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：
10647744
负责人：
ALEXIS R. DEMONBREUN
金额：
$ 56.53万
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/10647744
关键词：
Affinity Animal Model Antibodies Antibody Therapy Antibody-mediated protection Binding Biodistribution Biological Biological Assay Biological Markers Biological Response Modifier Therapy Breathing 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 Predisposition Process Production Proteins Proteolysis Qualifying Recovery Regulation Research Contracts Route Scheme Serum Signal Transduction Steroids Surrogate Markers Therapeutic Tissues Toxicokinetics Toxicology Transforming Growth Factor beta Variant Walking Wasting Syndrome absorption boys candidate identification 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 latent TGF-beta binding protein lead optimization manufacture mdx mouse mouse model muscle regeneration neuromuscular nonhuman primate permanent cell line pharmacodynamic biomarker pharmacokinetics and pharmacodynamics pre-Investigational New Drug meeting 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.

项目摘要神经肌肉疾病通常是可遗传的，通常会导致力量逐渐丧失和无能为力站立，走路和呼吸。 Duchenne肌肉营养不良（DMD）是一种遗传性神经肌肉疾病引起的由于肌营养不良蛋白的丧失，它使肌肉膜极易受到损伤。现在，有限的疗法可用于纠正DMD或延迟疾病中的神经肌肉缺陷尽管最近已批准了许多治疗方法或正在临床试验中进行进展。尽管如此成功，这些治疗仅适用于少数患者，并且效率有限。潜 TGF-β结合蛋白4（LTBP4）被发现是使用A肌营养不良的遗传修饰剂无偏的基因组屏幕。随后证明它在人类中具有相似的遗传修饰信号 DMD患者。 LTBP4蛋白本地定位于肌外移，其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下游信号传导。过量的TGF-β激活是许多形式的神经肌肉的病理发现疾病，尤其是DMD，肢体肌肉营养不良和先天性肌营养不良的疾病。在肌肉营养不良，超过或过度激活的TGF-β与肌肉的纤维化浸润和受损有关肌肉再生。遗传数据用于识别LTBP4的铰链区域对潜在至关重要 TGF-β释放和激活。 LTBP4的铰链区域可以蛋白水解裂解，并且这种裂解促进潜在TGF-β的释放，然后通过其他步骤充分激活。遗传保护小鼠中LTBP4的形式不易受到蛋白酶裂解的影响，与正常的降低相关肌肉营养不良中的多动性TGF-β态，这与营养不良的进展相关。在人类，LTBP4的受保护作用与三个独立的DMD队列中的较长的野蛮性相关。我们设计了一种稳定LTBP4铰链并限制潜在的TGF-β释放的抗体策略。证明 DMD的MDX小鼠模型中的概念数据表明，针对铰链的抗LTBP4抗体区域可用于减轻疾病进展。抗LTBP4铰链区域抗体免受 LTBP4裂解，纤维化的形成减少以及肌肉损伤后的恢复增强。该提案概述了铅LTBP4生物学用于治疗神经肌肉疾病的发展计划分为两种阶段。第1阶段的第一个目的旨在优化铅LTBP4生物学并评估短期优化导线的体内效率。第1阶段的第二个目的是验证药效生物标志物测定。第二阶段的目标1将重点介绍临床前研究和制造计划，而AIM 2将把临床候选人纳入生物武器的早期发展和IND归档。