First-in-class TREM-1 inhibitors for neovascular retinal diseases

用于治疗新生血管性视网膜疾病的一流 TREM-1 抑制剂

基本信息

批准号：
10597284
负责人：
Alexander B Sigalov
金额：
$ 27.81万
依托单位：
SIGNABLOK, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10597284
关键词：
Achievement Adult Affect Angiogenesis Inhibitors Animal Model Antiinflammatory Effect Apolipoprotein A-I Area Arthritis Binding Biodistribution Biological Assay Blindness Blood Vessels CSF1 gene Cell Therapy Child Clinical Complex Data Development Diabetic Retinopathy Disease Dose Drug Delivery Systems Drug Kinetics Drug or chemical Tissue Distribution Eye diseases Failure Filtration Formulation France Friends Goals Half-Life Histology Human Hypoxia In Vitro Inflammation Interleukin-1 beta Interleukin-6 Intraperitoneal Injections Lasers Lead Ligands Macrophage Macrophage Colony-Stimulating Factor Malignant Neoplasms Maximum Tolerated Dose Measures Modeling Mus Myeloid Cells Oxygen Pathologic Pathologic Neovascularization Pathology Peptides Persons Pharmaceutical Preparations Phase Phenotype Plasma Premature Infant Preparation Procedures Rattus Regimen Research Retina Retinal Diseases Retinal Neovascularization Retinal Vein Occlusion Retinopathy of Prematurity Risk Safety Signal Pathway Systemic Therapy TNF gene Techniques Testing Therapeutic Therapeutic Effect Tissues Toxicology Vascular Endothelial Growth Factors Vision Disorders conventional therapy cost cytokine efficacy testing follow-up improved in vivo in vivo evaluation inhibitor innovation intravenous injection mouse model neovascular novel novel therapeutics overexpression peptide I prevent protein aminoacid sequence prototype receptor response septic side effect

项目摘要

Project Summary/Abstract Retinal neovascularization (RNV) is a major cause of vision loss in retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion. In the US, about 16,000 of premature infants are affected by ROP annually and about 4.1 million adults years have DR. Complications of conventional treatments suggest an unmet need for new therapies. The long-term objective of this project is to develop a systemic, new mechanism-based, efficient and well-tolerable therapy for ROP and other RNV diseases. Triggering receptor expressed on myeloid cells (TREM-1) is upregulated upon inflammation and is involved in angiogenic signaling pathways, suggesting TREM-1 as a promising target for treatment of RNV. Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To minimize clinical failure risks, we developed well-tolerable TREM-1 inhibitory peptides GF9 and GA31 that employ a novel, ligand-independent mechanism of action. They can be used in a free form or formulated in macrophage-specific lipopeptide complexes (LPC) to improve half-life and reduce off-target risks. Previously, we showed that ligand-independent TREM-1 blockade using either a free (GF9) or LPC- formulated peptide (GA31-LPC): 1) prevents and treats RNV in mice with oxygen-induced retinopathy (OIR); 2) improves vessel sprouting during hypoxia, 3) inhibits retinal TREM-1 and CSF-1 expression, and 4) reduces cytokine release (TNFα, IL-1β, IL-6 and CSF-1) in vitro, while control peptides have no effect. The goal of the proposed project is to further develop this first-in-class TREM-1 therapy for neovascular retinal diseases. Considering pros and cons of GF9 and GA31-LPC, we suggest to start with both leads. Due to differences in the manifestation of vascular phenotypes, we suggest to use both OIR mice and rats. Phase I aims are to: 1) generate GMP-compliant formulations of free GF9 and GA31-LPC and test them in vitro, and 2) test the developed formulations of GF9 and GA31-LPC in the OIR mouse model. GMP-friendly tangential flow filtration technique to prepare GA31-LPC will be explored. Phase II aims are to: 1) develop an LC-MS-assay to measure GF9 and GA31 in ocular tissues, 2) test pharmacokinetics and ocular tissue distribution of GF9 and GA31-LPC in vivo, 3) test the preventative and therapeutic effects of GF9 and GA31-LPC in two OIR models and select the lead, and 4) test the lead in non-clinical toxicology studies. Comprehensive histology/IHC will be performed. Cytokines will be tested. Follow-up Phase IIb will include other administration and combination (eg, laser + GF9) regimens, GLP- TOX, ADME, CMC and other IND-enabling studies. The final product will represent safe and stable systemic therapy. Its anticipated safety is supported by safety of GF9 therapy in long-term treated healthy, cancer and arthritic mice. Prototypes of SignaBlok's LPC are well-tolerated in humans. TREM-1 blockade by SignaBlok competitor's peptide LR12 (Inotrem) is safe and well-tolerated in healthy and septic subjects.

项目概要/摘要视网膜新生血管（RNV）是早产儿视网膜病变（ROP）视力丧失的主要原因，糖尿病视网膜病变 (DR) 和视网膜静脉阻塞在美国，大约有 16,000 名早产儿患有糖尿病视网膜病变 (DR) 和视网膜静脉阻塞。每年约有 410 万名成年人受到 ROP 的影响，患有传统 DR 并发症。治疗表明对新疗法的需求尚未得到满足。该项目的长期目标是开发一种新疗法。针对ROP和其他RNV疾病的系统的、基于新机制的、高效且耐受性良好的治疗。骨髓细胞上表达的触发受体 (TREM-1) 在炎症时上调，并且参与血管生成信号通路，表明 TREM-1 作为 RNV 治疗的有希望的靶点。目前的 TREM-1 抑制剂都试图阻止 TREM-1 与其仍不确定的配体的结合。为了最大限度地降低临床失败风险，我们开发了耐受性良好的 TREM-1 抑制肽 GF9 和 GA31，它们采用一种新颖的、不依赖于配体的作用机制。巨噬细胞特异性脂肽复合物 (LPC) 可延长半衰期并降低脱靶风险。之前，我们展示了使用游离（GF9）或LPC-的配体独立的TREM-1阻断配方肽 (GA31-LPC)：1) 预防和治疗患有氧诱导性视网膜病变的小鼠 RNV (OIR)；2) 改善缺氧期间的血管萌芽，3) 抑制视网膜 TREM-1 和 CSF-1 表达，以及 4) 减少体外细胞因子释放（TNFα、IL-1β、IL-6 和 CSF-1），而对照肽则没有影响。该项目的目标是进一步开发这种首创的 TREM-1 新生血管疗法考虑到 GF9 和 GA31-LPC 的优缺点，我们建议从这两种导联开始。由于血管表型表现的差异，我们建议同时使用 OIR 小鼠和大鼠。第一阶段的目标是：1) 生成符合 GMP 要求的游离 GF9 和 GA31-LPC 配方并进行测试 2) 在 OIR 小鼠模型中测试开发的 GF9 和 GA31-LPC 制剂。将探索 GMP 友好的切向流过滤技术来制备 GA31-LPC。第二阶段的目标是：1) 开发 LC-MS 测定法来测量眼组织中的 GF9 和 GA31，2) 测试 GF9和GA31-LPC在体内的药代动力学和眼组织分布，3)测试预防性和 GF9和GA31-LPC在两种OIR模型中的治疗效果并选择先导，4)测试先导将进行综合组织学/免疫组化研究。后续 IIb 期将包括其他给药和组合（例如激光 + GF9）方案、GLP- TOX、ADME、CMC 和其他支持 IND 的研究最终产品将代表安全和稳定。其预期的安全性得到了 GF9 治疗在长期治疗的健康人群中的安全性的支持。 SignaBlok 的 LPC 原型在人类中具有良好的耐受性。 SignaBlok 竞争对手的肽 LR12 (Inotrem) 在健康和脓毒症受试者中是安全且耐受性良好的。