SBIR-STTR Award

Scleroderma that includes localized scleroderma (LS) and systemic sclerosis (SSc) is a rare but devastating autoimmune disorder. Current therapies all have side effects, are limited and associate with 10 year survival of 55%, showing the need for novel approaches. The long-term goal of this project is to develop a new mechanism-based, efficient and well tolerable scleroderma therapy. Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, contributes to the development of fibrosis in SSc. In patients, number of activated macrophages in the fibrotic areas is increased and associates with fibrosis severity. Activation of TREM-1 leads to overproduction of MCP- 1/CCL2 and M-CSF/CSF-1, resulting in macrophage recruitment to an injured area and the sclerotic lesion formation in rats with scleroderma. In animal models, TREM-1 blockade inhibits inflammation and ameliorates a variety of autoimmune diseases. The hypothesis of the "proof-of-concept" Phase I is that TREM-1 blockade can prevent and treat scleroderma. Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To minimize risk of failure in clinical development, we developed a first-in-class ligand-independent TREM-1 inhibitory peptide GF9 that is well-tolerated and can be formulated into SignaBlok's long half-life macrophage-specific lipopeptide complexes (LPC) to improve its half-life and targeting to the inflammation areas. The major goal of the Phase I study is to show that TREM-1 blockade by GF9-LPC alleviates the disease in a bleomycin (BLM)-induced mouse model of scleroderma. Phase I specific aims are to: 1) optimize TREM-1 inhibitory compositions for their functionality in vitro and pharmacokinetics in vivo and select the lead, 2) test two doses of the lead selected in a BLM-induced mouse model of scleroderma. We will generate, optimize and select the lead based upon its functionality in vitro and its PK profile in vivo. We will test two doses of the lead for its ability to prevent and treat lung, heart, muscle and skin fibrosis in a mouse model of multiorgan fibrosis in vivo. Histology/IHC studies will be performed. Serum and tissue MCP-1, CSF-1, VEGF, TGF?, TNF?, IL-6, and IL-1? will be analyzed. It is anticipated that the Phase I study will identify a novel, first-in-class, well tolerable agent as a powerful platform for development of an effective and well-tolerable systemic scleroderma therapy, thereby improving treatment and survival of patients. Its anticipated safety is supported by good tolerability of SignaBlok's GF9-based formulations by long term-treated mice. Prototypes of SignaBlok's LPC are well tolerated in humans. TREM-1 blockade by SignaBlok competitor's inhibitory peptide LR12 (Inotrem, France) was safe in healthy and septic subjects. If successful, Phase I will be followed in Phase II by toxicology, ADME, pharmacology and CMC studies, filing an IND and subsequent evaluation in humans.

Public Health Relevance Statement:
Project Narrative Scleroderma (also known as systemic sclerosis) is a rare autoimmune disorder that affects about 20 to 24 people per million population in the US each year, with the majority being women of childbearing age. There is no approved drug for scleroderma. Current therapies all have side effects, are limited and associated with 10 year survival of 55%, highlighting the urgent need for novel approaches The proposed research is anticipated to result in the development of novel mechanism-based first-in-class therapeutics that could substantially improve treatment of scleroderma and patient survival.

Project Terms:
Affect; Amplifiers; Animal Model; Animals; Area; Arthritis; Autoimmune Diseases; base; Binding; Biological Assay; Bleomycin; Body Weight Changes; CCL2 gene; Cells; Chronic; Clinic; clinical development; Collagen Arthritis; Complex; cytokine; Data; Development; disability; Disease; Dose; Drug Kinetics; Evaluation; Failure; Female of child bearing age; Fibrosis; Formulation; France; Goals; Half-Life; Histologic; Histology; Human; immunomodulatory therapies; improved; In Vitro; in vivo; in vivo evaluation; indium-bleomycin; Infection; Inflammation; inhibitor/antagonist; Injectable; injured; innovation; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-6; Lead; lead optimization; Lesion; Life; Ligands; Lipids; Liver diseases; Localized scleroderma; Lung; macrophage; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mediating; Morbidity - disease rate; mortality; mouse model; Mus; Muscle; Musculoskeletal Diseases; Myeloid Cells; Myocardium; novel; novel strategies; novel therapeutics; Organ; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; phase 1 study; Platelet-Derived Growth Factor; Play; Population; prevent; prototype; Pulmonary Fibrosis; Rattus; receptor; recruit; Research; Rheumatism; Risk; risk minimization; Role; Safety; Scleroderma; Sepsis; septic; Serum; Severities; side effect; Site; Skin; skin disorder; skin fibrosis; Subcutaneous Injections; Systemic Scleroderma; targeted treatment; Testing; Therapeutic; Therapeutic Effect; Tissues; TNF gene; Toxic effect; Toxicology; Transforming Growth Factor beta; uptake; Vascular Endothelial Growth Factors