A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys
A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys
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DOI：
10.1124/jpet.115.229690
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发表时间：
2016-02-01
影响因子：
3.5
通讯作者：
Johnson, Kirk
中科院分区：
文献类型：
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作者：
Bezwada, Padma;Zhao, Jingsong;Johnson, Kirk
XMetA是一种全人变构单克隆抗体，其以高亲和力结合胰岛素受体，并模拟胰岛素的葡萄糖调节作用，但不模拟促有丝分裂作用。在这里，我们评估了单次和重复s.c.在一些实施方案中，本发明提供了XMetA给药在具有天然发展的2型糖尿病的肥胖食蟹猴中降低高血糖症的方法，所述2型糖尿病是一种共享人类糖尿病的许多特征的模型。数据显示，单个s.c.以1.5至10 mg/kg的剂量水平施用XMetA显著降低空腹高血糖症，在施用后1至2天出现峰值效应，并持续长达1周。即使在最低剂量下，也观察到XMetA对高血糖症的作用，而血清胰岛素不升高，并且伴随血清C肽水平降低。通过每周一次s.c.给药XMetA，10 mg/kg，持续6周。在整个研究期间，XMeta治疗导致空腹血糖水平每周显著降低，平均约30%，沿着血红蛋白A1 c（长期血糖状态的标志物）较溶媒对照基线显著绝对降低1.2%。XMetA治疗耐受性良好，无注射部位反应，无体重增加，无临床低血糖发作。因此，XMetA在自发性糖尿病食蟹猴中显示出血糖控制的急性和亚慢性改善，具有广泛的安全范围。这一特征支持XMetA作为一种新型降糖治疗药物用于2型糖尿病的开发。
XMetA is a fully human, allosteric monoclonal antibody that binds the insulin receptor with high affinity and mimics the glucoregulatory, but not the mitogenic, actions of insulin. Here we evaluated the efficacy of both single and repeat s.c. administrations of XMetA in reducing hyperglycemia in obese cynomolgus monkeys with naturally developed type 2 diabetes, a model that shares many features of human diabetes. The data show that a single s.c. administration of XMetA at dose levels ranging from 1.5 to 10 mg/kg markedly reduced fasting hyperglycemia, with a peak effect occurring 1 to 2 days after administration, and sustained for up to 1 week. XMetA's effect on hyperglycemia was observed without elevations in serum insulin and was concomitant with reduced serum C-peptide levels, even at the lowest dose. Subchronic effects were evaluated via once weekly s.c. administration of XMetA, 10 mg/kg, for 6 weeks. XMetA treatment resulted in robust weekly decreases in fasting glucose levels averaging approximately 30% throughout the study, along with a significant absolute reduction from the vehicle control baseline of 1.2% in hemoglobin A1c, a marker of long-term glycemic status. XMetA treatment was well tolerated with no injectionsite reactions, no body weight gain, and no episodes of clinical hypoglycemia. Thus, XMetA shows acute and subchronic improvements in glycemic control in spontaneously diabetic cynomolgus monkeys with a broad safety margin. This profile supports the development of XMetA as a novel glucose-lowering therapeutic agent for the management of type 2 diabetes.