Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-01-17
2002-10-15
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S012200, C514S021800, C514S411000, C530S300000, C530S350000, C435S068100, C435S069100, C424S094640
Reexamination Certificate
active
06465424
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions useful to inhibit angiogenesis, including proliferation, migration and tube formation. The compositions comprise at least one kringle region, preferably from plasminogen, plus the upstream pre-activation domain of plasminogen. The compositions of the present invention are capable of inhibiting angiogenesis related diseases and modulating angiogenic processes.
BACKGROUND OF THE INVENTION
As used herein, the term “angiogenesis” means the generation of new blood vessels into tissue or organ. Under normal physiological conditions, humans or animals undergo angiogenesis only in very restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development and formation of the corpus luteum, endometrium and placenta. The term “endothelium” means a thin layer of flat endothelial cells that line serous cavities, lymph vessels, and blood vessels.
Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessels, where the endothelial cells undergo mitosis and proliferation. The endothelial sprouts merge with each other to form capillary loops, creating new blood vessels.
Pathological angiogenesis occurs in a number of disease states, for example, tumor metastasis and abnormal growth by endothelial cells, and supports the pathological damages seen in these conditions. The diverse pathological disease states in which abnormal angiogenesis is present have been grouped together as “angiogenic dependent” or “angiogenic associated” disorders. For a review of angiogenesis and its relation to tumor growth, see PCT publication WO 95/29242 and references cited therein, hereby incorporated by reference in its entirety.
Angiogenesis is tightly regulated by both positive and negative signals. Angiogenic stimulators, such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF), are potent mitogens for endothelial cell proliferation and strong chemoattractants for endothelial cell migration. These positive regulators can promote neovascularization to sustain the expansion of both primary and metastatic tumors (Gross, J. L. et. al., (1993)
J. Natl. Cancer Inst.
85(2):121-131; Kim, K. J. et. al., (1993)
Nature
362(6243) :841-844). Among the negative regulators described to date, Angiostatin ranks as one of the most effective endogenous inhibitors of angiogenesis (O'Reilly, M. S. et. al., (1994)
Cell
79:315-328; O'Reilly, M. S. et. al., (1996)
Nat. Med.
2:689-692; Wu, Z. et. al., (1997)
Biochem. Biophys. Res. Commun.
236:651-654). Angiostatin comprises an internal fragment of plasminogen and consists of four triple-looped kringle domains constrained by three disulfide bonds. Angiostatin was shown to inhibit endothelial cell proliferation in vitro and to suppress growth factor-induced angiogenesis in vivo (O'Reilly (1994), supra). Inhibition of angiogenesis by treatment with angiostatin results in significant suppression of tumor growth in both murine and human tumor models (O'Reilly (1994); O'Reilly (1996); Wu (1997), supra).
Angiostatin has been described as a potent angiogenesis inhibitor that could markedly suppress the growth of a variety of tumors, including carcinomas of lung, prostate, colon, and breast (Cao, Y. et. al., (1998)
J. Clin. Invest.
101(5): 1055-1063; O'Reilly, et. al., (1996) supra; O'Reilly, et. al., (1994) supra).
The individual kringle domains of angiostatin have distinct anti-proliferative and anti-migratory activities toward endothelial cells (Cao, Y. et. al., (1996)
J Biol. Chem.
271:29461-29467; Ji, W. R. et. al., (1998)
FASEB Jrnl
12(15):1731-1738). It has been documented that the first three kringles of angiostatin exhibit potent inhibitory activities on endothelial cell proliferation whereas kringle 4 has a marginal effect. It was also shown that the intact kringle structure is essential for the anti-proliferative activities of angiostatin.
The kringle 5 of human plasminogen displays high structural similarity and about 50% sequence identity to the four kringles of angiostatin. Kringle 5 was reported to inhibit bFGF-elicited endothelial cell growth in a dose-dependent manner (Ji, W. R. et. al., (1998)
Biochem Biophys Res Commun.
247(2):414-419; Cao, Y. et. al., (1997)
J. Biol. Chem.
272:22924-22928). These data suggest that kringle 5, like angiostatin, may have potent anti-angiogenic activities.
The pre-activation domain of plasminogen is known to be essential for the stability of plasminogen.
SUMMARY OF THE INVENTION
In accordance with the present invention, compositions are provided comprising at least one kringle region from plasminogen and the pre-activation domain of plasminogen (“PAD”). The new molecules, which include the 5 kringle domains of plasminogen, or fragments thereof, including but not limited to PAD-K1-4, PAD-K1-3, PAD-K1-2, PAD-K2-3, PAD-K1, and PAD-K5, or any combination thereof, optionally in a monovalent or bivalent Ig-linked form, including fusion molecules, are encompassed herein. Applicants herein provide evidence that compositions comprising at least one kringle region plus the PAD show superior results over Angiostatin (K1-4 of plasminogen), and the K5 region alone.
The present invention also comprises a process for making anti-angiogenic compounds, wherein the anti-angiogenic compounds comprise at least one kringle region from plasminogen, the method comprising associating the PAD of plasminogen with said at least one kringle region from plasminogen. The novel method provides a way to recombinantly manufacture active anti-angiogenic compounds comprising, for example, Angiostatin (K1-4 of plasminogen), K5, K1-5, or any other combination of kringle regions from plasminogen.
The present invention provides methods and compositions for treating diseases and processes mediated by undesired and uncontrolled angiogenesis by administering to a human or animal a composition comprising at least one kringle region plus the PAD of plasminogen. The present invention is particularly useful for treating, or for repressing the growth of, tumors. Administration of compositions of the present invention to a human or animal with prevascularized metastasized tumors will prevent the growth or expansion of those tumors.
The methods of the present invention encompass the use of a composition comprising at least one kringle region plus the PAD of plasminogen. Additionally, the methods of the present invention encompass the use of two or more compositions, wherein each composition comprises at least one klingle region plus the PAD of plasminogen, said compositions administered simultaneously or sequentially.
All references cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.
REFERENCES:
patent: 5639725 (1997-06-01), O'Reilly et al.
patent: 5733876 (1998-03-01), O'Reilly et al.
patent: 5801146 (1998-09-01), Davidson
patent: 5945403 (1999-08-01), Folkman et al.
patent: 5972896 (1999-10-01), Davidson
patent: 5981484 (1999-11-01), Davidson
patent: 5981568 (1999-11-01), Kunz et al.
patent: 6024688 (2000-02-01), Folkman et al.
patent: 6057122 (2000-05-01), Davidson
patent: WO 91/18989 (1991-12-01), None
Gross et al., Journal of the National Cancer Institute, 1993, 85 (2), 121-131.
Kim et al., Nature, 1993, 362, 841-844.
O'Reilly et al., Cell, 1994, 79, 315-328.
O'Reilly et al., Nature Medicine, 1996, 2 (6), 689-692.
Wu et al., Biochemical and Biophysical Research Communications, 1997, 236, 651-654.
Cao et al., J. Clin. Invest., 1998, 101 (5), 1055-1063.
Cao et al., J. Biol. Chem., 1996, 271 (46), 29461-29467.
J
Ji Richard-Weidong
Kondri Mohammad Eghtedarzadeh
Trail Pamela A.
Bristol--Myers Squibb Company
Carlson Karen Cochrane
Klein Christopher A.
Robinson Hope A.
Switzer Joan E.
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