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Preparation, characterization, and pharmacological study of a novel long-acting FGF21 with a potential therapeutic
Daejin Kim1, Jongsoo Lee2, InHwan Bae1
1Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea; Hanmi Research Center, Hanmi Pharm. Co.Ltd, 550, Dongtangiheung-ro, Dongtan-myeon, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
Abstract:
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.
Insights
A novel long-acting Fibroblast Growth Factor 21 (FGF21) therapy, LAPS-FGF21, significantly reduces body weight and improves metabolic health. This engineered FGF21 exhibits a dramatically extended serum half-life, offering a promising treatment for metabolic diseases.
Area of Science:
- Metabolic diseases
- Endocrinology
- Pharmacology
Background:
- Fibroblast Growth Factor 21 (FGF21) is vital for metabolic homeostasis but has a short serum half-life, limiting therapeutic use.
- Developing FGF21-based drugs for metabolic disorders faces challenges due to its rapid degradation.
Purpose of the Study:
- To develop and evaluate a novel long-acting FGF21 (LAPS-FGF21) engineered for an extended serum half-life.
- To assess the efficacy of LAPS-FGF21 in a mouse model of diet-induced obesity.
Main Methods:
- Chemical conjugation of FGF21 to a human IgG4 Fc fragment to create LAPS-FGF21.
- Production of recombinant human IgG4 Fc fragment and FGF21 using E. coli overexpression systems.
- Pharmacokinetic and efficacy studies in diet-induced obesity and normal mouse models.
Main Results:
- LAPS-FGF21 demonstrated significant dose-dependent body weight reduction in diet-induced obese mice.
- Improved glucose tolerance and blood lipid profiles (cholesterol, triglycerides) were observed with LAPS-FGF21 administration.
- Pharmacokinetic studies revealed LAPS-FGF21 has a serum half-life approximately 64-fold longer than native FGF21.
Conclusions:
- LAPS-FGF21 represents a feasible therapeutic candidate for metabolic diseases, offering substantial weight loss efficacy.
- The extended half-life of LAPS-FGF21 allows for less frequent dosing intervals, enhancing its clinical potential.
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