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
2001-08-24
2004-10-12
Fredman, Jeffrey (Department: 1636)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S455000, C530S350000, C530S351000, C536S023100, C536S023500
Reexamination Certificate
active
06803211
ABSTRACT:
The present invention relates to polynucleotide sequences which are shown herein to be associated with the regulation of angiogenesis. More specifically, the present invention relates to novel polynucleotide sequences which encode the angiogenesis inhibitor endostatin, and more particularly, the canine angiogenesis inhibitor. The invention encompasses endostatin nucleic acids, recombinant DNA molecules, cloned genes and degenerate variants thereof, vectors containing such endostatin nucleic acids, and hosts that have been genetically engineered to express and/or contain such molecules. The invention further relates to endostatin gene products and antibodies directed against such gene products. The invention further relates to methods for the identification of compounds that modulate the expression, synthesis and activity of such endostatin nucleic acids, and to methods of using compounds such as those identified herein as therapeutic agents in the treatment of angiogenesis-related disorders, including, but not limited to, cancer. The invention also relates to methods for the diagnostic evaluation, genetic testing and prognosis of an angiogenesis-related disorder, including, but not limited to, cancer.
BACKGROUND OF THE INVENTION
Angiogenesis, defined as the growth or sprouting of new blood vessels from existing vessels, is a complex process that primarily occurs during embryonic development. Under normal physiological conditions in adults, angiogenesis takes place only in very restricted situations such as hair growth and wounding healing (Auerbach, W. and Auerbach, R., 1994,
Pharmacol Ther
63(3):265-3 11; Ribatti et al.,1991,
Haematologica
76(4):3 11-20; Risau, 1997,
Nature
386(6626):67 1-4). Unregulated angiogenesis has gradually been recognized to be responsible for a wide range of disorders, including, but not limited to, cancer, cardiovascular disease, rheumatoid arthritis, psoriasis and diabetic retinopathy (Folkman, 1995,
Nat Med
1(1):27-31; Isner, 1999,
Circulation
99(13): 1653-5; Koch, 1998,
Arthritis Rheum
41(6):951-62; Walsh, 1999,
Rheumatology
(
Oxford
) 38(2):103-12; Ware and Simons, 1997,
Nat Med
3(2): 158-64). Of particular interest is the observation that angiogenesis is required by solid tumors for their growth and metastases (Folkman, 1986, Cancer Res, 46(2) 467-73. Folkman 1990, J Natl. Cancer Inst., 82(1) 4-6, Folkman, 1992,
Semin Cancer Biol
3(2):65-71; Zetter, 1998,
Annu Rev Med
49:407-24). A tumor usually begins as a single aberrant cell which can proliferate only to a size of a few cubic millimeters due to the distance from available capillary beds, and it can stay ‘dormant’ without further growth and dissemination for a long period of time. Some tumor cells then switch to the angiogenic phenotype to activate endothelial cells, which proliferate and mature into new capillary blood vessels. These newly formed blood vessels not only allow for continued growth of the primary tumor, but also for the dissemination and recolonization of metastatic tumor cells. The precise mechanisms that control the angiogenic switch is not well understood, but it is believed that neovascularization of tumor mass results from the net balance of a multitude of angiogenesis stimulators and inhibitors (Folkman, 1995,
Nat Med
1(1):27-31).
One of the most potent angiogenesis inhibitors is endostatin identified by O'Reilly and Folkman (O'Reilly et al., 1997,
Cell
88(2):277-85; O'Reilly et al., 1994, Cell 79(2):3 15-28). Its discovery was based on the phenomenon that certain primary tumors can inhibit the growth of distant metastases. O'Reilly and Folkman hypothesized that a primary tumor initiates angiogenesis by generating angiogenic stimulators in excess of inhibitors. However, angiogenic inhibitors, by virtue of their longer half life in the circulation, reach the site of a secondary tumor in excess of the stimulators. The net result is the growth of primary tumor and inhibition of secondary tumor. Endostatin is one of a growing list of such angiogenesis inhibitors produced by primary tumors. It is a proteolytic fragment of a larger protein: endostatin is a 20 kDa fragment of collagen XVIII (amino acid H1132-K1315 in murine collagen XVIII). Endostatin has been shown to specifically inhibit endothelial cell proliferation in vitro and block angiogenesis in vivo. More importantly, administration of endostatin to tumor-bearing mice leads to significant tumor regression, and no toxicity or drug resistance has been observed even after multiple treatment cycles (Boehm et al., 1997,
Nature
390(6658):404-407). The fact that endostatin targets genetically stable endothelial cells and inhibits a variety of solid tumors makes it a very attractive candidate for anticancer therapy (Fidler and Ellis, 1994,
Cell
79(2):185-8; Gastl et al., 1997,
Oncology
54(3):177-84; Hinsbergh et al., 1999,
Ann Oncol
10 Suppl 4:60-3). In addition, angiogenesis inhibitors have been shown to be more effective when combined with radiation and chemotherapeutic agents (Klement, 2000, J. Clin Invest, 105(8) R15-24. Browder, 2000, Cancer Res. 6-(7) 1878-86, Arap et al., 1998,
Science
279(5349):377-80; Mauceri et al., 1998,
Nature
394(6690):287-91).
Cancer is not only devastating to humans, but is also the most common cause of natural death in dogs. (Bronson, 1982, Am J Vet Res, 43(11) 2057-9). Dogs develop tumors twice as frequently as humans and it has been reported that 45-50% of dogs that live to 10 years or older die of cancer; regardless of age, and that 23% of dogs that present for necropsy died of cancer(Bronson, 1982, Am J Vet Res, 43(11) 2057-9). Surgical removal of the tumor is the most common treatment, but the prognosis for invasive/metastatic tumor is very poor, with median survival time ranging from weeks to months. Other treatments, such as radiation therapy and chemotherapy, have only very limited success (Bostock, 1986, Br Vet J 142(6):506-15; Bostock, 1986, Br Vet J 142(1):1-19; MacEwen, 1990,
Cancer Metastasis Rev
9(2): 125-36). Thus, more effective treatments for angiogenic diseases, such as, for example, canine cancers, are necessary.
SUMMARY OF THE INVENTION
The present invention encompasses novel nucleotide sequences that are associated with angiogenesis related disorders, e.g., cancer. The invention more specifically relates to nucleotide sequences that encode endostatin. In addition, endostatin nucleic acids, recombinant DNA molecules, cloned genes or degenerate variants thereof are provided herein. The invention also provides vectors, including expression vectors, containing endostatin nucleic acid molecules, and hosts that have been genetically engineered to express and/or contain such endostatin gene products.
The invention further relates to novel endostatin gene products and to antibodies directed against such gene products, or variants or fragments thereof.
The invention further relates to methods for modulation of endostatin-mediated processes and for the treatment of disorders involving angiogenesis, such as cancer, including the amelioration or prevention of at least one symptom of the disorders, wherein such methods comprise administering a compound which modulates the expression of an endostatin gene and/or the synthesis or activity of an endostatin gene product. In one embodiment, the invention relates to methods for the use of a novel endostatin gene product or fragment, analog, or mimetic thereof, or an antibody or antibody fragment directed against an endostatin gene product, to treat or ameliorate a symptom of such disorders.
Such disorders include, but are not limited to, angiogenesis-dependent cancer, including, for example, solid tumors, blood born tumors such as leukemias, and tumor metastases; benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; rheumatoid arthritis; psoriasis; ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia,
Sheppard Michael G.
Tong Xiao
Fredman Jeffrey
Kaushal Sumesh
Kohn & Associates PLLC
Ling Lorraine B.
Pfizer Inc.
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