1. Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat
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Weike Bao, John J. Lepore, Elena DeAngelis, Gavin C. Jones, Rob D Prince, Karpagam Aravindhan, Mathew Szapacs, Robert N. Willette, April M. Barbour, Beat M. Jucker, Lucy J Holt, and Larry J. Jolivette
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Male ,Immunoconjugates ,Endocrinology, Diabetes and Metabolism ,Myocardial Infarction ,Cardioprotection ,Ventricular Function, Left ,Rats, Sprague-Dawley ,Glucagon-Like Peptide 1 ,Receptors, Glucagon ,Receptor ,Original Investigation ,biology ,digestive, oral, and skin physiology ,Antibody ,Cardiology and Cardiovascular Medicine ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Agonist ,medicine.medical_specialty ,endocrine system ,Cardiotonic Agents ,medicine.drug_class ,Injections, Subcutaneous ,Serum albumin ,Myocardial Reperfusion Injury ,Glucagon-Like Peptide-1 Receptor ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Serum Albumin ,Exendin-4 ,Venoms ,business.industry ,Myocardium ,Single-Domain Antibodies ,medicine.disease ,Myocardial Contraction ,Peptide Fragments ,Anti-albumin-binding domain antibody ,Rats ,Disease Models, Animal ,Endocrinology ,biology.protein ,Rat ,Exenatide ,Peptides ,business ,Reperfusion injury ,Glucagon-like peptide-1 (GLP-1) - 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 (Cmin). 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
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