RT Journal Article
SR Electronic
T1 Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaaz9890
DO 10.1126/sciadv.aaz9890
VO 6
IS 35
A1 Gilroy, C. A.
A1 Capozzi, M. E.
A1 Varanko, A. K.
A1 Tong, J.
A1 D'Alessio, D. A.
A1 Campbell, J. E.
A1 Chilkoti, A.
YR 2020
UL http://advances.sciencemag.org/content/6/35/eaaz9890.abstract
AB There is great interest in identifying a glucagon-like peptide-1 (GLP-1)–based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.