Novel myostatin-specific antibody enhances muscle strength in muscle disease models

Hiroyasu Muramatsu,Masaki Honda,Kenta Haraya,Hitoshi Katada,Meiri Shida-Kawazoe,Taichi Kuramochi,Rie Miyano-Nishizawa,Kunihiro Hattori,Madoka Hayashi,Hidetomo Kitamura,Tomoyuki Igawa,Yuichiro Shimizu,Atsunori Ueyama,Yoshinao Ruike,Ken Ohmine,Momoko Okuda,Takio Kitazawa ,Yojiro Kawabe ,Takeshi Nonaka ,Yuji Hori,Nobuhiro Ban,Jun-Ichi Nezu

doi:10.1038/s41598-021-81669-8

Abstract

Myostatin, a member of the transforming growth factor-β 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.

Highlights

Myostatin, a member of the transforming growth factor-β superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength
Myostatin is predominantly expressed in skeletal muscle and synthetized as a precursor called pro-myostatin that is cleaved by a furin to give the latent myostatin/latent complex, which will be cleaved by proteases such as bone morphogenetic protein 1 (BMP1) or Tolloid-like protein 2 (TLL2) allowing the release of the mature/active dimer[1,9,10,11,12,13]
We demonstrate that this antibody exhibits better muscle strength improvement activity than conventional anti-myostatin agents, showing that GYM329 is a potent novel agent for the treatment of muscle diseases

Summary

Introduction

A member of the transforming growth factor-β superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. GYM329, that binds the latent form of myostatin and inhibits its activation. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models. The aforementioned agents in clinical studies inhibit myostatin and other TGF-β superfamily members, such as GDF11, which has a high sequence similarity with myostatin[18,24,25]. We tried to generate antibodies that prevent myostatin activation to the mature form by binding the prodomain of the latent form of myostatin, which has a lower sequence similarity (52%) with the prodomain of G DF1131

Objectives

Methods

Results

Conclusion