Caina Li1, Miaomiao Yang1, Xiaofeng Wang2, Hua Zhang2, Chenjiang Yao2, Sujuan Sun1, Quan Liu1, Hao Pan2, Shuainan Liu1, Yi Huan1, Shengnan Li2, Jun Cao2, Xing Wang1, Yong Guo2, Nan Guo1, Shuqian Jing2, Cheng Zhang3, Zhufang Shen4. 1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050, China. 2. Gmax Biopharm, 288 Qiuyi Road, Binjiang District, Hangzhou 310052, Zhejiang, China. 3. Gmax Biopharm, 288 Qiuyi Road, Binjiang District, Hangzhou 310052, Zhejiang, China. Electronic address: czhang@gmaxbiopharm.com. 4. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050, China. Electronic address: shenzhf@imm.ac.cn.
Abstract
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.
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 humanGLP-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.