University of California

Meyer Pharmaceuticals LLC

Tetsuya Gatanaga

Gale Arthur Granger

Ronald L Niece

Sheldon Broedel

The biological effects of the cytokine TNF are mediated by binding to receptors on the surface of cells. This disclosure describes new proteins and polynucleotides that promote enzymatic cleavage and release of TNF receptors. Also provided are methods for identifying additional compounds that influence TNF receptor shedding. As the active ingredient in a pharmaceutical composition, the products of this invention increase or decrease TNF signal transduction, thereby alleviating the pathology of disease.

Pharmaceutical compositions for treating arthritis and inflammatory disease

This disclosure describes inventions related to the use of biological agents that cause cytokine receptors to be released from the surface of cells. One aspect of this invention is based on the unexpected finding that extending the length of an exemplary agent at the N-terminus enhances expression and production of the product by at least 10-fold. The extended protein can be used to prepare pharmaceutical compositions for treating inflammatory conditions such as rheumatoid arthritis. Another aspect of this invention is based on the identification of biological agents that cause release of cytokine receptors not previously known as natural enzyme targets, such as the IL-1 Type I receptor, IL-1 Type II receptor and the IL-6 receptor. This disclosure provides products, assays, expression systems, purification methods, and production protocols useful for developing cytokine receptor releasing proteins as therapeutic agents.

Biological agent that causes IL-6 receptor release

The biological effects of the cytokine TNF are mediated by binding to receptors on the surface of cells. This disclosure describes new proteins and polynucleotides that promote enzymatic cleavage and release of TNF receptors. Also provided are method for identifying additional compounds that influence TNF receptor shedding. As the active ingredient in a pharmaceutical composition, the products of this invention increase or decrease TNF signal transduction, thereby alleviating the pathology of disease.

Method for producing TNF receptor releasing enzyme

Treating arthritis with TNF receptor releasing enzyme

Screening for drugs that affect TNF receptor releasing enzyme

The present invention relates to methods of regulating TNF activity indirectly by regulating the activity or concentration of TNF receptor releasing enzyme (TRRE). Preferably, the TRRE activity is regulated local to the site of the condition to be treated. In the case of diseases associated with elevated levels of TNF, such as rheumatoid arthritis, TRRE is administered to the site of inflammation in an amount sufficient to decrease the local levels of TNF. In the case of diseases, such as cancer, that benefit from increased levels of TNF, the level of TRRE is decreased at the disease site.

System for discovering and producing polypeptides that cause TNF receptor shedding

The present invention relates to methods of regulating TNF receptor releasing enzyme (TRRE) activity. Composition altering TRRE activity, including a family of proteins and the genes encoding these proteins having TRRE activity, are provided. These proteins, RNA products, or DNA sequences can be administered to individuals suffering from a disease characterized by abnormal TRRE activity. In the case of diseases associated with elevated levels of TNF, such as rheumatoid arthritis, an inhibitor of TRRE is administered to the disease site to decrease the local levels of TNF. Methods of isolating other compositons which increase or decrease TRRE activity are also provided.

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Irvine, CA, United States of America

Tetsuya Gatanaga