Development of anti-LTBP4 as a biologic to treat Neuromuscular Diseases

开发抗 LTBP4 作为治疗神经肌肉疾病的生物制剂

基本信息

批准号：
10467836
负责人：
ALEXIS R. DEMONBREUN
金额：
$ 149.49万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467836
关键词：
Affinity Animal Model Antibodies Antibody Therapy Binding Binding Proteins Biodistribution Biological Biological Assay Biological Markers Biological Response Modifier Therapy Cell model Cells Chemicals Chemistry Clinical Trials Creatine Kinase Data Defect Development Disease Disease Progression Dose Drug Kinetics Duchenne muscular dystrophy Dystrophin Enzyme-Linked Immunosorbent Assay Excretory function Fibrosis Formulation Generations Genes Genetic Growth Heritability Human Hyperactivity Impairment In Vitro Infiltration Inherited Injury Lead Legal patent Limb-Girdle Muscular Dystrophies Link Magnetic Resonance Imaging Measures Membrane Metabolism Modeling Mus Muscle Muscle Weakness Muscle function Muscular Atrophy Muscular Dystrophies Myopathy Natural regeneration Neuromuscular Diseases No-Observed-Adverse-Effect Level Pathologic Pathway interactions Patients Peptide Hydrolases Performance Pharmacodynamics Phase Process Production Proteins Proteolysis Recovery Regulation Research Contracts Route Scheme Serum Signal Transduction Steroids Surrogate Markers Therapeutic Tissues Toxicokinetics Toxicology Variant Walking Wasting Syndrome absorption base boys clinical candidate cohort congenital muscular dystrophy cross reactivity cytotoxicity design efficacy study exon skipping gene replacement therapy gene therapy genetic variant genome-wide good laboratory practice improved improved outcome in vitro Assay in vivo injury recovery lead optimization mdx mouse meetings mouse model muscle regeneration neuromuscular nonhuman primate permanent cell line pharmacodynamic biomarker pharmacokinetics and pharmacodynamics pre-clinical preclinical study protective effect repaired scale up standard of care success tool

项目摘要

PROJECT SUMMARY Neuromuscular disorders are often heritable and typically result in progressive loss of strength and inability to stand, walk, and breathe. Duchenne Muscular Dystrophy (DMD) is a inherited neuromuscular disorder caused by the loss of dystrophin protein, which renders the muscle membrane highly susceptible to injury. Currently, there are limited therapies available to correct the neuromuscular defects in DMD or delay disease progression, although a number of treatments have been recently approved or are in clinical trials. Despite this success, these treatments are only available to small percentage of patients and have limited efficacy. Latent TGF-β Binding Protein 4 (LTBP4) was discovered as a genetic modifier of muscular dystrophy using an unbiased genomewide screen. It was subsequently shown to have a similar genetic modifying signal in human DMD patients. LTBP4 protein localizes to the myofiber exterior where it binds and sequesters all three forms of TGF-β, regulating latent TGF-β release and activation and its subsequent cascade of pathological downstream signaling. Excess TGF-β activation is a pathological finding in many forms of neuromuscular disease, especially DMD, the limb girdle muscular dystrophies and the congenital muscular dystrophies. In the muscular dystrophies, excess or hyper-activated TGF-β is linked to fibrotic infiltration of muscle and impaired muscle regeneration. The genetic data was used to identify the hinge region of LTBP4 as critical to latent TGF-β release and activation. LTBP4's hinge region can be proteolytically cleaved and this cleavage promotes release of latent TGF-β, which is then fully activated by additional steps. The genetically protective form of LTBP4 in mice is less susceptible to protease cleavage, correlating with a decrease of the normally hyperactive TGF-β state in muscular dystrophy, and this correlates with delayed dystrophy progression. In humans, the protective effect of LTBP4 correlated with longer ambulation in three independent DMD cohorts. We devised an antibody strategy to stabilizes the LTBP4 hinge and limit latent TGF-β release. Proof of concept data in the mdx mouse model of DMD demonstrates that an anti-LTBP4 antibody directed at the hinge region can be used to mitigate disease progression. Anti-LTBP4 hinge region antibodies protected against LTBP4 cleavage, reduced fibrosis formation, and enhanced recovery after muscle injury. This proposal outlines the developmental plan of a lead LTBP4 biologic for the treatment of neuromuscular disorders split into two phases. The first aim of phase 1 is designed to optimize the lead LTBP4 biologic and evaluate short-term in vivo efficacy of the optimized leads. The second aim of phase 1 is to validate pharmacodynamic biomarker assays. Aim 1 of the second phase will focus on pre-clinical studies and initiation of manufacturing, while aim 2 will progress the clinical candidate into BioPharm Early Development and IND filing.

项目概要神经肌肉疾病通常具有遗传性，通常会导致力量逐渐丧失和无法活动。杜氏肌营养不良症 (DMD) 是一种遗传性神经肌肉疾病。目前，肌营养不良蛋白的丢失导致肌肉膜极易受到损伤。用于纠正 DMD 神经肌肉缺陷或延缓疾病的治疗方法有限尽管许多治疗方法最近已获得批准或正在进行临床试验，但进展仍在继续。尽管这些治疗方法取得了成功，但仅适用于一小部分患者，而且疗效有限。 TGF-β 结合蛋白 4 (LTBP4) 被发现是肌营养不良症的遗传修饰剂随后进行的无偏基因组筛选显示其在人类中具有类似的基因修饰信号。 DMD 患者的 LTBP4 蛋白定位于肌纤维外部，在此结合并隔离所有三种形式。 TGF-β，调节潜在的 TGF-β 释放和激活及其随后的病理级联反应下游信号传导过度是许多形式的神经肌肉的病理学发现。疾病，特别是 DMD、肢带型肌营养不良症和先天性肌营养不良症。肌营养不良症、过量或过度激活的 TGF-β 与肌肉纤维化浸润和受损有关遗传数据被用来确定 LTBP4 的铰链区对于潜在的至关重要。 TGF-β 的释放和激活可以通过蛋白水解方式裂解 LTBP4 的铰链区。促进潜在 TGF-β 的释放，然后通过其他步骤将其完全激活。小鼠体内的 LTBP4 形式不易受到蛋白酶裂解的影响，这与正常情况下 LTBP4 的减少相关。肌营养不良症中 TGF-β 过度活跃，这与肌营养不良症进展延迟相关。在人类中，LTBP4 的保护作用与三个独立 DMD 队列中较长的步行时间相关。我们设计了一种抗体策略来稳定 LTBP4 铰链并限制潜在的 TGF-β 释放。 DMD mdx 小鼠模型中的概念数据表明，针对铰链的抗 LTBP4 抗体区域可用于减缓疾病进展。该提案概述了 LTBP4 裂解、减少纤维化形成和增强肌肉损伤后的恢复。用于治疗神经肌肉疾病的先导 LTBP4 生物制剂的开发计划分为两部分第一阶段的首要目标是优化先导 LTBP4 生物制剂并评估短期疗效。第一阶段的第二个目标是验证药效生物标志物的体内功效。第二阶段的目标 1 将侧重于临床前研究和启动生产，而目标 1 将侧重于临床前研究和启动生产。 2 将把临床候选药物推进 BioPharm 早期开发和 IND 备案。