Antibody-directed fibrinolysis: a bispecific (Fab')2 that binds to fibrin and tissue plasminogen activator.
A bispecific (Fab')2 molecule was constructed by linking the monovalent Fab' from an anti-fibrin monoclonal antibody to the Fab' from an anti tissue plasminogen activator (tPA, single chain) monoclonal antibody by means of inter-heavy-chain disulfide bonds. An immunochemical complex composed of the bispecific (Fab')2 molecule bound to tPA [tPA-bispecific (Fab')2 complex] was then generated and purified. Its molecular weight was 170 kDa [less than half the molecular weight of a previously described tPA-bispecific antibody complex containing the entire anti-fibrin and anti-tPA immunoglobulin molecules; Runge, M. S., et al. (1987) Trans. Assoc. Am. Phys. 100, 250-255]. The tPA-bispecific (Fab')2 complex was 8.6-fold more efficient in fibrinolysis than tPA alone and 94-fold more potent than urokinase. This enhancement in the fibrinolytic potency of tPA compares favorably with that observed for the bispecific whole-antibody complex. These results suggest that this smaller, less immunogenic molecule is capable of binding both fibrin and tPA with high affinity and of enhancing the thrombolytic efficiency of exogenous and, perhaps, endogenous tPA.
Runge
M S
MS
Cardiac Unit, Massachusetts General Hospital, Boston 02114.
Bode
C
C
Savard
C E
CE
Matsueda
G R
GR
Haber
E
E
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005337:Fibrin / Q000276:immunology / Q000378:metabolism*; D005342:Fibrinolysis; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007128:Immunoglobulin Fragments / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D005337:Fibrin; D010959:Tissue Plasminogen Activator