Production of Fc-fused receptor agonists for glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) in the milk of transgenic mice.
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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.
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.
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Should report significant developments in methodology and experimental transgenic higher organisms