1016-P: A Novel GLP-1 and FGF-21 Dual Agonist Drug Protects Mice from Obesity and Hyperglycemia
GILROY, CA; CAPOZZI, M; SU, JC; TONG, J; D’ALESSIO, DA; CAMPBELL, J; CHILKOTI, A
Published in: Diabetes
As the incidence of diabetes increases, the development of new therapeutic strategies is essential. Recent evidence supports combination therapies that incorporate complementary mechanisms of action as potent and effective. We have developed a unimolecular dual agonist by combining the incretin glucagon-like peptide-1 (GLP-1) and the metabolic regulatory factor fibroblast growth factor 21 (FGF-21). We hypothesized that this agent would merge the insulinotropic and anorectic effects of GLP-1 with enhanced insulin sensitivity and energy expenditure due to FGF-21 signaling. The dual agonist is a single polypeptide fusion, with GLP-1 located at the N-terminus and FGF-21 at the C-terminus. This orientation allows each peptide to activate its receptor, while the linear architecture enables facile synthesis in a bacterial expression system. Fused between GLP-1 and FGF-21 is an elastin-like polypeptide (ELP) that serves as both a flexible linker and a circulation-enhancing scaffold. The ELP used herein is designed such that it undergoes a thermally initiated phase transition triggered by body heat upon subcutaneous (s.c.) injection, resulting in a slow-dissolving drug depot. A single s.c. injection of GLP-1-ELP-FGF-21 into diabetic db/db mice significantly reduced ambient blood glucose levels from above 300 mg/dL to sustained levels below 150 mg/dL for 8 days. Db/db mice treated once-weekly for 4 weeks had mean body weights that were 24% and 16% lower than mice treated weekly with vehicle or long-acting GLP-1, respectively. Dual agonist treatment also conferred greater reductions in % HbA1c and circulating lipids. These results demonstrate the efficacy of a novel unimolecular drug to correct multiple metabolic abnormalities in a diabetic mouse model. Moreover, the improved outcomes compared to a GLP-1-based drug support the dual agonist mechanism. Incorporation of an ELP allows advantageous temporal control of drug delivery, thus making the GLP-1/FGF-21 dual agonist a promising new diabetes treatment.
