Development of anti-LTBP4 as a biologic to treat Limb Girdle Muscular Dystrophy 2C - Project Summary Muscular Dystrophies are often rare, genetic disorders that typically result in progressive loss of muscle strength effecting the ability to stand, walk, and breathe. Sarcoglycanopathies are an inherited form of Limb Girdle Muscular Dystrophy (LGMD) caused by the loss of a, b, d, or g sarcoglycan proteins, rendering the muscle membrane highly susceptible to injury. LGMD 2C is a severe subtype of LGMD resulting from loss of g- sarcoglycan, with onset generally in the first decade of life. LGMD 2C is also known as R5. LGMD 2C is clinically similar to the more common Duchenne Muscular Dystrophy (DMD) caused by the loss of dystrophin. This similarity arises from sarcoglycan and dystrophin together contributing to the essential membrane stabilizing dystrophin-glycoprotein complex (DGC). Currently, there are limited therapies available to correct or delay LGMD 2C disease progression. Using an unbiased genomewide screen in LGMD 2C mice, Latent TGF- b Binding Protein 4 (LTBP4) was discovered as a genetic modifier of muscle disease specifically modulating muscle membrane stability and fibrosis. LTBP4 localizes to the exterior of the myofiber and extracellular matrix where it binds and sequesters all three forms of TGF-b. LTBP4’s hinge can be proteolytically cleaved promoting release of latent TGF-b, which is then activated triggering the downstream fibrotic cascade. Excess TGF-b activation is a pathological finding in many forms of muscular dystrophy, especially LGMDs and DMD, and excess TGF-b is linked to fibrotic accumulation in muscle and impaired muscle regeneration. In mice, the genetic protective form of LTBP4 is less susceptible to protease cleavage, correlating with decreased TGF- b activity and delayed muscle disease progression. Importantly, a similar protective genetic effect of LTBP4 was shown to modify disease progression in humans with DMD, reducing TGF-b release, correlating with longer ambulation and improved heart function in three independent DMD cohorts. Combined, these data provided the rationale to develop antibodies that stabilize the LTBP4 hinge and limit latent TGF-b release as a therapeutic to treat muscular dystrophy. We demonstrated in the mdx mouse model of DMD that anti-LTBP4 antibodies directed at the hinge region are effective at mitigating disease progression. Anti-LTBP4 hinge region antibodies protected against LTBP4 cleavage, reduced fibrosis formation, enhanced muscle performance, and improved recovery after muscle injury. This proposal outlines a preclinical plan for testing a 2nd generation antibody for the treatment of LGMD 2C. This lead candidate has already been affinity and sequence optimized. The milestones are designed to evaluate the PK PD relationship of this lead anti-LTBP4 antibody and assess in vivo efficacy in a validated mouse model of LGMD 2C. Completion of this award will position the program to secure external funding from strategic investors and partners, which will aid in advancing the anti-LTBP4 biologic therapy into the clinic.
