TREM-1 therapy for rheumatoid arthritis

TREM-1 治疗类风湿性关节炎

• 批准号: 10080141
• 负责人: Alexander B Sigalov
• 金额: $ 25.86万
• 依托单位: SIGNABLOK, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080141
• 关键词: Achievement; Adjuvant Arthritis; Affect; American; Amplifiers; Animal Model; Animals; Anti-Inflammatory Agents; Arthritis; Binding; Biological Assay; Blood; CSF1 gene; Chronic; Clinical; Clinical Treatment; Collagen Arthritis; Comparative Study; Complex; Data; Development; Dexamethasone; Disease; Dose; Drug Kinetics; Failure; Film; Formulation; France; Goals; Half-Life; Histology; Human; Humira; Hydration status; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Kineret; Lead; Life; Ligands; Lipids; Macrophage Activation; Macrophage Colony-Stimulating Factor; Maintenance Therapy; Maximum Tolerated Dose; Measures; Methods; Methotrexate; Microfluidics; Modeling; Mus; Oral; Pathogenesis; Patients; Peptides; Phase; Population; Prednisone; Process; Property; Rattus; Regimen; Research; Rheumatoid Arthritis; Risk; Safety; Serum; Severities; Societies; Synovial Membrane; TNF gene; Technology; Testing; Therapeutic; Therapeutic Effect; Thinness; Toxicology; Water; arthritis therapy; base; cost; cytokine; disability; follow-up; improved; in vivo; inhibitor/antagonist; innovation; joint inflammation; lead candidate; lead optimization; macrophage; meetings; microbial; mouse model; novel; overexpression; prototype; scale up; septic; side effect; standard care; targeted treatment; uptake

Project Summary/Abstract Rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder that causes chronic inflammation of the joints, affects about 1.5 million Americans and costs society more than $40 billion each year. Despite advances in therapy, RA has no cure and 30-40% of RA patients do not respond to the first-line treatment of RA – methotrexate (MTX), highlighting the need for new treatments. The long-term goal of this project is to develop a novel, first-in-class, efficient and well-tolerable therapy for RA. Overexpression of TREM-1 on the synovial macrophages as well as the abundance and activation of macrophages in the synovium of RA patients correlate with the severity of RA. Current TREM-1 inhibitors all attempt to block binding of the uncertain ligand(s) to TREM-1. To minimize clinical failure risks, we developed a ligand-independent TREM-1 inhibitory peptides GF9, GA31 and GE31 that can be formulated into macrophage-specific lipopeptide complexes (LPC) to improve half-life and reduce off-target risks. Previously, we showed that: 1) in CIA mice, GF9 therapy reduces systemic inflammation and inhibits arthritis as effective as 0.1 mg/kg dexamethasone, widely used in the clinical treatment of RA; 2) GF9 therapy reduces cytokine release (TNFα, IL-1β, IL-6 and CSF-1) in vitro and in vivo up to 5-fold, while control peptide has no effect; 3) GF9, GF9-LPC and GA/E31-LPC are non-toxic and well-tolerated by mice at least up to 300 mg GF9/kg; and 4) formulation of GF9 into LPC reduces the effective dose by 80%. The goal of this project is to further develop this first-in-class well tolerable TREM-1 therapy to be used standalone or with MTX as induction/maintenance therapy. Systemic and oral delivery will be tested. Phase I (Year 1) aims are to: 1) prepare and test GMP-friendly formulations of free and LPC-bound trifunctional peptides GA31 and GE31 in vitro, and 2) test free and LPC-bound trifunctional peptides GA31 and GE31 in the CIA mouse model. GMP-friendly microfluidic method to prepare peptide-LPC will be used. Phase II (Years 2 & 3) aims are to: 1) develop an LC-MS assay to measure GA31 and GE31 in blood, 2) determine pharmacokinetics of free and LPC-bound peptides GA31 and GE31 and select two leads, 3) test two leads identified in Aim 2 as monotherapy and with methotrexate in two animal models of rheumatoid arthritis, and 4) test the leads further in toxicology studies and select the lead candidate for Phase IIb. Follow-up Phase IIb will include testing other administration (eg, transdermal) and combination (eg, Prednisone) regimen, further optimization of the lead and its manufacturing technology, TOX, ADME, CMC and other IND-enabling studies. Upon completion, an IND application will be filed. The final product will represent safe and stable RA therapy. Its anticipated safety is supported by safety of GF9 therapy in long treated healthy and arthritic mice. SignaBlok's LPC prototypes are well tolerated in humans. TREM-1 blockade by SignaBlok competitor's peptide LR12 is safe and well-tolerated in healthy and septic subjects.

项目总结/文摘