Combined Factor VIII Replacement and Tolerance Therapy for Hemophilia A

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DESCRIPTION (provided by applicant): 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.