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.

项目概要/摘要 类风湿性关节炎 (RA) 是一种慢性全身性炎症性疾病，可导致慢性炎症 关节问题影响着大约 150 万美国人，每年给社会造成的损失超过 400 亿美元。尽管 随着治疗的进步，RA 无法治愈，30-40% 的 RA 患者对一线治疗没有反应 RA——甲氨蝶呤（MTX），强调了对新疗法的需求。该项目的长期目标是 开发一种新颖、一流、高效且耐受性良好的 RA 疗法。 TREM-1 在滑膜巨噬细胞上的过度表达以及 TREM-1 的丰度和激活 RA 患者滑膜中的巨噬细胞与 RA 的严重程度相关。目前的 TREM-1 抑制剂 所有这些都试图阻止不确定配体与 TREM-1 的结合。为了最大限度地降低临床失败风险，我们 开发了一种配体独立的 TREM-1 抑制肽 GF9、GA31 和 GE31，可配制 转化为巨噬细胞特异性脂肽复合物（LPC），以延长半衰期并降低脱靶风险。 之前，我们表明：1）在 CIA 小鼠中，GF9 疗法可减少全身炎症并抑制 关节炎与0.1mg/kg地塞米松一样有效，广泛应用于RA的临床治疗； 2）GF9 治疗在体外和体内减少细胞因子释放（TNFα、IL-1β、IL-6 和 CSF-1）高达 5 倍，同时 对照肽没有作用； 3) GF9、GF9-LPC和GA/E31-LPC无毒且小鼠耐受性良好 至少高达 300 毫克 GF9/kg； 4)将GF9配制成LPC可减少80％的有效剂量。 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，以供使用 单独或与 MTX 一起作为诱导/维持治疗。将测试全身和口服递送。 第一阶段（第一年）的目标是：1) 制备和测试游离和 LPC 结合的 GMP 友好配方 体外三功能肽 GA31 和 GE31，以及 2) 测试游离和 LPC 结合的三功能肽 GA31 和 CIA 小鼠模型中的 GE31。将使用 GMP 友好的微流体方法来制备肽-LPC。 II 期（第 2 年和第 3 年）的目标是：1) 开发一种 LC-MS 检测方法来测量血液中的 GA31 和 GE31，2) 确定游离肽和 LPC 结合肽 GA31 和 GE31 的药代动力学并选择两个先导物，3) 测试 在两个类风湿动物模型中，Aim 2 中确定了两条线索作为单一疗法和甲氨蝶呤疗法 关节炎，4) 在毒理学研究中进一步测试先导化合物，并选择 IIb 期的先导候选药物。 后续 IIb 期将包括测试其他给药方式（例如透皮给药）和联合给药（例如 泼尼松）方案，进一步优化先导物及其制造技术、TOX、ADME、CMC 以及其他支持 IND 的研究。完成后，将提交 IND 申请。最终产品将 代表了安全稳定的 RA 治疗。其预期的安全性得到了 GF9 治疗长期安全性的支持。 治疗健康和关节炎小鼠。 SignaBlok 的 LPC 原型在人类中具有良好的耐受性。特雷姆-1 SignaBlok 竞争对手的肽 LR12 的阻断在健康和脓毒症受试者中是安全且耐受性良好的。