title: Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke.
abstract: Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissue-type plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding.
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium;
authors.forename: Tine
authors.initials: T
authors.lastname: Wyseure
authors.affiliation: INSERM Unité Mixte de Recherche Scientifique U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Université de Caen Basse Normandie, Groupement d'Intérêt Public Cyceron, Caen, France; and.
authors.forename: Marina
authors.identifier: http://orcid.org/0000-0002-6120-4053
authors.initials: M
authors.lastname: Rubio
authors.affiliation: Laboratory for Thrombosis Research, Katholieke Universiteit Leuven Kulak, Kortrijk, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Denorme
authors.affiliation: INSERM Unité Mixte de Recherche Scientifique U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Université de Caen Basse Normandie, Groupement d'Intérêt Public Cyceron, Caen, France; and.
authors.forename: Sara
authors.initials: S
authors.lastname: Martinez de Lizarrondo
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium;
authors.forename: Miet
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium;
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.affiliation: Laboratory for Thrombosis Research, Katholieke Universiteit Leuven Kulak, Kortrijk, Belgium.
authors.forename: Simon F
authors.initials: SF
authors.lastname: De Meyer
authors.affiliation: INSERM Unité Mixte de Recherche Scientifique U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Université de Caen Basse Normandie, Groupement d'Intérêt Public Cyceron, Caen, France; and.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium;
authors.forename: Paul J
authors.identifier: http://orcid.org/0000-0003-1259-9105
authors.initials: PJ
authors.lastname: Declerck
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D051548:Histone Acetyltransferases / Q000276:immunology*; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055503:Protein Multimerization; D058258:Serpin E2 / Q000276:immunology*; D020521:Stroke / Q000473:pathology / Q000628:therapy*; D035381:TATA-Binding Protein Associated Factors / Q000276:immunology*; D035703:Therapies, Investigational / Q000379:methods*; D035362:Transcription Factor TFIID / Q000276:immunology*; D054556:Venous Thromboembolism / Q000473:pathology / Q000628:therapy*
chemical_list: D018033:Antibodies, Bispecific; D005343:Fibrinolytic Agents; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa