Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1994-06-13
2003-01-21
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S350000
Reexamination Certificate
active
06509314
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to cell biology and more specifically to the control of cell proliferation. Proteoglycans are proteins that carry one or more glycosaminoglycan chains. The known proteoglycans carry out a wide variety of functions and are found in a variety of cellular locations. Many proteoglycans are components of extracellular matrix, where they participate in the assembly of cells and effect the attachment of cells to the matrix.
Decorin, also known as PG-II or PG-40, is a small proteoglycan produced by fibroblasts. Its core protein has a molecular weight of about 40,000 daltons. The core has been sequenced (Krusius and Ruoslahti, Proc. Natl. Acad. Sci. USA 83:7683 (1986); Day et al. Biochem. J. 248:801 (1987), both of which are incorporated herein by reference) and it is known to carry a single glycosaminoglycan chain of a chondroitin sulfate/dermatan sulfate type (Pearson, et al., J. Biol. Chem. 258:15101 (1983), which is incorporated herein by reference). The only previously known function for decorin is binding to type I and type II collagen and its effect on the fibril. formation by these collagens (Vogel, et al., Biochem. J. 223:587 (1984); Schmidt et al., J. Cell Biol. 104:1683, (1987)). Two proteoglycans, biglycan (Fisher et al., J. Biol. Chem. 264:4571 (1989)) and fibromodulin, (Oldberg et al., Embo J. 8:2601, (1989) have core proteins the amino acid sequences of which are closely related to that of decorin and they, together with decorin, can be considered a protein family. Each of their sequences is characterized by the presence of a leucine-rich repeat of about 24 amino acids. Several other proteins contain similar repeats. Together all these proteins form a superfamily of proteins (Ruoslahti, Ann. Rev. Cell Biol. 4:229, (1988); McFarland et al., Science 245:494 (1989)).
Transforming growth factor &bgr;'s (TGF&bgr;) are a family of multi-functional cell regulatory factors produced in various forms by many types of cells (for review see Sporn et al., J. Cell Biol. 105:1039, (1987)). Five different TGF&bgr;'s are known, but the functions of only two, TGF&bgr;-1 and TGF&bgr;-2, have been characterized in any detail. TGF&bgr;'s are the subject of U.S. Pat. Nos. 4,863,899; 4,816,561; and 4,742,003 which are incorporated by reference. TGF&bgr;-1 and TGF&bgr;-2 are publicly available through many commercial sources (e.g. R & D Systems, Inc., Minneapolis, Minn.). These two proteins have similar functions and will be here collectively referred to as TGF&bgr;. TGF&bgr; binds to cell surface receptors possessed by essentially all types of cells, causing profound changes in them. In some cells, TGF&bgr; promotes cell proliferation, in others it suppresses proliferation. A marked effect of TGF&bgr;. is that it promotes the production of extracellular matrix proteins and their receptors by cells (for review see Keski-Oja et al., J. Cell Biochem 33:95 (1987); Massague, Cell 49:437 (1987); Roberts and Sporn in “Peptides Growth Factors and Their Receptors”[ Springer-Verlag, Heidelberg] in press (1989)).
While TGF&bgr; has many essential cell regulatory functions, improper TGF&bgr; activity can be detrimental to an organism. Since the growth of mesenchyme and proliferation of mesenchymal cells is stimulated by TGF&bgr;, some tumor cells may use TGF&bgr; as an autocrine growth factor. Therefore, if the growth factor activity of TGF&bgr; could be prevented, tumor growth could be controlled. In other cases the inhibition of cell proliferation by TGF&bgr; may be detrimental, in that it may prevent healing of injured tissues. The stimulation of extracellular matrix production by TGF&bgr; is important in situations such as wound healing. However, in some cases the body takes this response too far and an excessive accumulation of extracellular matrix ensues. An example of excessive accumulation of extracellular matrix is glomerulonephritis, a disease with a detrimental involvement of TGF&bgr;.
Thus, there exists a critical need to develop compounds that can modulate the effects of cell regulatory factors such as TGF&bgr;. The present invention satisfies this need and provides related advantages.
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting an activity of a cell regulatory factor comprising contacting the cell regulatory factor with a purified polypeptide, wherein the polypeptide comprises a cell regulatory factor binding domain of a protein and wherein the protein is characterized by a leucine-rich repeat of about 24 amino acids. In a specific embodiment, the present invention relates to the ability of decorin, a 40,000 dalton protein that usually carries a glycosaminoglycan chain, to bind TGF&bgr;. The invention also provides a novel cell regulatory factor designated Morphology Restoring Factor, (MRF). Also provided are methods of identifying, detecting and purifying cell regulatory factors and proteins which bind and affect the activity of cell regulatory factors.
The present invention further relates to methods for the prevention or reduction of scarring by administering decorin or a functional equivalent of decorin to a wound. The methods are particularly useful for dermal wounds resulting from burns, injuries or surgery. In addition, the present invention includes pharmaceutical compositions containing decorin or its functional equivalent and a pharmaceutically acceptable carrier useful in such methods. Finally, methods for preventing or inhibiting pathological conditions by administering decorin are also provided.
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Bassols and Massague, Transforming
Border Wayne A.
Ruoslahti Erkki I.
Campbell & Flores LLP
Gambel Phillip
The Burnham Institute
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