Immunotherapy for Factor VIII Inhibition in Hemophilia A

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Hemophilia A is one of the most common X-linked recessive disorders, affecting one in 5,000 male births globally. Intravenous FVIII replacement is the standard of care therapy and resistance develops to FVIII in 20– 30% of patients with severe disease from the production of anti-FVIII antibodies (inhibitors). Clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no approved prophylactic protocols to suppress FVIII-specific antibody responses. Recent findings have reported that tolerance to replacement FVIII protein is strongly modulated by T regulatory cells (Treg). Teichos Laboratories proposes to evaluate TL-003, a unique immune response attenuator from its platform of totally synthetic peptidoglycan (sPGN) molecules for tolerance induction against Factor VIII resistance in Hemophilia A. TL-003 treatment produced anti-inflammatory activity at low doses in preclinical models. These responses were associated with in vitro findings that TL-003 produces no stimulatory signal from TLR2, unlike natural PGN and other immune response activator sPGNs. TL-003 is taken up avidly by monocyte-derived dendritic cells (DC). TL-003 does not up-regulate costimulatory molecules on antigen presenting cells (APCs) and treatment of peripheral blood mononuclear cells (PBMCs) stimulates production of the anti-inflammatory cytokine, IL-10. Abrogation of TLR2 signalling, diminished up-regulation of costimulatory molecules, potential activation of Treg, and in vivo anti-inflammatory activity provide a compelling rationale to evaluate an immune response attenuator adjuvant (TL-003) combined with a recombinant therapeutic protein antigen (FVIII) in a tolerizing vaccine therapy for Hemophilia A resistance. TL-003 is synthesized by a chemoenzymatic process that produces otherwise inaccessible single-strand bacterial cell wall peptidoglycan. This synthesis is efficient, scalable, and controllable, producing homogenous, soluble, single strand, uncrosslinked PGN with molecular weight in the antibody range. Given the molecular properties of sPGN, scale-up production and chemical manufacturing issues are addressable using processes similar to those employed in standard pharmaceutical development. The Specific Aims of this proposal are to establish preclinical parameters that will support clinical development of TL-003 as a new tolerizing vaccine adjuvant to treat Factor VIII resistance in Hemophilia A. We will 1) prepare sPGN test articles and 2) determine how TL-003 induces peripheral (p) Treg via modulation of antigen presenting cells (APC) and 3) evaluate the effects of this new synthetic immune response attenuator on the production of FVIII inhibitors in an established mouse model of Hemophilia A.