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. [ABSTRACT FROM AUTHOR]