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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.

项目总结