Children's Medical Center Corporation

Karolinska Innovations Ab

Yihai Cao

M Judah Folkman

Michael S O'Reilly

Judah M Folkman

Kim Lee Sim

Nucleic acid sequence encoding kringle region fragment of plasminogen vectors comprising such nucleic acid, and methods of use of such nucleic acids, Ribonucleic and deoxyribonucleic acid sequence that encode for kringle region fragments are useful for gene therapy or recombinant expression for the treatment of angiogenesis-related diseases, specifically angiogenesis-dependent cancer.

Nucleic acids encoding plasminogen fragments and methods of use

The present invention provides plasminogen fragments containing kringle region domains having anti-angiogenic activity and termed angiostatin protein. The plasminogen fragments of the present invention may be used for the treatment of angiogenesis-dependent diseases such as cancer.

Angiostatin protein

Proteolytic enzymes are involved in generation of a number of endogenous angiogenesis inhibitors and it has been shown that urokinase-activated plasmin can process plasminogen to release an angiogenesis inhibitor, K1&#x2013;5 (protease-activated kringles 1&#x2013;5). However, this proteolytic protein (proteolytic K1&#x2013;5) cannot be secreted (exported) from cells and thus is limited in its application as a therapeutic. The present inventor has now engineered a recombinant protein derived from plasminogen which is folded correctly such that it can be secreted from cells in which it is expressed. The inventor surprisingly found that in order to fold correctly such that it can be secreted, the recombinant protein must comprise a secretory signal peptide and a pre-activation peptide derived from plasminogen.

Materials and methods relating to endothelial cell growth inhibitors

The present invention provides methods of inhibiting angiogenesis by increasing the concentration of kringle region fragments of plasminogen molecules in vivo. The methods of the present invention may be used for the treatment of angiogenesis-dependent diseases such as cancer.

Methods of inhibiting angiogenesis via increasing in vivo concentrations of kringle region fragments of plasminogen

Nucleic acid sequences encoding kringle region fragments of plasminogen. Ribonucleic and deoxyribonucleic acid sequences that encode for kringle region fragments are useful for gene therapy or recombinant expression for the treatment of angiogenesis-related diseases, specifically angiogenesis-dependent cancer.

Nucleic acids encoding plasminogen fragments

Fragments of an endothelial cell proliferation inhibitor and method of use therefor are provided. The endothelial proliferation inhibitor is a protein derived from plasminogen, or more specifically is an angiostatin fragment. The angiostatin fragments generally correspond to kringle structures occurring within the endothelial cell proliferation inhibitor. The endothelial cell inhibiting activity of these fragments provides a means for inhibiting angiogenesis of tumors and for treating angiogenic-mediated disease.

Angiostatin fragments and method of use

The present invention comprises an endothelial inhibitor and method of use therefor. The endothelial cell proliferation inhibitor is a protein having a molecular weight of approximately 14 kD and having an amino acid sequence substantially similar to Kringle 5 of a plasminogen molecule, that has the ability to inhibit endothelial cell proliferation in in vitro assays.

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Stockholm, Sweden

Yihai Cao