Caina Li
Peking Union Medical College | China
Title: A completely novel long-acting GLP-1 receptor agonist, Glutazumab
Biography
Biography: Caina Li
Abstract
GLP-1-based drugs have been proposed as a mono- or combined therapy for type 2 diabetes mellitus for the outstanding features, but natural GLP-1 is hardly used in clinic due to its short half-life, while short-acting analogs/receptor agonists have poor compliance in patients for frequent dosing. This study aims to introduce a novel long-acting GLP-1 receptor agonist,
which is an antibody fusion protein by linking the human GLP-1 derivative to a humanized GLP-1R antibody via a peptide linker, and to evaluate its anti-diabetic effects and duration. Glutazumab is characterized by receptor binding and reporter gene assay, and its specificity was investigated through addition of exendin (9-39) and Ab1 which were the cognate receptor antagonist and antibody respectively. To evaluate the anti-diabetic effects, glutazumab was studied in diabetic KKAy mice by single dose and repeated doses. The blood glucose, food/water intake, body weight and gastric emptying was measured in
the single dose study, while blood glucose, GSP, HbA1c, insulin and lipid were determined in the repeated-dose study. The oral glucose tolerance and hyperglycemic clamp test were performed to assess the β-cell function. In all the experiments, dulaglutide served as a control. Glutazumab significantly binds and activates GLP-1R, while the natural receptor antagonist exendin (9-39) showed no inhibition except in the presence of the antibody Ab1. Single injection of Glutazumab remarkably decreased blood glucose for 3~6 days in normal ICR mice and diabetic KKAy mice. Repeated injections of glutazumab also evidently reduced non-fasting and fasting blood glucose fluctuation, decreased GSP and HbA1c levels, improved impaired oral glucose tolerance and β-cell function and ameliorated the dyslipidemia in diabetic KKAy mice. These results demonstrated that glutazumab is a novel long-acting GLP-1 receptor agonist with excellent anti-diabetic effect in KKAy mice, and suggested thatit may be a potential treatment for type 2 diabetes.