title: Monoclonal antibodies targeting the antifibrinolytic activity of activated thrombin-activatable fibrinolysis inhibitor but not the anti-inflammatory activity on osteopontin and C5a.
abstract: BACKGROUND
  Recently, anti-thrombin-activatable fibrinolysis inhibitor (TAFI) mAbs selectively inhibiting plasmin-mediated TAFI activation were shown to stimulate fibrinolysis in vitro and in vivo, suggesting, in contrast to other findings, that plasmin-mediated TAFI activation plays an important role in fibrinolysis regulation.
  
  
  OBJECTIVE
  To further characterize the effects of two plasmin-specific anti-TAFI mAbs (MA-TCK11A9 and MA-TCK26D6) on TAFI-dependent inhibition of fibrinolysis.
  
  
  RESULTS
  Both mAbs inhibited plasmin-mediated but not thrombin/thrombomodulin-mediated TAFI activation, whereas neither inhibited the cleavage of hippuryl-arginine by activated TAFI (TAFIa). They stimulated tissue-type plasminogen activator-induced fibrinolysis in different clot lysis models through a TAFI-dependent mechanism, especially in the presence of thrombomodulin (TM), a condition in which TAFI is largely activated by the thrombin-TM complex. In a fibrinolysis-based TAFIa activity assay, both mAbs inhibited TAFIa, whereas other mAbs targeting thrombin-TM-mediated TAFI activation did not. The inhibition of TAFIa activity, however, was substrate-specific, because neither mAb inhibited the cleavage of thrombin-activated osteopontin and C5a by TAFIa, thus sparing the anti-inflammatory activity of TAFIa.
  
  
  CONCLUSIONS
  Our anti-TAFI mAbs, by selectively inhibiting TAFIa activity on fibrin, may represent the prototype of a new class of TAFI inhibitors with improved pharmacologic activity.
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Section of General and Experimental Pathology, Aldo Moro University, Bari, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Semeraro
authors.forename: C T
authors.initials: CT
authors.lastname: Ammollo
authors.forename: A
authors.initials: A
authors.lastname: Gils
authors.forename: P J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: M
authors.initials: M
authors.lastname: Colucci
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D025901:Carboxypeptidase B2 / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology* / Q000502:physiology; D005342:Fibrinolysis / Q000276:immunology*; D006801:Humans; D053495:Osteopontin / Q000276:immunology* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D053495:Osteopontin; D015936:Complement C5a; D025901:Carboxypeptidase B2
keywords: fibrinolysis; inflammation; plasmin; thrombin; thrombin-activatable fibrinolysis inhibitor