FGF21 (Fibroblast Growth Factor 21), which is expressed in the liver, adipose tissue, and pancreas, has been widely known as a therapeutic candidate for metabolic diseases. Though FGF21 is crucial to glucose, lipid, and energy homeostasis, it is not straightforward to develop a new drug with FGF21 due to its short half-life in serum. Here, we derived a novel long-acting FGF21 (LAPS-FGF21), which is chemically conjugated to the human IgG4 Fc fragment for longer half-life in serum. The recombinant human IgG4 Fc fragment and FGF21 were prepared by the refolding of inclusion body and periplasmic expression in Escherichia coli overexpression systems, respectively. The efficacy study of LAPS-FGF21 in a Diet-Induced Obesity (DIO) mouse model revealed that LAPS-FGF21 reduced body weight effectively accompanied by improved glucose tolerance in a dose-dependent manner. The administration of LAPS-FGF21 also improved the blood profiles with a significant reduction in cholesterol and triglyceride levels. Additionally, the pharmacokinetic (PK) studies of LAPS-FGF21 using normal ICR mice demonstrated that the half-life of LAPS-FGF21 was approximately 64-fold longer than FGF21. Taken together, the LAPS-FGF21 could be a feasible drug candidate with excellent bodyweight loss efficacy and longer dosing interval by half-life increase in serum.

FGF21（成纤维细胞生长因子 21）在肝脏、脂肪组织和胰腺中表达，已被广泛认为是代谢疾病的治疗候选物。尽管 FGF21 对葡萄糖、脂质和能量稳态至关重要，但由于 FGF21 在血清中的半衰期很短，因此开发一种含有 FGF21 的新药并非易事。在这里，我们获得了一种新型长效 FGF21 (LAPS-FGF21)，它与人 IgG4 Fc 片段化学偶联，在血清中具有更长的半衰期。重组人IgG4 Fc片段和FGF21在大肠杆菌中通过包涵体重折叠和周质表达制备过表达系统，分别。LAPS-FGF21 在饮食诱导肥胖 (DIO) 小鼠模型中的功效研究表明，LAPS-FGF21 可有效降低体重，同时以剂量依赖性方式改善葡萄糖耐量。LAPS-FGF21 的给药还改善了血液特征，显着降低了胆固醇和甘油三酯水平。此外，使用正常 ICR 小鼠对 LAPS-FGF21 进行的药代动力学 (PK) 研究表明，LAPS-FGF21 的半衰期比 FGF21 长约 64 倍。总而言之，LAPS-FGF21 可能是一种可行的候选药物，具有出色的减重功效和更长的给药间隔（通过增加血清半衰期）。