Article
作者: Cao, Jun ; Yao, Chenjiang ; Zhang, Cheng ; Guo, Nan ; Zhang, Hua ; Shen, Zhufang ; Huan, Yi ; Jing, Shuqian ; Pan, Hao ; Sun, Sujuan ; Guo, Yong ; Li, Caina ; Yang, Miaomiao ; Li, Shengnan ; Wang, Xiaofeng ; Liu, Quan ; Wang, Xing ; Liu, Shuainan
AIMS:Glucagon like-peptide-1 (GLP-1)-based drugs have been proposed as mono- or combined therapy for type 2 diabetes mellitus. Thus we characterized a novel antibody fusion protein engineered by linking the human GLP-1 derivative to a humanized GLP-1 receptor (GLP-1R) antibody via a peptide linker.
MATERIALS AND METHODS:Glutazumab was characterized by receptor binding and reporter activation assays, and its specificity was investigated with the aid of the cognate receptor antagonist exendin (9-39) and antibody Ab1. Pharmacokinetics was evaluated in Sprague-Dawley (SD) rats and cynomolgus monkeys, and pharmacodynamics was assessed in normal ICR and spontaneous type 2 diabetic KKAy mice. Hypoglycemic effects were evaluated after acute administration and glucose metabolism and β-cell function were assessed with repeated administrations. Dulaglutide was a positive control in all experiments.
RESULTS:Glutazumab significantly bound and activated GLP-1R, but the receptor antagonist exendin (9-39) did not inhibit the activation except when combined with Ab1. Single injection of glutazumab reduced the blood glucose in ICR mice and KKAy mice, and the half-lives in SD rats and cynomolgus monkeys were 18 h and 33.6 h. Repeated injections of glutazumab controlled glycemic fluctuations and improved β-cell function in KKAy mice.
CONCLUSIONS:As a novel GLP-1R agonist, glutazumab may be a potential treatment for T2DM.
