title: Treatment with OPN-305, a humanized anti-Toll-Like receptor-2 antibody, reduces myocardial ischemia/reperfusion injury in pigs.
abstract: BACKGROUND
  Toll-like receptor (TLR)-2 is an important mediator of innate immunity and ischemia/reperfusion-induced cardiac injury. We have previously shown that TLR2 inhibition reduces infarct size and improves cardiac function in mice. However, the therapeutic efficacy of a clinical grade humanized anti-TLR2 antibody, OPN-305, in a large-animal model remained to be addressed.
  
  
  RESULTS
  Pigs (n=38) underwent 75 minutes ischemia followed by 24 hours of reperfusion. Saline or OPN-305 (12.5, 6.25, or 1.56 mg/kg) was infused intravenously 15 minutes before reperfusion. Cardiac function and geometry were assessed by echocardiography. Infarct size was calculated as the percentage of the area at risk and by serum Troponin-I levels. Flow cytometry analysis revealed specific binding of OPN-305 to porcine TLR2. In vivo, OPN-305 exhibited a secondary half-life of 8±2 days. Intravenous administration of OPN-305 before reperfusion significantly reduced infarct size (45% reduction, P=0.041) in a dose-dependent manner. In addition, pigs treated with OPN-305 exhibited a significant preservation of systolic performance in a dose-dependent fashion, whereas saline treatment completely diminished the contractile performance of the ischemic/reperfused myocardium.
  
  
  CONCLUSIONS
  OPN-305 significantly reduces infarct size and preserves cardiac function in pigs after ischemia/reperfusion injury. Hence, OPN-305 is a promising adjunctive therapeutic for patients with acute myocardial infarction.
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. f.arslan@umcutrecht.nl
authors.forename: Fatih
authors.initials: F
authors.lastname: Arslan
authors.forename: Jaco H
authors.initials: JH
authors.lastname: Houtgraaf
authors.forename: Brian
authors.initials: B
authors.lastname: Keogh
authors.forename: Kushan
authors.initials: K
authors.lastname: Kazemi
authors.forename: Renate
authors.initials: R
authors.lastname: de Jong
authors.forename: William J
authors.initials: WJ
authors.lastname: McCormack
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Peter
authors.initials: P
authors.lastname: McGuirk
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Smeets
authors.forename: Lars
authors.initials: L
authors.lastname: Akeroyd
authors.forename: Mary
authors.initials: M
authors.lastname: Reilly
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017024:Chemotherapy, Adjuvant / Q000639:trends; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006207:Half-Life; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007113:Immunity, Innate; D007262:Infusions, Intravenous; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051195:Toll-Like Receptor 2