Activity-balanced GLP-1/GDF15 dual agonist reduces body weight and metabolic disorder in mice and non-human primates

被引：23

作者：

Zhang, Yuanyuan ^{[1
]}

Zhao, Xinyu ^{[1
]}

Dong, Xiaona ^{[1
]}

Zhang, Yuying ^{[1
]}

Zou, Haixia ^{[1
]}

Jin, Yaoguang ^{[1
]}

Guo, Wei ^{[1
]}

Zhai, Peng ^{[1
]}

Chen, Xu ^{[1
]}

Kharitonenkov, Alexei ^{[1
]}

机构：

[1] Beijing QL Biopharmaceut Co Ltd, Beijing, Peoples R China

来源：

CELL METABOLISM | 2023年 / 35卷 / 02期

关键词：

BARIATRIC SURGERY; OBESITY; GLUCAGON;

D O I：

10.1016/j.cmet.2023.01.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its weight-lowering potential in animals. The molecule, QL1005, is engineered via fusing GLP-1 and GDF15 analogs by a peptide linker and conjugating it to a fatty acid for time-action extension. In vitro, the potency of QL1005 is superior to the GLP-1 analog semaglutide. In obese mice, QL1005 induces reductions in body weight, food intake, insulin, fasting glucose, and triglycer-ides. Notably, these metabolic effects come as a result of activities emanating from both GLP-1 and GDF15, in an individual pathway-balanced fashion. In a cynomolgus monkey model of obesity, QL1005 reduces body weight, food intake, insulin, and glucose in a dose-dependent manner with limited incidence of GI side ef-fects. Altogether, this long-acting, dual GLP-1/GDF15 molecule demonstrates the promise of poly -pharma-ceutical approaches in metabolic drug discovery and development.

引用

页码：287 / +

页数：17

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