A mouse anti-myostatin antibody increases muscle mass and improves muscle strength and contractility in the mdx mouse model of Duchenne muscular dystrophy and its humanized equivalent, domagrozumab (PF-06252616), increases muscle volume in cynomolgus monkeys

Abstract

BackgroundThe treatments currently approved for Duchenne muscular dystrophy (DMD), a progressive skeletal muscle wasting disease, address the needs of only a small proportion of patients resulting in an urgent need for therapies that benefit all patients regardless of the underlying mutation. Myostatin is a member of the transforming growth factor-β (TGF-β) family of ligands and is a negative regulator of skeletal muscle mass. Loss of myostatin has been shown to increase muscle mass and improve muscle function in both normal and dystrophic mice. Therefore, myostatin blockade via a specific antibody could ameliorate the muscle weakness in DMD patients by increasing skeletal muscle mass and function, thereby reducing patients’ functional decline.MethodsA murine anti-myostatin antibody, mRK35, and its humanized analog, domagrozumab, were developed and their ability to inhibit several TGB-β ligands was measured using a cell-based Smad-activity reporter system. Normal and mdx mice were treated with mRK35 to examine the antibody’s effect on body weight, lean mass, muscle weights, grip strength, ex vivo force production, and fiber size. The humanized analog (domagrozumab) was tested in non-human primates (NHPs) for changes in skeletal muscle mass and volume as well as target engagement via modulation of circulating myostatin.ResultsBoth the murine and human antibodies are specific and potent inhibitors of myostatin and GDF11. mRK35 is able to increase body weight, lean mass, and muscle weights in normal mice. In mdx mice, mRK35 significantly increased body weight, muscle weights, grip strength, and ex vivo force production in the extensor digitorum longus (EDL) muscle. Further, tibialis anterior (TA) fiber size was significantly increased. NHPs treated with domagrozumab demonstrated a dose-dependent increase in lean mass and muscle volume and exhibited increased circulating levels of myostatin demonstrating target engagement.ConclusionsWe demonstrated that the potent anti-myostatin antibody mRK35 and its clinical analog, domagrozumab, were able to induce muscle anabolic activity in both rodents, including the mdx mouse model of DMD, and non-human primates. A Phase 2, potentially registrational, clinical study with domagrozumab in DMD patients is currently underway.

Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)

“…Myostatin is a negative regulator of muscle mass. The efficacy of myostatin blockade by the monoclonal antibody RK35 has been examined in the murine models of amyotrophic lateral sclerosis, DMD, and nemaline myopathy, and this antibody is currently in phase II clinical trial for DMD (NCT02907619 and NCT02310763). In this study, we tested the effect of myostatin inhibition to ameliorate atrophic symptoms in the A17 OPMD mouse model system using this antibody.…”

“…The increase in body mass was most evident during the first 5 weeks of the 10‐week treatment regimen, after which the difference was maintained. Using the same antibody, a similar effect in DMD and nemaline myopathy models was observed by St. Andre et al . and Tinklenberg et al ., respectively.…”

“…Though early clinical trials in DMD, or Becker's muscular dystrophy with the first generation anti‐myostatin antibody MYO‐029 displayed limited therapeutic potential, other therapeutic candidates have been since developed. The anti‐myostatin antibody RK35 developed by Pfizer presents a next generation hybridoma and has been previously tested in models of amyotrophic lateral sclerosis, nemaline myopathy, and DMD, where it demonstrated efficacy in improving muscle mass and function . The humanized equivalent of RK35 (Domagrozumab) is currently in clinical testing in DMD patients following a Phase 1 study in healthy volunteers .…”

Sarcopenia: Tilting the Balance of Protein Homeostasis

“…Hence, myostatin antagonism seems like an attractive approach for muscle wasting since myostatin is a secreted protein and acts predominantly on skeletal muscle. Furthermore, application of anti‐myostatin antibody increases muscle mass and improves muscle strength in animal models of Duchenne muscular dystrophy and natural ageing . In particular, a preclinical study by Latres et al .…”

Detection of the myostatin‐neutralizing antibody Domagrozumab in serum by means of Western blotting and LC‐HRMS

“…They comprise drug candidates specifically targeting the cytokine such as anti‐myostatin antibodies, peptibodies, adnectin‐ and follistatin‐Fc fusion proteins, and agents derived from the myostatin propeptide, as well as multi‐target approaches such as receptor competitors and anti‐ActRII antibodies . Domagrozumab (PF‐06252616; Pfizer, New York City, NY) is a humanized monoclonal anti‐myostatin antibody developed for the treatment of Duchenne muscular dystrophy, which prevents receptor activation through binding to the circulating cytokine . In different animal models, it was found to have positive effects on body weight, lean mass, muscle weight, and muscle strength.…”