Development of a novel Fc fusion protein dual glucagon‐like peptide‐1 and gastric inhibitory polypeptide receptor agonists

AIM: To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon-like peptide-1 receptor (GLP-1 R) agonist with Fc fusion protein structure. METHODS: We designed and constructed an Fc fusion protein that is a dual agonist (HEC-CG115) with an empirically optimized potency ratio for GLP-1R and GIPR. The long-term effects of HEC-CG115 on body weight and glycaemic control were evaluated in diet-induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC-CG115 in Sprague-Dawley rats. RESULTS: HEC-CG115 displayed high potency for GIPR and relatively low potency for GLP-1R, and we labelled it 'imbalanced'. In animal models, HEC-CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet-induced obese model mice. HEC-CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4-week subcutaneous toxicity study conducted to assess the biosafety of HEC-CG115, the no observed adverse effect level was determined to be 3 mg/kg. CONCLUSION: HEC-CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat-dose toxicity study. Therefore, the use of HEC-CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes.