期刊
BIOCHEMICAL PHARMACOLOGY
卷 150, 期 -, 页码 46-53出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2018.01.029
关键词
Diabetes; Long-acting GLP-1 analog; Glutazumab; Glucose metabolism; beta-Cell function
资金
- CAMS Initiative for Innovative Medicine (CAMS-I2M) [2016-I2M-2-006]
- Key Research and Development Plan of Zhejiang Province [2017C03043]
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 beta-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 beta-cell function in KKAy mice. Conclusions: As a novel GLP-1R agonist, glutazumab may be a potential treatment for T2DM.
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