University of Toledo

Medical College of Ohio

Jerzy Jankun

Steven H Selman

Ewa Skrzypczak-Jankun

Richard K Hart

Joanna Chorostowska-Wynimko

Rafal Swiercz

The present invention relates to a modified plasminogen activator inhibitor type-1 (PAI-1) molecule that displays an increased in vivo half-life of the active form of PAI-1, but is deficient in one or more functional activities as compared to the wild-type PAI-1 protein. The modified PAI-1 molecule that displays an increased half-life further displays at least one of the following functional characteristics: (i) decreased binding activity to at least one of the following molecules: urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and vitronectin (Vn); and (ii) decreased specific activity against at least one of the following molecules: uPA, tPA and Vn. The invention further relates to pharmaceutical compositions comprising modified PAI-1 molecules and methods of using these pharmaceutical compositions for treatment.

Modified plasminogen activator inhibitor type-1 molecule and methods based thereon

The present invention is based upon the discovery that modified plasminogen activator inhibitor type-I (PAI-1) in which two or more amino acid residues that do not contain a sulfhydryl group have been replaced with amino acid residues that contain a sulfhydryl group and, therefore, forms intramolecular disulfide bonds, have increased in vivo half-life. Also disclosed are the modified PAI-1 proteins, derivatives and analogs thereof, specific antibodies, nucleic acid molecules and host cells. Methods for producing modified PAI-1, derivatives and analogs are also provided. The invention further relates to Therapeutics, pharmaceutical compositions and method of using the composition for treatment. The invention may be used to inhibit angiogenesis in a subject, thereby treating diseases or conditions associated with undesired angiogenesis and cell proliferation. Such conditions include psoriasis, chronic inflammation, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. The modifide PAI-1 molecules of the present invention are useful for the treatment, prophylaxis, management and amelioration of cardiovascular diseases such as, but not limited to those that are related to hyperfibrinolysis, hemophilia, and vessel leakage syndrome.

Modified plasminogen activator inhibitor type-1 and methods based thereon

A method of delivering a medicament to the surface of a cancer cell and transferring the medicament into the cancer cell using an activated plasminogen activator material such as a plasminogen activator inhibitor type-1 or type-2 (PAI-1, PAI-2). The medicament is coupled to PAI-1 or PAI-2 to form a reaction product that is coupled with the urokinase plasminogen activator (uPA) that is bound to the cell surface by the uPA receptor (uPAR). The medicament is coupled to PAI-1 or PAI-2 (for example, using a preserving agent such as saporin) in such a way that the medicament does not interfere with active sites responsible for binding to uPA or LRP proteins responsible for the internalization of the plasminogen activator material/conjugated medicament. The conjugated medicament prevents the conversion of the plasminogen activator inhibitor material into its latent inactive form. The resulting complex is internalized into the cancer cell to deliver the medicament within the cell.

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Sylvania, OH, United States of America

Jerzy Jankun