Modulation of TAFI function through different pathways – implications for the development of TAFI inhibitors

Objective: To elucidate the mechanism and the binding regions of monoclonal antibodies (MA) that interfere with thrombin‐activatable fibrinolysis inhibitor (TAFI)/activated thrombin‐activatable fibrinolysis inhibitor (TAFIa) activity. Results: Of 42 MA, 19 interfere with the TAFI activation/TAFIa ac...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2005-12, Vol.3 (12), p.2745-2753
Main Authors: GILS, A., CERESA, E., MACOVEI, A. M., MARX, P. F., PEETERS, M., COMPERNOLLE, G., DECLERCK, P. J.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
Binding Sites
Carboxypeptidase B2 - antagonists & inhibitors
Carboxypeptidase B2 - genetics
Carboxypeptidase B2 - metabolism
epitope
Fibrinolysin - metabolism
fibrinolysis
Genetic Variation
Humans
Mice
monoclonal antibody
proCPU
Protein Interaction Mapping
Thrombin - metabolism
thrombin‐activatable fibrinolysis inhibitor
Thrombomodulin - metabolism
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Summary:Objective: To elucidate the mechanism and the binding regions of monoclonal antibodies (MA) that interfere with thrombin‐activatable fibrinolysis inhibitor (TAFI)/activated thrombin‐activatable fibrinolysis inhibitor (TAFIa) activity. Results: Of 42 MA, 19 interfere with the TAFI activation/TAFIa activity resulting in an inhibition of up to 92%. Characterization of the mechanism of inhibition revealed that 14 MA blocked the activation of TAFI by thrombin/thrombomodulin completely whereas five MA interfered directly with the enzymatic activity of TAFIa. Surprisingly, the former, except one, induced a significant reduction of clot lysis time whereas the latter did not. Affinity studies using a human/murine TAFI chimer revealed that the binding region of the 14 activation blocking MA is located between AA1 and AA67. MA that inhibit exclusively the activation of TAFI by thrombin/thrombomodulin bind to Gly66. A MA that inhibits the activation of TAFI by both thrombin/thrombomodulin and plasmin binds to Val41. The MA that interfere with the enzymatic activity bind to the TAFIa moiety. Conclusions: The current study reveals at least three different putative molecular targets in the search for pharmacologically active compounds to modulate TAFIa activity.
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2005.01629.x