Novel GLP-1/anti-apolipoprotein B bifunctional fusion protein alleviates diabetes and diabetic complications in combination with low-intensity ultrasound

• Published in: Life sciences (1973) 2021-08, Vol.278, p.119549-119549, Article 119549
• Main Authors: Li, Xing, Bai, Lianjie, Zhang, Yinghui, Wang, Ying, Shi, Yang, Liu, Huilin
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - therapeutic use; apoB; Apolipoprotein B; Apolipoproteins; Apolipoproteins B - antagonists & inhibitors; CHO Cells; Complications; Cricetulus; Diabetes; Diabetes Complications - pathology; Diabetes Complications - therapy; Diabetes mellitus; Diabetes Mellitus - pathology; Diabetes Mellitus - therapy; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - therapy; Diabetic complication; Display devices; Epitopes; Fusion protein; GLP-1; Glucagon-Like Peptide 1 - therapeutic use; Hep G2 Cells; Humans; Hyperglycemia; Hyperlipidemia; Low density lipoprotein; Low-intensity ultrasound; Male; Mice; Mice, Inbred C57BL; Phage display; Phages; Proteins; Recombinant Fusion Proteins - therapeutic use; Ultrasonic imaging; Ultrasonic testing; Ultrasonic Therapy - methods; Ultrasound
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119549

To engineer and screen a novel GLP-1/anti-apolipoprotein B (apoB) bifunctional fusion protein with therapeutic potential on alleviating diabetes and diabetic complication in combination with low-intensity ultrasound. Anti-apoB antibodies were screened by phage display technology and further fused to mutated GLP-1 (7–37) via light or heavy fusion to generate bifunctional fusion protein (termed aBG). The optimal design of aBG fusion protein was further confirmed by in vitro epitope competition assay and cAMP accumulation assay. Subsequently, chronic study in DIO mice were subjected to assess the long-term efficacy of screened fusion protein. The selected GLP-1/anti-apoB fusion protein, aBG-8, exerted either the highest binding affinities for GLP-1R and apoB, or the greatest LDL-C uptake capacity and GLP-1R activation activity. After 60-day treatment in DIO mice, aBG-8 was proved to exert the promising improvement on hyperglycemia, hyperlipidemia, and obesity in DIO mice. Furthermore, combined therapy of aBG-8 and low-intensity ultrasound could accelerate skin wound closure in diabetic mice. A novel long-lasting bifunctional fusion molecule, aBG-8, was designed with the enormous potential on alleviating diabetes and diabetic complications in combination with low-intensity ultrasound.