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 类风湿性关节炎(RA)是一种慢性全身性炎症性疾病，可引起慢性炎症 这些关节影响了大约150万美国人，每年给社会造成超过400亿美元的损失。尽管 治疗进展：类风湿关节炎无法治愈，30%-40%的类风湿关节炎患者对一线治疗无效 对RA-甲氨蝶呤(MTX)的研究，突出了新疗法的必要性。这个项目的长期目标是 开发一种新的、一流的、有效的、耐受性好的类风湿关节炎治疗方法。 TREM-1在滑膜巨噬细胞上的过表达及其活性和丰度的研究 RA患者滑膜中的巨噬细胞与RA的严重程度相关。目前使用的TREM-1抑制剂 都试图阻止不确定的配体(S)与TREM-1的结合。为了尽量减少临床失败的风险，我们 开发出可配制的非配体依赖的TREM-1抑制肽GF9、GA31和GE31 转化为巨噬细胞特异性脂肽复合体(LPC)，以改善半衰期并降低偏离目标的风险。 此前，我们发现：1)在CIA小鼠中，GF9治疗减少了全身炎症并抑制了 关节炎与0.1 mg/kg地塞米松一样有效，广泛用于RA的临床治疗；2)GF9 治疗将细胞因子(肿瘤坏死因子α、白介素1β、白介素6和脑脊液1)在体外和体内的释放减少多达5倍，而 3)GF9、GF9-LPC和GA/E31-LPC无毒，对小鼠耐受性好 至少高达300毫克GF9/公斤；4)将GF9配制成LPC可使有效剂量减少80%。 该项目的目标是进一步开发这种一流的耐受性良好的TREM-1疗法。 单独或联合甲氨蝶呤作为诱导/维持治疗。将对全身分娩和口头分娩进行测试。 第一阶段(第1年)的目标是：1)制备和测试自由和LPC结合的GMP友好配方 三功能多肽GA31和GE31的体外实验，以及2)游离和LPC结合的三功能多肽GA31 中情局小鼠模型中的GE31。将采用GMP友好的微流控方法制备多肽-LPC。 第二阶段(第2年和第3年)的目标是：1)建立测定血液中GA31和GE31的LC-MS分析方法；2) 测定游离和LPC结合肽GA31和GE31的药代动力学，并选择两个引线，3)试验 在两种类风湿动物模型中，AIM 2中确定的两个导联为单一疗法和甲氨蝶呤 关节炎，以及4)在毒理学研究中进一步测试这些铅，并选择第二阶段b的主要候选者。 后续阶段IIb将包括测试其他给药(例如透皮)和联合给药(例如， 强的松)方案，铅及其制造工艺的进一步优化，TOX，ADME，CMC 以及其他支持IND的研究。完成后，将提交IND申请。最终的产品将是 代表安全稳定的类风湿关节炎治疗。其预期的安全性得到了GF9治疗的安全性的支持 治疗健康和关节炎的小鼠。SignaBlok的LPC原型在人类中具有很好的耐受性。TREM-1 SignaBlok竞争对手的肽LR12的阻滞剂在健康和败血症患者中是安全和耐受性良好的。