Yeda Research and Develpment & Co. Ltd

Ibex Technologies R and D, Inc.

Hadassa Medical Organization

Israel Vlodavsky

Irun R Cohen

Yaakov Naparstek

Amiram Eldor

Joseph J Zimmermann

Clark Bennett

Pamela Danagher

Richard Broughton

Glycosaminoglycans, including heparinases 1, 2 and 3 as well as chondroitinases AC and B from the Gram negative bacteria Flavobacterium heparinum, can be used either separately or in combination to manipulate cell proliferation. In one embodiment, heparinases are administered to degrade heparan sulfate components of the extracellular matrix, thereby allowing the heparin binding growth factors which are stored in the extracellular matrix to migrate to adjacent cells. The mobility of chemoattractant agents, growth factors and cells also can be increased by treating tissues with glycosaminoglycan degrading enzymes, both chondroitinases and heparinases. The enzymatic removal of chondroitin sulfates from cell surfaces effectively increases the availability of growth factor receptors on the cell's surface. Selectively removing heparan sulfate from cell surfaces while leaving the extracellular matrix intact, conversely, inhibits cell proliferation by down regulating the cell's response to growth factors. This is achieved by targeting heparin or heparan sulfate degrading activities to the cell surface. Targeting the heparin degrading activity can be achieved by genetically engineering a ligand binding functionality into the heparinase proteins, or by physically controlling the localized enzyme concentration through the method of administration.

Attenuation of wound healing processes

Heparanase activity in a patient may be inhibited by administering an effective heparanase-inhibiting amount of heparin or an effective chemically modified derivative of heparin which inhibits heparanase activity. Such derivatives are preferably N-desulfated, N-acetylated heparin or O-desulfated, N-acetylated heparin. By means of this invention, allograft rejection may be prevented or delayed and autoimmune diseases such as arthritis may be alleviated and treated.

Method for inhibiting heparanase activity

The invention relates to pharmaceutical compositions intended to decrease the incidence of tumor metastasis in patients who suffer from malignant diseases. The pharmaceutical compositions of the invention contain as active ingredient heparin or a suitable derivative thereof. Amongst suitable derivatives are N-desulfated and N-acetylated heparin. The dosage of the administered heparin or heparin derivative is quite critical and will generally be in the range of from 0.05 mg/kg/day to about 0.5 mg/kg/day. A preferred range is between about 0.1 mg/kg/day to about 0.5 mg/kg/day.

Method for decreasing tumor metastasis

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Jerusalem, Israel

Israel Vlodavsky