Rare Disease Research Unit, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, USA.
NIGMS Training Program in Biomolecular Pharmacology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
Skelet Muscle. 2017 Nov 9;7(1):25. doi: 10.1186/s13395-017-0141-y.
The 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.
A 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.
Both 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.
We 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.
目前批准用于杜氏肌营养不良症（DMD）的治疗方法，这是一种进行性骨骼肌消耗疾病，仅能满足一小部分患者的需求，因此迫切需要治疗方法，使所有患者受益，无论其潜在突变如何。肌抑素是转化生长因子-β（TGF-β）配体家族的成员，是骨骼肌质量的负调节剂。已证明肌抑素的缺失可增加正常和营养不良小鼠的肌肉质量并改善肌肉功能。因此，通过特异性抗体阻断肌抑素可通过增加骨骼肌质量和功能来改善 DMD 患者的肌肉无力，从而减少患者的功能下降。
开发了一种鼠抗肌抑素抗体 mRK35 及其人源化类似物 domagrozumab，并使用基于细胞的 Smad 活性报告系统测量了它们抑制几种 TGF-β配体的能力。用 mRK35 治疗正常和 mdx 小鼠，以检查抗体对体重、瘦体重、肌肉重量、握力、离体力产生和纤维大小的影响。人源化类似物（domagrozumab）在非人类灵长类动物（NHPs）中进行了测试，以检测骨骼肌质量和体积的变化以及通过调节循环肌抑素来靶向结合。
鼠和人抗体都是肌抑素和 GDF11 的特异性和有效抑制剂。mRK35 能够增加正常小鼠的体重、瘦体重和肌肉重量。在 mdx 小鼠中，mRK35 显著增加了体重、肌肉重量、握力和伸趾长肌（EDL）的离体力产生。此外，胫骨前肌（TA）纤维大小显著增加。用 domagrozumab 治疗的 NHPs 表现出剂量依赖性的瘦体重和肌肉体积增加，并表现出循环肌抑素水平升高，表明靶标结合。
我们证明了强效抗肌抑素抗体 mRK35 及其临床类似物 domagrozumab 能够在包括 DMD 模型 mdx 小鼠在内的啮齿动物和非人类灵长类动物中诱导肌肉合成活性。目前正在进行一项使用 domagrozumab 治疗 DMD 患者的 2 期潜在注册临床研究。
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