Title: Comparative study of inhibitory antibody derivatives towards thrombin activatable fibrinolysis inhibitor
Authors: Develter, Jan
Dewilde, Maarten
Gils, Ann
Declerck, Paul # ×
Issue Date: Jul-2009
Publisher: Schattauer gmbh-verlag medizin naturwissenschaften
Series Title: Thrombosis and haemostasis vol:102 issue:1 pages:69-75
Abstract: Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis and is considered as an attractive drug target. We generated two different antibody fragments,an antigen-binding fragment (Fab) and a single-chain variable fragment (scFv), derived from three distinct monoclonal antibodies (MAs) that inhibit the activation of TAR by the thrombin/thrombomodulin complex (T/TM) and plasmin (MA-TIC 10 and MA-T94H3) or by T/TM alone (MA-T12D11). The Fabs were obtained by papain digestion of the purified MAs, whereas the scFvs were cloned and subsequently expressed in bacteria. All antibody fragments revealed similar or slightly decreased affinities compared to those of the respective MAs, except scFv-T94H3. In the presence of a 16-fold molar excess of all antibody fragments, activation of TAFI by T/TM was completely blocked. Furthermore, Fab and scFv-derivatives from MA-TIC10 and MA-T94H3 were capable of interfering with the plasmin-mediated activation of TAFI. Addition of 850 nM of MA, Fab or scFv to an in-vitro clot lysis assay caused a significant reduction of clot lysis time (except for scFv-T94H3) and this effect was comparable to that of potato tuber carboxypeptidase inhibitor, a well-known TAFIa inhibitor. Dose-response experiments with the antibody (derivatives) in clot lysis and chromogenic assay revealed that the inhibitory capacity of the Fabs was comparable to that of the MAs, whereas the scFvs had a more reduced potency. In conclusion, these highly specific TAFI inhibitors are interesting tools to further evaluate the concept of TAR inhibition in various in-vitro and in-vivo models.
ISSN: 0340-6245
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Pharmaceutical Biology (-)
× corresponding author
# (joint) last author

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