Novel Myostatin-Specific Antibody Enhances Muscle Strength in Muscle Disease Models

Abstract

Myostatin, a member of the transforming growth factor-b superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy. We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via “sweeping antibody technology”, GYM329 reduces or “sweeps” myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models. We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.

Degradation from the outside in: Targeting extracellular and membrane proteins for degradation through the endolysosomal pathway

“…A sweeping antibody derived from tocilizumab, an antibody against the interleukin-6 receptor (IL-6R), was shown to reduce soluble IL-6R concentration more effectively compared with a conventional antibody in vivo (Igawa et al, 2013). Following this demonstration, Muramatsu et al applied the technology to inhibit activation of latent myostatin for improving muscle strength in vivo (Muramatsu, 2019;Muramatsu et al, 2021). In addition, Sampei et al cleared complement C5 through a similar pH-dependent C5-binding antibody that was further engineered to increase the surface charges of the antibody to preferably interact with a negatively charged cellular membrane (Sampei et al, 2018).…”

Advances and limitations for the treatment of spinal muscular atrophy

“…Since these positive TOPAZ results were obtained, other therapies that target myostatin signaling are now being explored in SMA, including the GYM329 antibody against latent myostatin, which in animal models increased muscle mass and improved grip strength in mice [44,100]. Other ongoing SMA trials include a phase 3 apitegromab study in combination with nusinersen or risdiplam [NCT05156320 ] [101], a phase 2/3 study of GYM329 in combination with risdiplam [102], a phase 2b/3 study of taldefgrobep alfa, an anti-myostatin adnectin [103], and a phase 1 of BIIB110, ActRIIA/B ligand trap [104,105].…”