Production of Fc-fused receptor agonists for glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) in the milk of transgenic mice.

IF 2 3区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS
Yu Rao, Shuai Yu, Bao-Zhu Wang, Sheng Cui, Ke-Mian Gou
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引用次数: 0

Abstract

Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play pivotal roles in glucose homeostasis and metabolic regulation. Therapeutic incretin receptor agonists (RAs), such as tirzepatide, are widely used to manage type 2 diabetes and obesity. However, incretin RAs are facing production challenges at present. Therefore, we engineered transgenic (tg) mice to secrete incretin RAs in milk, leveraging mammary gland bioreactors for cost-effective peptide production. The goat beta-casein promoter-driven constructs encoding tirzepatide-derived peptide linked to human IgG4 Fc via a (GGGGS)₃ spacer were used to produce tg mice. Founders tg-1 and tg-5 exhibited mammary-specific expression, yielding 0.8-1.42 g/l recombinant protein exclusively in milk. Progeny nursed by founders showed sustained hypoglycemia (10-39% reduction; p < 0.05) and marked weight loss (14-49%; p < 0.01) compared to wild-type controls, validating the bioactivity of milk-derived GLP-1/GIP RAs. Moreover, tg-5-nursed offspring experienced high mortality post-Day 16, likely due to overdosing. This proof-of-concept demonstrates the mammary gland bioreactor as a viable platform for incretin RAs production, circumventing complex synthesis and enabling scalable biologics manufacturing.

转基因小鼠乳中胰高血糖素样肽-1/葡萄糖依赖性胰岛素多肽(GLP-1/GIP) fc融合受体激动剂的产生
肠促胰岛素激素,包括胰高血糖素样肽-1 (GLP-1)和葡萄糖依赖性胰岛素性多肽(GIP),在葡萄糖稳态和代谢调节中起关键作用。治疗性肠促胰岛素受体激动剂(RAs),如替西肽,被广泛用于治疗2型糖尿病和肥胖。然而,促肠促胰岛素RAs目前面临着生产上的挑战。因此,我们设计了转基因(tg)小鼠在乳中分泌肠促胰岛素RAs,利用乳腺生物反应器生产具有成本效益的肽。山羊β -酪蛋白启动子驱动的构建物编码通过(GGGGS)₃间隔物与人IgG4 Fc连接的替西肽衍生肽,用于生产tg小鼠。奠基者tg-1和tg-5表现出乳房特异性表达,仅在牛奶中产生0.8-1.42 g/l的重组蛋白。创始人护理的后代出现持续低血糖(降低10-39%);p
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来源期刊
Transgenic Research
Transgenic Research 生物-生化研究方法
CiteScore
5.40
自引率
0.00%
发文量
38
审稿时长
4-8 weeks
期刊介绍: Transgenic Research focusses on transgenic and genome edited higher organisms. Manuscripts emphasizing biotechnological applications are strongly encouraged. Intellectual property, ethical issues, societal impact and regulatory aspects also fall within the scope of the journal. Transgenic Research aims to bridge the gap between fundamental and applied science in molecular biology and biotechnology for the plant and animal academic and associated industry communities. Transgenic Research publishes -Original Papers -Reviews: Should critically summarize the current state-of-the-art of the subject in a dispassionate way. Authors are requested to contact a Board Member before submission. Reviews should not be descriptive; rather they should present the most up-to-date information on the subject in a dispassionate and critical way. Perspective Reviews which can address new or controversial aspects are encouraged. -Brief Communications: Should report significant developments in methodology and experimental transgenic higher organisms
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