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

项目总结 神经肌肉疾病通常是可遗传的，通常会导致进行性力量丧失和无法 站立、行走和呼吸。杜氏肌营养不良症(DMD)是一种遗传性神经肌肉疾病 由于肌营养不良蛋白的丢失，使肌肉膜对损伤高度敏感。目前， 纠正DMD的神经肌肉缺陷或延迟疾病的治疗方法有限。 进展，尽管一些治疗方法最近已获得批准或正在进行临床试验。尽管如此 如果成功，这些治疗方法只对一小部分患者有效，而且疗效有限。潜伏期 转化生长因子-β结合蛋白4(LTBP4)被发现是肌营养不良症的遗传修饰物。 无偏见的全基因组屏幕。随后发现它在人类身上也有类似的遗传修饰信号。 DMD患者。LTBP4蛋白定位于肌纤维的外部，在那里它结合和隔离所有三种形式 转化生长因子-β，调节潜在转化生长因子-β的释放和激活及其随后的病理级联 下行信令。转化生长因子-β过度激活是许多形式的神经肌肉组织的病理发现。 疾病，特别是DMD、四肢带状肌营养不良和先天性肌营养不良。在 肌营养不良、过度或过度激活的转化生长因子-β与肌肉纤维化浸润和受损有关 肌肉再生。遗传数据被用来确定LTBP4的铰链区对潜伏期至关重要 转化生长因子-β的释放和激活。LTbP4‘S铰链区可以被蛋白水解性切割，这种切割 促进潜在的转化生长因子-β的释放，然后通过额外的步骤完全激活。受基因保护的 小鼠体内的LTBP4形式不太容易被蛋白酶切割，这与正常的 肌营养不良中转化生长因子-β的过度活跃状态，并与延迟性营养不良进展相关。在……里面 在三个独立的DMD队列中，LTBP4的保护作用与较长的步行时间相关。 我们设计了一种抗体策略来稳定LTBP4铰链并限制潜在的转化生长因子-β的释放。证明 DMD的MDX小鼠模型中的概念数据表明，抗LTBP4抗体指向铰链 区域可以用来减缓疾病的进展。抗LTBP4铰链区抗体保护作用 LTBP4裂解，减少纤维化形成，促进肌肉损伤后的恢复。这份提案概述了 一种治疗神经肌肉疾病的先导生物LTBP4的研制方案 阶段。第一阶段的第一个目标是优化Lead LTBP4生物并在短期内评估 优化后的引线的体内药效。第一阶段的第二个目标是验证药效学生物标记物 化验。第二阶段的目标1将集中在临床前研究和开始生产，而AIM 2将使临床候选人进入生物制药早期开发和IND备案。

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.