematology; Orphan Drug; Rare Diseases
Project Terms: Antibody Formation; Antigen Presentation; Antigen Targeting; Binding (Molecular Function); Biological Markers; Blocking Antibodies; Blood Coagulation Factor; Cell Line; Cells; chemical conjugate; Chemicals; Clinical Research; Clinical Trials; Clinical Trials Design; Coagulation Process; Collaborations; Complex; cost effective; cytokine; Disease; Dose; drug development; Drug Formulations; Endogenous Factors; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; experience; Factor VIII; Fermentation; Flow Cytometry; Future; gel electrophoresis; Goals; Half-Life; Health; Health Sciences; Hemophilia A; Hemorrhage; Human; human F8 protein; immune function; Immune response; Immune system; Immune Tolerance; immunogenicity; Immunoglobulins; Immunologist; Immunology; immunoregulation; Immunosuppressive Agents; In Vitro; in vivo; Incidence; Infection; Inflammation; Infusion procedures; inhibitor/antagonist; interest; Intervention; Knockout Mice; Ligands; Link; Liquid substance; Mass Spectrum Analysis; Measures; Mediating; Methods; Modeling; Monitor; Mus; Neoadjuvant Therapy; neutralizing antibody; novel; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; phase 2 study; Phenotype; Positioning Attribute; Prevention; Process; Production; programs; Proteins; Protocols documentation; Publications; Recombinants; Regulatory T-Lymphocyte; Replacement Therapy; Research; response; Risk; Running; Saline; Services; Small Business Innovation Research Grant; Surface Antigens; T cell response; T-Lymphocyte; Target Populations; Testing; Therapeutic; Thrombosis; Universities; Work
