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

Neuromuscular disorders are a large group of diseases that affect the nervous system and muscle, resulting in progressive muscle weakness. 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. Latent TGF- Binding Protein 4 (LTBP4) modifies muscular dystrophy in both mice and humans. LTBP4 localizes to the myofiber exterior where it binds and sequesters all three forms of TGF- , regulating TGF- activation and downstream signaling. Increased TGF- signaling has been documented in a number of diseases, including muscular dystrophies, and is linked to increased fibrosis formation and reduced muscle regeneration. Genetic studies illustrate that the hinge region of LTBP4 is susceptible to protease cleavage and this cleavage promotes release of TGF- . The protective form of LTBP4 in mice is less susceptible to protease cleavage, correlating with decreased TGF- activity and delayed dystrophy progression. In humans, the protective effect of LTBP4 was documented as prolonged ambulation in three independent Duchenne muscular dystrophy cohorts. A therapeutic that targets and stabilizes the LTBP4 hinge is an attractive mechanism as this would allow localized regulation of the TGF- pathway and is mutation agnostic. We have shown proof of concept data in the mdx mouse model of DMD, that an LTBP4 biologic can be used to mitigate disease progression. Specifically, antibodies raised against the LTBP4 hinge region, 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 LTBP4 biologic to a lead compound and evaluate short-term in vivo efficacy. 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 lead biologic candidate into BioPharm Early Development and IND filing.