title: Expression and Characterization of a Potent Long-Acting GLP-1 Receptor Agonist, GLP-1-IgG2σ-Fc.
abstract: Human GLP-1 (glucagon-like peptide-1) can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2σ-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G) to a human IgG2σ constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2σ-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2σ-Fc in cynomolgus monkeys was approximately 57.1 ± 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2σ-Fc (1 mg/kg) reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2σ-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2σ-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1-IgG2σ-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes.
authors.affiliation: Anhui Medical University, Hefei, Anhui, China.|Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Deyou
authors.initials: D
authors.lastname: Wan
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Hongru
authors.initials: H
authors.lastname: Feng
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Cui
authors.affiliation: Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Anhui Medical University, Hefei, Anhui, China.|Research Center of Pharmacokinetics, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Song
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D019518:Postprandial Period / Q000187:drug effects; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D000097789:Glucagon-Like Peptide-1 Receptor Agonists