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

• 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
• 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

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.

项目总结/摘要 视网膜新生血管（RNV）是早产儿视网膜病变（ROP）中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 每年约有410万成年人患有DR。 治疗表明对新疗法的需求未得到满足。该项目的长期目标是开发一个 为ROP和其他RNV疾病提供了系统的、基于新机制的、有效的和耐受性良好的治疗。 在骨髓细胞上表达的触发受体（TREM-1）在炎症时上调，并且在炎症后表达。 参与血管生成信号通路，表明TREM-1是治疗RNV的有希望的靶点。 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 为了使临床失败风险最小化，我们开发了耐受性良好的TREM-1抑制肽GF 9和GA 31， 采用一种新的，配体独立的作用机制。它们可以以游离形式使用或配制成 巨噬细胞特异性脂肽复合物（LPC），以改善半衰期和降低脱靶风险。 以前，我们表明使用游离（GF 9）或LPC-1阻断配体非依赖性TREM-1， 配制的肽（GA 31-LPC）：1）预防和治疗患有氧诱导的视网膜病变的小鼠中的RNV (OIR)3）抑制视网膜TREM-1和CSF-1表达，和 4)在体外减少细胞因子释放（TNFα、IL-1β、IL-6和CSF-1），而对照肽没有作用。 拟议项目的目标是进一步开发这种一流的TREM-1疗法，用于新生血管 视网膜疾病考虑到GF 9和GA 31-LPC的利弊，我们建议从两种电极导线开始。 由于血管表型表现的差异，我们建议使用OIR小鼠和大鼠。 阶段I的目标是：1）产生游离GF 9和GA 31-LPC的符合GMP的制剂，并测试 2）在OIR小鼠模型中测试所开发的GF 9和GA 31-LPC制剂。 将探索GMP友好的切向流过滤技术来制备GA 31-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GF 9和GA 31，2）测试 体内GF 9和GA 31-LPC的药代动力学和眼组织分布，3）测试预防性和 在两种OIR模型中观察GF 9和GA 31-LPC的治疗作用并筛选出先导物; 非临床毒理学研究。将进行全面的组织学/IHC。将检测细胞因子。 IIb期随访将包括其他给药和联合（例如，激光+GF 9）方案，GLP- TOX、ADME、CMC和其他IND赋能研究。最终产品将代表安全稳定 全身治疗其预期的安全性得到了GF 9疗法在长期治疗的健康， 癌症和关节炎小鼠。SignaBlok的LPC原型在人类中耐受良好。TREM-1阻断 SignaBlok竞争者的肽LR 12（Inotrem）在健康和脓毒症受试者中安全且耐受良好。