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; 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.

项目摘要/摘要 视网膜新血管形成（RNV）是视网膜早产（ROP）的视力丧失的主要原因， 糖尿病性视网膜病（DR）和视网膜静脉阻塞。在美国，大约16,000名早产儿 每年受ROP的影响，大约有410万成年人有DR。常规并发症 治疗表明对新疗法的需求未满足。该项目的长期目标是开发 针对ROP和其他RNV疾病的全身性，新机制，高效且易溶解的疗法。 注射后更新在髓样细胞上表达的受体（TREM-1），为 参与血管生成信号通路，表明TREM-1是RNV治疗的有希望的靶标。 当前的TREM-1抑制剂都试图阻止TREM-1与其仍然不确定的配体的结合。到 最小化临床衰竭风险，我们开发了易忍受的Trem-1抑制性辣椒GF9和GA31 员工是一种新颖的，独立于配体的作用机制。它们可以以自由形式使用或在 巨噬细胞特异性的脂肽复合物（LPC）改善半衰期并降低脱靶风险。 以前，我们证明了使用自由（GF9）或LPC-的非配体无关TREM-1阻断。 配方肽（GA31-LPC）：1）用氧诱导的视网膜病变预防和治疗RNV （oir）; 2）改善缺氧期间血管发芽，3）抑制残留的TREM-1和CSF-1表达，以及 4）在体外减少细胞因子释放（TNFα，IL-1β，IL-6和CSF-1），而对照肽无效。 拟议项目的目的是进一步开发这种新的trem-1疗法用于新生血管 视网膜疾病。考虑到GF9和GA31-LPC的优缺点，我们建议从这两个潜在客户开始。 由于血管表型的表现差异，我们建议同时使用OIR小鼠和大鼠。 第一阶段的目的是：1）生成免费GF9和GA31-LPC的GMP兼容公式和测试 它们在体外，以及2）在OIR小鼠模型中测试GF9和GA31-LPC的开发公式。 将探索针对GMP友好的切向流动过滤技术来准备GA31-LPC。 第二阶段的目的是：1）开发一个LC-MS-测定以测量眼组织中的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在两个OIR模型中的治疗作用，然后选择铅，4）测试铅中的铅 非临床毒理学研究。将进行全面的组织学/IHC。细胞因子将进行测试。 随访期IIB将包括其他给药和组合（例如，激光 + GF9）方案，GLP- TOX，ADME，CMC和其他辅助研究。最终产品将代表安全稳定 全身疗法。 GF9治疗在长期治疗健康中的安全性支持，其预期的安全性支持 癌症和关节性小鼠。 Signablok的LPC的原型在人类中具有良好的耐受性。 TREM-1封锁 通过Signablok竞争对手的肽LR12（INOTREM）在健康和化粪池受试者中安全且耐受性良好。