Hemophilia A is one of the most common X-linked recessive disorders, affecting one in 5,000 male birthsglobally. 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 immunetolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no approvedprophylactic protocols to suppress FVIII-specific antibody responses. Recent findings have reported thattolerance 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 platformof totally synthetic peptidoglycan (sPGN) molecules for tolerance induction against Factor VIII resistance inHemophilia A. TL-003 treatment produced anti-inflammatory activity at low doses in preclinical models. Theseresponses were associated with in vitro findings that TL-003 produces no stimulatory signal from TLR2, unlikenatural PGN and other immune response activator sPGNs. TL-003 is taken up avidly by monocyte-deriveddendritic 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-inflammatorycytokine, IL-10. Abrogation of TLR2 signalling, diminished up-regulation of costimulatory molecules, potentialactivation of Treg, and in vivo anti-inflammatory activity provide a compelling rationale to evaluate an immuneresponse attenuator adjuvant (TL-003) combined with a recombinant therapeutic protein antigen (FVIII) in atolerizing vaccine therapy for Hemophilia A resistance. TL-003 is synthesized by a chemoenzymatic process that produces otherwise inaccessible single-strandbacterial 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 molecularproperties of sPGN, scale-up production and chemical manufacturing issues are addressable using processessimilar to those employed in standard pharmaceutical development. The Specific Aims of this proposal are to establish preclinical parameters that will support clinicaldevelopment 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 modulationof antigen presenting cells (APC) and 3) evaluate the effects of this new synthetic immune response attenuatoron the production of FVIII inhibitors in an established mouse model of Hemophilia A.
Public Health Relevance Statement: Teichos proposes an improved treatment of Hemophilia A, relying on chemistry to synthesize the core structure
of a heretofore inaccessible biomolecule that provides a unique approach for immunotherapeutic applications:
modified bacterial cell wall peptidoglycan, sPGN. An immune response attenuator sPGN produces anti-
inflammatory activity at low doses in laboratory studies by blocking toll-like receptor signaling and diminishing
up-regulation of costimulatory molecules. Proof-of-concept studies will evaluate this non-toxic immune response
attenuator as a tolerizing vaccine adjuvant to provide significant improvements in Factor VIII replacement therapy
outcomes for Hemophilia A patients.
Project Terms: | <(TNF)-α> | | | | | | | 