title: Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury.
  
  
  METHODS
  Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 μg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury.
  
  
  RESULTS
  GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection.
  
  
  CONCLUSIONS
  Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.
authors.affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, King of Prussia, PA 19406, USA. Weike.2.Bao@gsk.com.
authors.forename: Weike
authors.initials: W
authors.lastname: Bao
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Holt
authors.forename: Rob D
authors.initials: RD
authors.lastname: Prince
authors.forename: Gavin X
authors.initials: GX
authors.lastname: Jones
authors.forename: Karpagam
authors.initials: K
authors.lastname: Aravindhan
authors.forename: Mathew
authors.initials: M
authors.lastname: Szapacs
authors.forename: April M
authors.initials: AM
authors.lastname: Barbour
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Jolivette
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
authors.forename: Elena
authors.initials: E
authors.lastname: DeAngelis
authors.forename: Beat M
authors.initials: BM
authors.lastname: Jucker
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D018796:Immunoconjugates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics; D012709:Serum Albumin / Q000276:immunology*; D061905:Single-Domain Antibodies / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018796:Immunoconjugates; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D012709:Serum Albumin; D061905:Single-Domain Antibodies; D014688:Venoms; C061970:glucagon-like peptide 1 (7-36); D052216:Glucagon-Like Peptide 1; D000077270:Exenatide