Abstract

An1 original drug, Glypin, has been developed for the treatment of type-II human diabetes mellitus. Its active pharmaceutical substance is a completely biosynthetic, recombinant, modified, human glucagon-like peptide (rmGlp-1) obtained via culturing of E. coli cells. In addition to the GLP-1 portion, which contains the well-known Ala8Gly substitution, the rmGLP-1 protein has an additional amino acid sequence at the C-terminus that includes the heparin-binding peptide of human HB-EGF. Preclinical testing of Glypin specific activity (with Lixumia as a reference drug) was performed. A commercial preparation of Lixumia served as the main reference drug for comparison with the specific activity of Glypin. During preclinical studies of both medicines, it was shown that Glypin and Lixumia have similar mechanisms, power, and time of action upon subcutaneous and intramuscular introductions, as well as comparable therapeutic effects under long-term use. Based on these data, the subcutaneous injection was selected as the main therapeutic method of Glypin administration; the minimal effective dose for Glypin preclinical study was established as 100 μg/kg body mass, and a single dose for human treatment was defined as 0.75 and 1.5 mg. The intranasal introduction of Glypin was observed to have a statistically reliable positive effect on the cognitive capacities of a mouse with Alzheimer’s disease model. The similarity of the characteristics of Glypin and Lixumia shown in our study make it possible to expect that they will have equal therapeutic efficacy with daily use of a single dose.

中文翻译：

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重组修饰的人胰高血糖素样肽1的比活性

摘要

An1的原始药物Glypin已开发用于治疗II型人类糖尿病。其活性药物是通过大肠杆菌培养获得的完全生物合成的，重组的，修饰的人胰高血糖素样肽（rmGlp-1）。细胞。除了包含众所周知的Ala8Gly取代的GLP-1部分之外，rmGLP-1蛋白在C末端还具有其他氨基酸序列，其中包括人HB-EGF的肝素结合肽。进行了Glypin比活性的临床前测试（以Lixumia作为参考药物）。商业上的Lixumia制剂用作主要参考药物，用于与Glypin的比活性进行比较。在对这两种药物进行临床前研究期间，都显示出Glypin和Lixumia在皮下和肌肉注射后具有相似的机制，功效和作用时间，并且在长期使用下具有可比的治疗效果。根据这些数据，选择皮下注射作为Glypin给药的主要治疗方法。Glypin临床前研究的最小有效剂量确定为100μg/ kg体重，人类治疗的单次剂量定义为0.75和1.5 mg。观察到鼻内引入Glypin对阿尔茨海默氏病模型小鼠的认知能力具有统计学上可靠的积极影响。在我们的研究中显示的Glypin和Lixumia的特性相似性使得我们有可能期望它们在每天使用单剂量时具有相同的治疗功效。