Document text
Principal Investigator: Larry C. Blaszczak
Organization: TEICHOS LABORATORIES, LLC
Fiscal Year: 2022
Award: $259,613
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <(TNF)-α><Abscission><Adjuvant><Affect><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antibody Response><Antibody Therapy><Antigen-Presenting Cells><Antigens><Antihemophilic Factor><Antiinflammatories><Antiinflammatory Agents><Attenuated><Autoimmune Status><Autoimmunity><Award><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Birth><Blood Coagulation Factor VIII><Blood Neutrophil><Blood Plasma><Blood Polymorphonuclear Neutrophil><Blood monocyte><CSIF><CSIF-10><Cachectin><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell Wall><Cells><Chemicals><Chemistry><Clinical><Co-Stimulator><Coagulation Factor VIII><Coagulation Factor VIII, Procoagulant Component><Coagulation Factor VIIIc><Costimulator><Cytokine Synthesis Inhibitory Factor><Cytotoxic cell><DXS1253E><Dendritic Cells><Development><Disease><Disorder><Dose><Endotoxins><Epidermal Thymocyte Activating Factor><Excision><Extirpation><F8 gene><F8 protein><F8B><F8C><FVIII><Factor VIII><Factor VIII Deficiency><Factor VIII F8B><Factor VIIIF8B><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><Genetic><Grant><HEMA gene><Hemophilia><Hemophilia A><IFN><IL-10><IL-2><IL10><IL10A><IL2 Protein><Immune><Immune Tolerance><Immune mediated therapy><Immune response><Immunes><Immunologic Tolerance><Immunological response><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><In Vitro><Interferons><Interleukin 10 Precursor><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-10><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Intravenous><K lymphocyte><Laboratories><Laboratory Study><Link><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Lymphocyte Mitogenic Factor><Macrophage-Derived TNF><Marrow Neutrophil><Marrow monocyte><Measures><Mediating><Messenger RNA><Mice><Mice Mammals><Mitogenic Factor><Modeling><Modification><Molecular><Molecular Weight><Monocyte-Derived TNF><Murein><Murine><Mus><NK Cells><Natural Killer Cells><Neutrophilic Granulocyte><Neutrophilic Leukocyte><PBMC><Parturition><Patients><Peptidoglycan><Peripheral><Peripheral Blood Mononuclear Cell><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phenotype><Physical condensation><Plasma><Plasma Serum><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Pre-Clinical Model><Preclinical Models><Process><Procoagulant Component><Production><Property><Protein Replacement Therapy><Proteins><Protocol><Protocols documentation><Publications><Rapamune><Rapamycin><Receptor Signaling><Recombinants><Regulatory T-Lymphocyte><Removal><Replacement Therapy><Reporting><Research><Resistance><Resistance development><Resistant development><Resource Allocation><Reticuloendothelial System, Serum, Plasma><SBIR><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Sirolimus><Small Business Innovation Research><Small Business Innovation Research Grant><Spleen><Spleen Reticuloendothelial System><Sterility><Structure><Surgical Removal><T cell growth factor><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cell Subsets><T-Lymphocyte Subsets><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><TLR7><TLR7 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Teff cell><Testing><Thromboplastinogen><Thymocyte Stimulating Factor><Toll-Like Receptor 2><Toll-Like Receptor 7><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Toxic effect><Toxicities><Treg><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Up-Regulation><Upregulation><VAC-TX><Vaccine Adjuvant><Vaccine Therapy><Vaccines><Validation><Veiled Cells><accessory cell><adaptive immunity><antibody based therapies><antibody inhibitor><antibody treatment><antibody-based therapeutics><antibody-based treatment><antihemophilic factor A><antiinflammatory><assess effectiveness><biological signal transduction><cell culture><cell cultures><chemical synthesis><clinical development><complex Blood-coagulation factor VIII><condensation><cytokine><determine effectiveness><developing resistance><developmental><effectiveness assessment><effectiveness evaluation><effector T cell><enzyme replacement therapy><evaluate effectiveness><exhaustion><experiment><experimental research><experimental study><flow cytophotometry><host response><immune drugs><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune system tolerance><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune unresponsiveness><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic preparation><immunologic therapeutics><immunological paralysis><immunoresponse><immunosuppressive activity><immunosuppressive function><immunotherapeutics><immunotherapy agent><improved><in vivo><inhibitor><lymph gland><lymph nodes><lymphnodes><mRNA><mTOR Inhibitor><male><monocyte><mouse model><murine model><native protein drug><neutrophil><novel><pharmaceutical protein><platelet cofactor I><polymerization><pre-clinical><preclinical><prophylactic><protein drug agent><protein-based drug><regulatory T-cells><resection><resistant><response><response to therapy><response to treatment><scale up><standard of care><sterile><therapeutic outcome><therapeutic protein><therapeutic response><therapeutic vaccination><therapy outcome><therapy response><thromboplastinogen A><treatment response>