title: A faster-acting and more potent form of tissue plasminogen activator.
abstract: Current treatment with tissue plasminogen activator (tPA) requires an intravenous infusion (1.5-3 h) because the clearance of tPA from the circulation is rapid (t 1/2 approximately 6 min). We have developed a tPA variant, T103N,N117Q, KHRR(296-299)AAAA (TNK-tPA) that has substantially slower in vivo clearance (1.9 vs. 16.1 ml per min per kg for tPA in rabbits) and near-normal fibrin binding and plasma clot lysis activity (87% and 82% compared with wild-type tPA). TNK-tPA exhibits 80-fold higher resistance to plasminogen activator inhibitor 1 than tPA and 14-fold enhanced relative fibrin specificity. In vitro, TNK-tPA is 10-fold more effective at conserving fibrinogen in plasma compared to tPA. Arterial venous shunt models of fibrinolysis in rabbits indicate that TNK-tPA (by bolus) induces 50% lysis in one-third the time required by tPA (by infusion). TNK-tPA is 8- and 13-fold more potent in rabbits than tPA toward whole blood clots and platelet-enriched clots, respectively. TNK-tPA conserves fibrinogen and, because of its slower clearance and normal clot lysis activity, is effective as a thrombolytic agent when given as a bolus at a relatively low dose.
authors.affiliation: Department of Cardiovascular Research, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: B A
authors.initials: BA
authors.lastname: Keyt
authors.forename: N F
authors.initials: NF
authors.lastname: Paoni
authors.forename: C J
authors.initials: CJ
authors.lastname: Refino
authors.forename: L
authors.initials: L
authors.lastname: Berleau
authors.forename: H
authors.initials: H
authors.lastname: Nguyen
authors.forename: A
authors.initials: A
authors.lastname: Chow
authors.forename: J
authors.initials: J
authors.lastname: Lai
authors.forename: L
authors.initials: L
authors.lastname: Peña
authors.forename: C
authors.initials: C
authors.lastname: Pater
authors.forename: J
authors.initials: J
authors.lastname: Ogez
mesh_terms: D000818:Animals; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D011817:Rabbits; D013329:Structure-Activity Relationship; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics
chemical_list: D005343:Fibrinolytic Agents; D005337:Fibrin; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator