FUSION PROTEINS FOR INHIBITION AND DISSOLUTION OF COAGULATION OF THROMBI
Fusion proteins containing a ligand which specifically binds to a selected vascular bed linked to an anti-thrombotic molecule are provided. Also provided are methods for use of these fusion proteins to prevent coagulation, to dissolve blood clots and to protect against the risk of iatrogenic side effects including those arising from cancer therapy and specific vascular occluding agents.
1 . (canceled)
2 . The method of claim 20 wherein said anti-thrombotic molecule has fibrinolytic, anticoagulant or platelet inhibiting activity.
3 - 4 . (canceled)
5 . The method of claim 20 wherein said anti-thrombotic molecule activates a precursor of an anti-coagulant to an active anti-coagulant.
6 . The method of claim 20 wherein said anti-thrombotic molecule comprises a plasminogen activator or active fragment thereof or an anticoagulant.
7 . The method of claim 6 wherein the plasminogen activator comprises tissue plasminogen activator, urokinase, tenectase, retavase, streptokinase or staphylokinase or an active fragment thereof.
8 . The method of claim 20 wherein said anti-thrombotic molecule is thrombomodulin.
9 . The method of claim 20 wherein the anticoagulant comprises protein C or activated protein C.
10 . The method of claim 20 wherein said anti-thrombotic molecule is activated locally at a site of a pathological process by a pathological factor presented at the site of the pathological process.
11 . The method of claim 10 wherein the pathological factor is a component of blood coagulation.
12 . The method of claim 10 wherein the site of the pathological process is a site of active thrombosis and the pathological factor is thrombin.
13 . The method of claim 10 wherein the pathological factor is a protease.
14 . The method of claim 20 wherein said ligand or said anti-thrombotic molecule comprises a natural or artificial protease cleavage site for activation or release.
15 . The method of claim 20 wherein said fusion protein is a recombinant fusion protein.
16 . The method of claim 20 wherein said fusion protein is delivered in a pharmaceutically acceptable vehicle.
17 . A method for inhibiting coagulation in a selected vascular bed of an animal comprising administering to said animal a fusion protein comprising a ligand which specifically binds to a luminal surface of vascular endothelium linked to an anti-thrombotic molecule, wherein the ligand comprises a single chain antigen-binding domain (scFv) of a monoclonal antibody that specifically binds to PECAM-1 or ICAM-1.
18 . A method for dissolving blood clots in a selected vascular bed of an animal diagnosed as being predisposed or at high risk for thrombosis or thrombosis recurrence comprising prophylactically administering to said animal a fusion protein comprising a ligand which specifically binds to a luminal surface of vascular endothelium linked to an anti-thrombotic molecule, wherein the ligand comprises a single chain antigen-binding domain (scFv) of a monoclonal antibody that specifically binds to PECAM-1 or ICAM-1.
19 . (canceled)
20 . A method for enhancing effects of an anti-thrombotic molecule in an animal comprising administering to said animal a fusion protein comprising a ligand which specifically binds to a luminal surface of vascular endothelium linked to an anti-thrombotic molecule, wherein the ligand comprises a single chain antigen-binding domain (scFv) of a monoclonal antibody that specifically binds to PECAM-1 or ICAM-1.