Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein

Diabetes Metab Res Rev. 2010 May;26(4):287-96. doi: 10.1002/dmrr.1080.


Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose-dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight-reducing profile. However, a short half-life (minutes), secondary to rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native GLP-1 hormone. Recently, the GLP-1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long-acting and efficacious GLP-1 analogues represents a pivotal research goal. We developed a GLP-1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

Methods: In vitro and in vivo activity of LY2189265 was characterized in rodent and primate cell systems and animal models.

Results: LY2189265 retained full receptor activity in vitro and elicited insulinotropic activity in islets similar to native peptide. Half-life in rats and cynomolgus monkeys was 1.5-2 days, and serum immunoreactivity representing active compound persisted > 6 days. In rats, LY2189265 enhanced insulin responses during graded glucose infusion 24 h after one dose. LY2189265 increased glucose tolerance in diabetic mice after one dose and lowered weight and delayed hyperglycaemia when administered twice weekly for 4 weeks. In monkeys, LY2189265 significantly increased glucose-dependent insulin secretion for up to a week after one dose, retained efficacy when administered subchronically (once weekly for 4 weeks) and was well tolerated.

Conclusions: LY2189265 retains the effects of GLP-1 with increased half-life and efficacy, supporting further evaluation as a once-weekly treatment of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Genes, Reporter
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptides / analogs & derivatives
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / pharmacology*
  • Incretins / genetics
  • Incretins / pharmacokinetics
  • Incretins / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Macaca fascicularis
  • Membrane Proteins / genetics
  • Mice
  • Mitochondrial Proteins / genetics
  • Protein Engineering
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / agonists*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / pharmacology*
  • beta-Lactamases / genetics


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Immunoglobulin Fc Fragments
  • Incretins
  • Insulin
  • Membrane Proteins
  • Mitochondrial Proteins
  • Receptors, Glucagon
  • Recombinant Fusion Proteins
  • Glucagon-Like Peptides
  • LACTB protein, human
  • beta-Lactamases
  • dulaglutide