Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1998-10-13
2001-05-01
Allen, Marianne P. (Department: 1631)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C536S023500, C435S320100, C435S325000, C435S252300
Reexamination Certificate
active
06225088
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention identifies a new fibroblast-derived mitogen called plasminogen-like growth actor (PLGF) with activity on melanocytes, epithelial and endothelial cells. In particular, the present invention relates to the purification, molecular cloning and recombinant expression of PLGF which bears strong sequence homology to HGF but yet exhibits broad target cell specificity whose pattern is distinct from HGF and any other known growth factor.
2. Background of the Invention
Growth factors are widely believed to play important roles in normal development and wound healing. R. James and R. A. Bradshaw, Annu. Rev. Biochem. 53, 259 (1984); T. F. Deuel, Annu. Rev. Cell Biol. 3, 443 (1987); A. Barbul, E. Pines, M. Caldwell, T. K. Hunt, Eds., Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications. Progress in Clinical and Biological Research Vol 266 (Alan R. Liss, New York, 1988) Their abnormal expression has been implicated in neoplasia as well as a variety of other proliferative disorders. (M. B. Sporn and E. D. Harris, Jr., AM. J. Med. 70, 1231 (1981); A. S. Goustin, E. B. Leof, G. D. Shipley, H. L. Moses, Cancer Res. 46, 1015 (1986); M. B. Sporn, A. B. Roberts, J. Clin. Invest. 78, 329 (1986); R. Ross, New. Engl. J. Med. 314, 488 (1986). Accumulating evidence indicates that mesenchymal interactions presumably mediated by diffusible substances have a major impact on epithelial cell proliferation (G. R. Cunha, L. W. K. Chung, J. M. Shannon, O. Taguchi & H. Fujii, Recent Prog. Hormone Res. 39, 559 (1983); R. H. Sawyer and J. F. Fallow, Eds., Epithelial-Mesenchymal Interaction During Development (Praegerm New York, 1983); S. L. Schor, A. M. Howell & D. Crowther, Exp. Cell Biol. 55, 11 (1987), yet there is relatively little knowledge of such stromal cell effectors. Systematic efforts to isolate and characterize epithelial-acting mitogens produced by stromal cells have led to the discovery of keratinocyte growth factor (KGF), a new member of the FGF family, specific for epithelial cells. (J. S. Rubin, H. Finch, P. W. Taylor, W. G. Rudikoff & S. A. Aaronson, Proc. Natl. Acad. Sci. U.S.A. 86, 802-806 (1989); P. W. Finch et al., Science 245, 752 (1989).
It is clear that a need exists for identifying new epithelial cell mitogenic activities produced by stromal fibroblasts. The present invention describes the purification and molecular cloning of a new growth factor called PLGF derived from stromal fibroblasts possessing a novel spectrum of target cells and its unexpected homology to other proteins involved in growth and tissue remodeling.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a biologically active growth factor called plasminogen-like growth factor (PLGF) having cell specificity for melanocytes, endothelial cells and epithelial cells and methods of treating wounds and tissue regeneration therewith.
Various other objects and advantages of the present invention will become obvious from the drawings and the following description of the invention.
In one embodiment, the present invention relates to plasminogen-like growth factor (PLGF) protein that is substantially free of proteins with which PLGF is normally associated and antibodies specific therefor.
In another embodiment, the present invention relates to a DNA segment encoding PLGF protein.
In yet another embodiment, the present invention relates to a DNA segment encoding the PLGF protein and recombinant constructs comprising the same.
In a further embodiment, the present invention relates to a a host cell comprising the above described DNA construct.
Another embodiment of the present invention relates to a process of making PLGF. The method comprises culturing host cells described above under conditions such that the DNA segment encoding PLGF is expressed and produced, and isolating the PLGF protein.
In a further embodiment, the present invention relates to methods of inhibiting cell proliferation comprising administering a therapeutic amount of antibody specific for PLGF protein to an animal.
In yet another embodiment, the present invention relates to a method of stimulating the growth of cells in which PLGF is contacted to cells under conditions such that stimulation of cell growth is effected.
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T. Nakamura et al., “Molecular Cloning and Expression of Human Hepatocyte Growth Factor”,Nature342: 440-443 (1989).
K. Miyazawa et al., “Molecular Cloning and Sequence Analysis of cDNA For Human Hepatocyte Growth Factor”,Biochem. And Biophys. Res. Comm.163(2): 967-973 (1989).
Gherardi et al., “Purification of Scatter Factor, a Fibroblast-Derived Basic Protein That Modulates Epithelial Interactions and Movement”, Proc. Natl. Acad. Sci. USA, vol. 86, pp. 5844-5848, 1989.
Nakamura et al., “Purification and Subunit Structure of Hepatocyte Growth Factor from Rat Platelets”, Febs Letters, vol. 224, No. 2, pp. 311-316, 1987.
Eiichi Gohda, et al., Purification and Partial Characterization of Hepatocyte Growth Factor from Plasma of a Patient with Fulminant Hepatic Failure, A.S.C.I, Feb. 1988, pp. 414-419.
Reza Zarnegar, et al., Purification and Biological Characterization of Human Hepatopoietin A, a Polypeptide Growth Factor for Hepatocytes, Cancer Research 49, Jun. 15, 1989, pp. 3314-3320.
Sone, S. et al.,Biotherapy, 1(3): 233-43, 1989. (Abstract only.).*
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Higashio, K. et al.,BBRC, 170(1): 397-404, Jul. 16, 1990. (Abstract only.).
Aaronson Stuart A.
Chan Andrew M. L.
Rubin Jeffrey S.
Allen Marianne P.
Needle & Rosenberg P.C.
The United States of America as represented by the Department o
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