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.

项目摘要/摘要 类风湿关节炎（RA）是一种慢性全身性炎症性疾病，导致慢性炎症 这些关节影响约150万美国人，每年使社会损失超过400亿美元。尽管 治疗的进展，RA无法治愈，30-40％的RA患者对一线治疗没有反应 RA - Methodoxate（MTX），强调了对新疗法的需求。这个项目的长期目标是 为RA开发一种新颖的，一流的，高效且可溶解的疗法。 TREM-1在滑膜巨噬细胞上的过表达以及丰度和激活 RA患者滑膜中的巨噬细胞与RA的严重程度相关。当前的TREM-1抑制剂 所有试图阻止不确定配体与TREM-1结合的结合。为了最大程度地降低临床衰竭风险，我们 开发了独立于配体的TREM-1抑制性肽GF9，GA31和GE31，可以配方 进入巨噬细胞特异性的脂肽复合物（LPC），以改善半衰期并降低脱靶风险。 以前，我们表明：1）在CIA小鼠中，GF9治疗可降低全身注射并抑制 关节炎高达0.1 mg/kg地塞米松，广泛用于RA的临床治疗； 2）GF9 治疗可在体外和体内降低细胞因子释放（TNFα，IL-1β，IL-6和CSF-1），而体内最多5倍 控制肽没有作用； 3）GF9，GF9-LPC和GA/E31-LPC无毒且耐受良好的小鼠 至少高达300 mg gf9/kg; 4）GF9的公式为LPC可将有效剂量降低80％。 该项目的目的是进一步开发这种使用的第一类可耐受性TREM-1疗法 独立或以MTX作为诱导/维持疗法。系统和口服分娩将进行测试。 第一阶段（第1年）的目的是：1）免费和LPC结合的GMP友好公式 三功能肽GA31和GE31在体外，以及2）自由测试和LPC结合的三功能肽GA31 和CIA小鼠模型中的GE31。将使用针对GMP友好的微流体方法来制备肽-LPC。 第二阶段（第2和3年）的目的是：1）开发LC-MS测定法以测量血液中的GA31和GE31，2） 确定自由和LPC结合肽GA31和GE31的药代动力学，然后选择两个导线，3）测试 在AIM 2中鉴定为单一疗法，在两个类风湿的动物模型中鉴定为单一疗法和方法特征 关节炎和4）在毒理学研究中进一步测试铅，并选择IIB期的主要候选者。 后续IIB将包括测试其他管理（例如，透皮）和组合（例如， 泼尼松）方案，进一步优化铅及其制造技术，托克斯，adme，cmc 和其他辅助研究。完成后，将提交IND申请。最终产品将 代表安全稳定的RA疗法。 GF9治疗的安全性支持其预期的安全性 治疗了健康和艺术的老鼠。 Signablok的LPC原型在人类中的耐受性良好。 trem-1 Signablok竞争对手的肽LR12在健康和化粪池受试者中安全且耐受性良好。