Glutazumab, a novel long-lasting GLP-1/anti-GLP-1R antibody fusion protein, exerts anti-diabetic effects through targeting dual receptor binding sites.

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Li C, Yang M, Wang X, Zhang H, Yao C, Sun S, Liu Q, Pan H, Liu S, Huan Y, Li S, Cao J, Wang X, Guo Y, Guo N, Jing S, Zhang C, Shen Z

Glutazumab, a novel long-lasting GLP-1/anti-GLP-1R antibody fusion protein, exerts anti-diabetic effects through targeting dual receptor binding sites.

Biochem Pharmacol. 2018 Apr;150:46-53. doi: 10.1016/j.bcp.2018.01.029. Epub 2018 Feb 3.

PubMed ID
29355505 [ View in PubMed
]
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 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 18h and 33.6h. 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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