TREM-1 inhibitor for the treatment of scleroderma

项目总结/摘要 硬皮病包括局限性硬皮病（LS）和系统性硬化症（SSc）是一种罕见的， 毁灭性的自身免疫性疾病目前的疗法都有副作用，是有限的，并与10 年生存率为55%，表明需要新的方法。该项目的长期目标是 开发一种新的机制为基础的，有效的和耐受性良好的硬皮病治疗。 髓样细胞上表达的触发受体1（TREM-1），一种炎症放大器，有助于 SSc中纤维化的发展。在患者中，纤维化区域中活化的巨噬细胞的数量是 增加并与纤维化严重程度相关。TREM-1的激活导致MCP-1的过度产生。 1/CCL2和M-CSF/CSF-1，导致巨噬细胞募集到损伤区域和硬化病变 硬皮病大鼠中的形成。在动物模型中，TREM-1阻断抑制炎症和炎症反应。 改善多种自身免疫性疾病。"概念验证"第一阶段的假设是， TREM-1阻断剂可以预防和治疗硬皮病。 目前的TREM-1抑制剂都试图阻断TREM-1与其仍不确定的配体的结合。到 为了最大限度地降低临床开发失败的风险，我们开发了一流的配体非依赖性TREM-1 抑制肽GF9，耐受性良好，可配制成SignaBlok的长半衰期 巨噬细胞特异性脂肽复合物（LPC），以改善其半衰期并靶向炎症 地区I期研究的主要目标是显示GF9-LPC阻断TREM-1可使TREM-1的表达降低。 在博莱霉素（BLM）诱导的硬皮病小鼠模型中观察到的疾病。 I期具体目标是：1）优化TREM-1抑制组合物的体外功能 和药代动力学在体内，并选择铅，2）测试两个剂量的铅选择在BLM诱导的 硬皮病小鼠模型。我们将根据其功能生成、优化和选择潜在客户， 体外和体内PK特征。我们将测试两种剂量的铅预防和治疗肺部疾病的能力， 在体内多器官纤维化小鼠模型中的心脏、肌肉和皮肤纤维化。组织学/IHC研究将 执行。将分析血清和组织MCP-1、CSF-1、VEGF、TGF β、TNF α、IL-6和IL-1 β。 预计I期研究将确定一种新的、一流的、耐受性良好的药物， 开发有效且耐受性良好的系统性硬皮病治疗的强大平台，从而 改善患者的治疗和生存。其预期的安全性得到了以下良好耐受性的支持： SignaBlok的基于GF9的制剂通过长期处理的小鼠进行。SignaBlok的LPC原型很好 在人类中被容忍。通过SignaBlok竞争者的抑制肽LR12（Inotrem， 法国）在健康和脓毒症受试者中是安全的。如果成功，第一阶段之后将是第二阶段， 毒理学、ADME、药理学和CMC研究，提交IND和后续人体评价。

Project Summary/Abstract 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, TGFβ, TNFα, IL-6, and IL-1β 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.