Recombinant Fusion of Glucagon‐Like Peptide‐1 and an Albumin Binding Domain Provides Glycemic Control for a Week in Diabetic Mice

Abstract

AbstractGlucagon‐like peptide‐1 (GLP1) is an intestinally derived incretin currently under investigation for treatment of type 2 diabetes. The clinical application of GLP1 is limited by its short half‐life, which necessitates frequent administration. To address this challenge, GLP1 is recombinantly synthesized as a fusion to an albumin binding domain (ABD). The native GLP1 sequence is engineered to inhibit an inactivating cleavage site and a rigid helical linker (HL) is utilized between the GLP1 and ABD to reduce interference of albumin binding by the ABD upon the ability of GLP1 to bind and activate its receptor. Upon subcutaneous administration (SC), the GLP1‐HL‐ABD fusion binds to endogenous albumin and exhibits an extended half‐life of ≈44 h in mice. In a diabetic (db/db) mouse model, a single SC injection of GLP1‐HL‐ABD affords up to 7 d of glycemic control, which is significantly longer than the ≈12 h duration of glucose control provided by liraglutide, an albumin binding fatty acid derivative of GLP1 currently on the market for treatment of type 2 diabetes.