Oklahoma Medical Research Foundation

Philip C Comp

Charles T Esmon

A method of inhibiting microvascular bleeding is provided. Antibody to protein C administered to a patient in a pharmaceutically acceptable carrier prevents anticoagulation by greater than 90% of activated protein C in human plasma.

Blockade of protein C activation reduces microvascular surgical blood loss

Compositions, and methods of use thereof, for the inhibition of tumor growth and killing of solid tumors wherein the active agent is a compound blocking the Protein C system, preferably anti-Protein C antibody, anti-Protein S antibody, and C4b binding protein. In the most preferred embodiment, the Protein C blocking compound is provided in combination with a cytokine such as tumor necrosis factor (TNF), gamma interferon, interleukin-1, interleukin-2,p or granulocyte-macrophage colony stimulating factor, or a compound eliciting cytokine production such as endotoxin. Examples are provided demonstrating the administration of the Protein C blocking compound, alone or in combination with TNF or endotoxin, to animals having canine veneral tumors, a fibrosarcoma, and an adenocarcinoma, followed by significant tumor reduction.

Inhibition of tumor growth by blockade of the protein C system

It has been discovered that it is possible to administer truncated tissue factor, not having the transmembrane region (tTF) in combination with factor VIIa (FVIIa) to treat bleeding disorders such as those resulting from hemophilia or cirrhosis of the liver. Preferably, the tTF is administered to produce up to 10 .mu.g tTF/ml of plasma. The FVIIa is administered to produce levels of between 40 ng FVIIa/ml and 4 .mu.g FVIIa/ml of plasma. The effective dosages of both tTF and FVIIa are significantly and surprisingly less than the administration of either alone to stop bleeding. Examples demonstrate safety and efficacy in normal and hemophilic dogs.

Treatment of bleeding with modified tissue factor in combination with

It has been discovered that it is possible to administer truncated tissue factor (not having the transmembrane region) (tTF) in combination with factor VIIa (FVIIa) or an activator of endogenous factor VII to treat bleeding disorders such as those resulting from hemophilia or cirrhosis of the liver. The tTF is administered to produce up to 10 .mu.g tTF/ml of plasma. The FVIIa or FVII activator is administered to produce levels of between 40 ng FVIIa/ml and 700 ng FVIIa/ml of plasma. The effective dosages of both tTF and FVIIa/factor VII activator are significantly and surprisingly less than the administration of either alone to stop bleeding. Examples demonstrate safety and efficacy in normal and hemophilic dogs.

Treatment of bleeding with modified tissue factor in combination with an

It has been discovered that it is possible to administer truncated tissue factor (not having the transmembrane region) (tTF) in combination with factor VIIa (F VIIa) to treat bleeding disorders such as those resulting from hemophilia or cirrhosis of the liver. The tTF is administered to produce up to 10 .mu.g tTF/ml of plasma. The F VIIa is administered to produce levels of between 40 ng VIIa/ml and 4 .mu.g F VIIa/ml of plasma. The effective dosages of both tTF and VIIa are significantly and surprisingly less than the administration of either alone to stop bleeding. Examples demonstrate safety and efficacy in normal and hemophilic dogs.

Compositions, and methods of use thereof, for the inhibition of tumor growth and killing of tumors having extensive microcirculation wherein the active agent is a compound blocking the Protein C system, preferably anti-Protein C antibody, anti-Protein S antibody, and C4b binding protein. In the most preferred embodiment, the Protein C blocking compound is provided in combination with a cytokine such as tumor necrosis factor (TNF), gamma interferon, interleukin-1, interleukin-2 and granulocyte-macrophage colony stimulating factor. Examples are provided demonstrating the administration of the Protein C blocking compound, alone or in combination with TNF, to dogs having canine veneral tumors, or fibrosarcoma, and an adenocarcinoma, and pigs with melanoma followed by significant tumor reduction.

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Oklahoma City, OK, United States of America

Philip C Comp