Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds expression product or fragment thereof of...
Reexamination Certificate
1994-05-06
2002-07-23
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds expression product or fragment thereof of...
C424S198100, C435S007230, C530S388250, C530S388260
Reexamination Certificate
active
06423313
ABSTRACT:
BACKGROUND OF THE INVENTION
This is generally in the area of compositions for treatment of cancer, in particular, compositions containing blockers of the protein C system in combination with a lymphokine.
A variety of mechanisms in tumors capable of promoting clot formation have been described (Dvorak, H. F.
Human Path
. 18,275-284 (1987); Rickles, F. R., Hancock, W. W., Edwards, R. L., et al.
Sem.Thromb.Hemost
. 14,88-94 (1988)). Initially, the discovery of extravascular fibrin deposits in a variety of animal and human tumors prompted the search for these tumor-associated clotting mechanisms. This extravascular fibrin disposition has been found in association with prothrombin, factor VII and factor X in certain tumor cells in situ by immunohistochemical techniques. A heat- and acid-stable glycoprotein present in mucin produced by certain adenocarcinomas is capable of catalyzing the conversion of factor X to factor X
a
. A 68,000 dalton cysteine protease has been identified in a number of tumor lines which activates factor X, independent of the actions of factor VII
a
and tissue factor. Some tumor homogenates display tissue factor activity, while other tumor cell lines have cell membranes with receptors for factor V
a
and are capable of catalyzing the conversion of prothrombin to thrombin. Abnormalities in coagulation parameters observed in certain cancer patients has prompted the hypothesis that tumor-associated clotting may be of sufficient magnitude to cause systemic activation of the clotting system.
Alterations in the fibrinolytic system are observed in tumors and transformed cells. Plasminogen activator activity has been found to be higher in extracts of surgically excised human cancer tissues than in surrounding benign tissue. In addition to other possible roles for plasminogen activator, such as participation in tumor invasion of normal tissue, this suggests that tumors have the capacity to promote fibrin degradation. Urokinase-type plasminogen activator appears to be produced by tumors with greater frequency than tissue-type plasminogen activator. It is not known if the production of plasminogen activators by tumors is involved in preventing thrombus accumulation within the bed of the tumor.
Protein C is a vitamin K-dependent plasma protein. Activated protein C serves as a natural anticoagulant by inhibiting the clotting cascade at the levels of factor V
a
and factor VIII
a
(Walker, F. J., Sexton, P. W. and Esmon, C. T.
Biochim.Biophys.Acta
571,333-342 (1979); Fletcher, C. A., Gardiner, J. E., Griffin, J. H., et al.
Blood
63,86-49 (1984)). Protein C is rapidly converted to activated protein C by a complex of thrombin and the endothelial cell surface protein, thrombomodulin. Thrombomodulin forms a 1:1 stoichiometric complex with thrombin and increases the rate at which thrombin activates protein C by approximately 20,000-fold. This activation occurs primarily in the capillaries, where the availability of a large endothelial surface area per unit of plasma volume favors complex formation between thrombin and thrombomodulin. The activation of protein C in the microvasculature forms a potential feedback loop which, when thrombin is formed in the circulation, generates activated protein C. The activated protein C in turn inhibits further thrombin formation. This has been demonstrated directly in dogs, where low level intravenous thrombin infusion results in the generation of activated protein C and anticoagulation of the animal. A more complete review of the roles of thrombomodulin and protein C in regulation of blood coagulation is by C. T. Esmon, in
J. Biol. Chem
. 264(9), 4743-4746 (1989).
Thrombomodulin has been identified on a variety of cultured endothelial cell lines and on the luminal surface of blood vessels (Esmon, N. L.
Semin.Thromb.Hemost
. 13,454-463 (1987)). Thrombomodulin has also been identified by functional and immunochemical means on tumor cells, including human lung carcinoma -line CL-185 and Bowes melanoma cells (Marks, C. A., Bank, N. U., Mattler, L. E., et al.
Thromb.Hemost
. 54,119 (1985)), A549 human lung cancer cells (Maruyama, I. and Majerus, P. W.
Blood
69,1481-144 (1987)), and angiosarcomas (Yonezawa, S., Maruyama, I., Sakae, K., et al.
Am.J.Clin.Pathol
. 88,405-11 (1987)). The functional role of thrombomodulin on the tumor cells is subject to speculation. Tumor associated thrombomodulin may help to protect the tumor from excess fibrin formation. If the protein C-thrombomodulin system is involved in determining the hemostatic balance in the tumor vasculature, blocking protein C activation may shift the hemostatic balance and result in thrombosis of tumor vessels.
In addition to functioning as an anticoagulant, activated protein C promotes fibrinolysis. This action involves complex formation between activated protein C and two inhibitors of plasminogen activator, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 3 (PAI-3). Complex formation between activated protein C and PAI-1 or PAI-3 may serve to protect plasminogen activators from inhibition and can thus potentially result in an increase in fibrinolytic activity. The extent to which in vivo protein C influences fibrinolytic activity in the body or in tumor beds in particular is unknown.
Protein S, another vitamin K-dependent plasma protein, serves as a cofactor for the anticoagulant and fibrinolytic effects of activated protein C (Walker, F. J.
Semin. Thromb. Hemost
. 10,131-138 (1984); de Fouw, N. J., Haverkate, F., Bertina, R. M., et al.
Blood
67, 1189-1192 (1986). Protein S exists in two forms in plasma. Forty percent of the protein S is free and serves as a cofactor for activated protein C, and 60% is in complex with C4b binding protein and is functionally inactive. C4b binding protein is an acute phase protein (Boerger, L. M., Morris, P. C., Thurnau, G. R., et al.
Blood
69,692-694 (1987); Dahlblack, B. J.Biol.Chem. 261,12022-12027 (1986)) and thus inflammation, by elevating the levels of C4 binding protein, may shift protein S to the inactive form by the law of mass action. This shift in protein S status may predispose to thrombosis. Hereditary protein S deficiency, at least in some kindreds, is linked to an increased risk of venous thrombosis. See, for example, P. C. Comp, et al.,
J. Clin. Invest
. 74, 2082-2088 (1984).
While heterozygous protein C deficiency in certain kindreds is also associated with an increased risk of venous thrombosis, two other protein C deficiency states are characterized by tissue necrosis: homozygous protein C deficiency and the coumarin-induced skin necrosis observed in heterozygous protein C deficient individuals after the initiation of coumarin therapy. In homozygous deficient individuals, skin necrosis occurs on the first or second day of life, resulting in a clinical condition termed purpura fulminans neonatalis. Thrombosis of the small vessels of the skin is characteristic, leading to loss of large areas of skin, which is often fatal. Major vessel thrombosis is also possible.
When oral anticoagulant therapy is initiated in heterozygous protein C deficient patients, extensive microvascular thrombosis may occur. The skin is again the primary target and extensive loss of skin and underlying tissue can occur. The postulated mechanism is a rapid fall in protein C levels in the heterozygous deficient individuals before the levels of clotting factors with a long half-life, such as prothrombin and factor IX, decrease to levels adequate for systemic anticoagulation. A transient hypercoagulable state may exist in these individuals and it is during this period that the tissue necrosis occurs.
Heterozygous protein C deficiency is relatively common in the population and may occur as frequently as 1 in 300 individuals. Coumarin necrosis is rare and this suggests that factors other than protein C deficiency alone must be present. A review of the literature indicates that most patients developing necrosis have some inflammatory condition as well such as an infection, recent surgery or extensive venous thrombi. These ac
Comp Philip C.
Esmon Charles T.
Eyler Yvonne
Holland & Knight LLP
Oklahoma Medical Research Foundation
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