title: Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model.
abstract: The enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Activated thrombin activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis and is an attractive target to develop profibrinolytic drugs. TAFI can be activated by thrombin, thrombin/thrombomodulin, or plasmin, but the in vivo physiologic TAFI activator(s) are unknown. Here, we generated and characterized MA-TCK26D6, a monoclonal antibody raised against human TAFI, and examined its profibrinolytic properties in vitro and in vivo. In vitro, MA-TCK26D6 showed a strong profibrinolytic effect caused by inhibition of the plasmin-mediated TAFI activation. In vivo, MA-TCK26D6 significantly decreased fibrin deposition in the lungs of thromboembolism-induced mice. Moreover, in the presence of MA-TCK26D6, plasmin-α(2)-antiplasmin complexes in plasma of thromboembolism-induced mice were significantly increased compared with a control antibody, indicative of an acceleration of fibrinolysis through MA-TCK26D6. In this study, we show that plasmin is an important TAFI activator that hampers in vitro clot lysis. Furthermore, this is the first report on an anti-TAFI monoclonal antibody that demonstrates a strong profibrinolytic effect in a mouse thromboembolism model.
authors.affiliation: Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Vercauteren
authors.forename: Jan
authors.initials: J
authors.lastname: Emmerechts
authors.forename: Miet
authors.initials: M
authors.lastname: Peeters
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology; D000990:Antithrombin III / Q000276:immunology; D025901:Carboxypeptidase B2 / Q000276:immunology* / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D010447:Peptide Hydrolases / Q000276:immunology; D013045:Species Specificity; D013923:Thromboembolism / Q000276:immunology / Q000378:metabolism / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases; D025901:Carboxypeptidase B2