title: Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN, USA. w.glaesn@lilly.com
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Glaesner
authors.forename: Andrew Mark
authors.initials: AM
authors.lastname: Vick
authors.forename: Rohn
authors.initials: R
authors.lastname: Millican
authors.forename: Bernice
authors.initials: B
authors.lastname: Ellis
authors.forename: Sheng-Hung
authors.initials: SH
authors.lastname: Tschang
authors.forename: Yu
authors.initials: Y
authors.lastname: Tian
authors.forename: Krister
authors.initials: K
authors.lastname: Bokvist
authors.forename: Martin
authors.initials: M
authors.lastname: Brenner
authors.forename: Anja
authors.initials: A
authors.lastname: Koester
authors.forename: Niels
authors.initials: N
authors.lastname: Porksen
authors.forename: Garret
authors.initials: G
authors.lastname: Etgen
authors.forename: Tom
authors.initials: T
authors.lastname: Bumol
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D017930:Genes, Reporter; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology*; D054795:Incretins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007141:Immunoglobulin Fc Fragments; D054795:Incretins; D007328:Insulin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; C486706:LACTB protein, human; D001618:beta-Lactamases; C555680:dulaglutide