TREM-1 inhibitor for the treatment of scleroderma

TREM-1抑制剂用于治疗硬皮病

• 批准号: 10079840
• 负责人: Alexander B Sigalov
• 金额: $ 24.96万
• 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: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079840
• 关键词: Affect; Amplifiers; Animal Model; Animals; Area; Arthritis; Autoimmune Diseases; Binding; Biological Assay; Bleomycin; Body Weight Changes; CCL2 gene; Cells; Chronic; Clinic; Collagen Arthritis; Complex; Data; Development; Disease; Dose; Drug Kinetics; Evaluation; Failure; Female of child bearing age; Fibrosis; Formulation; France; Goals; Half-Life; Histologic; Histology; Human; In Vitro; Infection; Inflammation; Injectable; Interleukin 6 Receptor; Interleukin-1 beta; Interleukin-6; Lead; Lesion; Life; Ligands; Lipids; Liver diseases; Localized scleroderma; Lung; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mediating; Morbidity - disease rate; Mus; Muscle; Musculoskeletal Diseases; Myeloid Cells; Myocardium; Organ; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Platelet-Derived Growth Factor; Play; Population; Pulmonary Fibrosis; Rattus; Research; Rheumatism; Risk; Role; Safety; Scleroderma; Sepsis; Serum; Severities; Site; Skin; Subcutaneous Injections; Systemic Scleroderma; TNF gene; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Toxicology; Transforming Growth Factor beta; Vascular Endothelial Growth Factors; base; clinical development; cytokine; disability; immunomodulatory therapies; improved; in vivo; in vivo evaluation; indium-bleomycin; inhibitor/antagonist; injured; innovation; lead optimization; macrophage; mortality; mouse model; novel; novel strategies; novel therapeutics; phase 1 study; prevent; prototype; receptor; recruit; risk minimization; septic; side effect; skin disorder; skin fibrosis; targeted treatment; uptake

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.

项目摘要/摘要 包括局限性硬皮病(LS)和系统性硬皮病(SSC)的硬皮病是一种罕见的 毁灭性的自身免疫性疾病。目前的治疗方法都有副作用，都是有限的，并与10 一年的存活率为55%，表明需要新的方法。这个项目的长期目标是 开发一种基于机制的、高效的、耐受性良好的硬皮病治疗方法。 触发髓样细胞上表达的受体1(TREM-1)是一种炎症放大因子，有助于 SSC纤维化的发生发展。在患者中，纤维化区域中激活的巨噬细胞数量为 增加并与纤维化严重程度相关。TREM-1的激活导致MCP-1的过度生产 1/CCL2和M-CSF/CSF-1，导致巨噬细胞重新聚集到损伤区域和硬化病变 硬皮病大鼠的形成。在动物模型中，TREM-1阻断可抑制炎症和 改善多种自身免疫性疾病。“概念验证”阶段第一阶段的假设是 TREM-1阻滞剂可预防和治疗硬皮病。 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(S)。至 在临床开发中将失败风险降至最低，我们开发了一流的配体非依赖性TREM-1 耐受性好的抑制肽GF9可制成SignaBlok的长半衰期 巨噬细胞特异性脂肽复合体(LPC)改善其半衰期和抗炎作用 区域。第一阶段研究的主要目标是证明GF9-LPC阻断TREM-1可以缓解 博莱霉素(BLM)诱导的硬皮病小鼠模型中的疾病。 第一阶段的具体目标是：1)优化TREM-1抑制组合物的体外功能 并在体内药代动力学和选择铅，2)试验两个剂量的铅选择在博莱姆诱导 硬皮病小鼠模型。我们将根据销售线索在中的功能生成、优化和选择销售线索 体外和体内的PK谱。我们将测试两种剂量的铅对肺部的预防和治疗能力， 小鼠体内多器官纤维化模型中的心脏、肌肉和皮肤纤维化。组织学/IHC研究将是 已执行。分析血清和组织中单核细胞趋化蛋白-1、脑脊液-1、血管内皮生长因子、转化生长因子β、肿瘤坏死因子α、白介素6和白介素1β。 预计第一阶段研究将确定一种新的、一流的、耐受性良好的制剂作为 为开发有效和耐受性良好的系统性硬皮病治疗提供了强大的平台，从而 提高患者的治疗水平和存活率。其预期的安全性得到了良好的耐受性的支持 SignaBlok的基于GF9的配方，用于长期治疗的小鼠。SignaBlok的LPC原型很好 在人类身上是可以容忍的。SignaBlok竞争对手抑制肽LR12(Inotrem， 法国)在健康和败血症受试者中是安全的。如果成功，第一阶段之后将在第二阶段 毒理学、ADME、药理学和CMC研究，提交IND和随后的人体评估。