Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Reexamination Certificate
2000-05-25
2004-08-17
Nickol, Gary B. (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
C514S002600
Reexamination Certificate
active
06777534
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to vascular endothelial growth factor (VEGF). More particularly, the invention relates to antagonists of VEGF and use of those antagonists in the treatment of disorders that are associated with VEGF.
BACKGROUND OF THE INVENTION
Blood vessels are the means by which oxygen and nutrients are supplied to living tissues and waste products are removed from living tissue. Angiogenesis refers to the process by which new blood vessels are formed. See, for example, the review by Folkman and Shing,
J. Biol. Chem
. 267, 10931-10934 (1992), Dvorak, et al.,
J. Exp. Med.
, 174, 1275-1278 (1991). Thus, where appropriate, angiogenesis is a critical biological process. It is essential in reproduction, development and wound repair. However, inappropriate angiogenesis can have severe negative consequences. For example, it is only after many solid tumors are vascularized as a result of angiogenesis that the tumors have a sufficient supply of oxygen and nutrients that permit it to grow rapidly and metastasize. Because maintaining the rate of angiogenesis in its proper equilibrium is so critical to a range of functions, it must be carefully regulated in order to maintain health. The angiogenesis process is believed to begin with the degradation of the basement membrane by proteases secreted from endothelial cells (EC) activated by mitogens such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The cells migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space, then, vascular loops are formed and capillary tubes develop with formation of tight junctions and deposition of new basement membrane.
In adults, the proliferation rate of endothelial cells is typically low compared to other cell types in the body. The turnover time of these cells can exceed one thousand days. Physiological exceptions in which angiogenesis results in rapid proliferation typically occurs under tight regulation, such as found in the female reproduction system and during wound healing.
The rate of angiogenesis involves a change in the local equilibrium between positive and negative regulators of the growth of microvessels. The therapeutic implications of angiogenic growth factors were first described by Folkman and colleagues over two decades ago (Folkman,
N. Engl. J. Med.
, 285:1182-1186 (1971)). Abnormal angiogenesis occurs when the body loses at least some control of angiogenesis, resulting in either excessive or insufficient blood vessel growth. For instance, conditions such as ulcers, strokes, and heart attacks may result from the absence of angiogenesis normally required for natural healing. In contrast, excessive blood vessel proliferation can result in tumor growth, tumor spread, blindness, psoriasis and rheumatoid arthritis.
Thus, there are instances where a greater degree of angiogenesis is desirable—increasing blood circulation, wound healing, and ulcer healing. For example, recent investigations have established the feasibility of using recombinant angiogenic growth factors, such as fibroblast growth factor (FGF) family (Yanagisawa-Miwa, et al.,
Science
, 257:1401-1403 (1992) and Baffour, et al.,
J Vasc Surg
, 16:181-91 (1992)), endothelial cell growth factor (ECGF)(Pu, et al.,
J Surg Res
. 54:575-83 (1993)), and more recently, vascular endothelial growth factor (VEGF) to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia (Takeshita, et al.,
Circulation
, 90:228-234 (1994) and Takeshita, et al.,
J Clin Invest
. 93:662-70 (1994)).
Conversely, there are instances, where inhibition of angiogenesis is desirable. For example, many diseases are driven by persistent unregulated angiogenesis, also sometimes referred to as “neovascularization.” In arthritis, new capillary blood vessels invade the joint and destroy cartilage. In diabetes, new capillaries invade the vitreous, bleed, and cause blindness. Ocular neovascularization is the most common cause of blindness. Tumor growth and metastasis are angiogenesis-dependent. A tumor must continuously stimulate the growth of new capillary blood vessels for the tumor itself to grow.
There is mounting evidence that VEGF may be a major regulator of angiogenesis (reviewed in Ferrara, et al.,
Endocr. Rev.
, 13, 18-32 (1992); Klagsbrun, et al.,
Curr. Biol.
, 3, 699-702 (1993); Klagsbrun, et al., Ferrara, et al.,
Biochem. Biophys. Res. Commun.
, 161, 851-858 (1989) ). VEGF was initially purified from the conditioned media of folliculostellate cells (Ferrara, et al.,
Biochem. Biopsy. Res. Commun.
, 161, 851-858 (1989)) and from a variety of tumor cell lines (Myoken, et al.,
Proc. Nat. Acad. Sci
. USA, 88:5819-5823 (1991); Plouet, et al.,
EMBO. J.
, 8:3801-3806 (1991)). VEGF was found to be identical to vascular permeability factor, a regulator of blood vessel permeability that was purified from the conditioned medium of U937 cells at the same time (Keck, et al.,
Science
, 246:1309-1312 (1989)). VEGF is a specific mitogen for endothelial cells (EC) in vitro and a potent angiogenic factor in vivo. The expression of VEGF is up-regulated in tissue undergoing vascularization during embryogenesis and the female reproductive cycle (Brier, et al.,
Development
, 114:521-532 (1992); Shweiki, et al.,
J. Clin. Invest.
, 91:2235-2243 (1993)). High levels of VEGF are expressed in various types of tumors, but not in normal tissue, in response to tumor-induced hypoxia (Shweiki, et al.,
Nature
359:843-846 (1992); Dvorak et al.,
J. Exp. Med.
, 174:1275-1278 (1991); Plate, et al.,
Cancer Res.
, 53:5822-5827; Ikea, et al.,
J. Biol. Chem.
, 270:19761-19766 (1986)). Treatment of tumors with monoclonal antibodies directed against VEGF resulted in a dramatic reduction in tumor mass due to the suppression of tumor angiogenesis (Kim, et al.,
Nature
, 382:841-844 (1993)). VEGF appears to play a principle role in many pathological states and processes related to neovascularization. Regulation of VEGF expression in affected tissues could therefore be key in treatment or prevention of VEGF induced neovascularization/angiogenesis.
VEGF is a secreted 40-45K homodimer (Tischer E. et. al.,
J. Biol. Chem
. 266: 11947-11954 (1991). It is a member of an expanding family that includes placenta-derived growth factor (PIGF), VEGF-B, VEGF-C, VEGF-D and VEGF-E (Olofsson et. al.,
Proc. Natl. Acad. Sci
. USA 93:2576-2581 (1996), Joukov et. al.,
EMBO J
. 15:290-298 (1996). Achen et. al.,
Proc. Natl.Acad. Sci
.USA 95:548-553 (1998). Ogawa et. al.,
J. Biol. Chem
. 273: 31273-31282 (1998)). VEGF exists in a number of different isoforms that are produced by alternative splicing from a single gene containing eight exons (Ferrara, et al.,
Endocr. Rev.
, 13:18-32 (1992); Tischer, et al.,
J. Biol. Chem.
, 806:11947-11954 (1991); Ferrara, et al.,
Trends Cardio Med.
, 3:244-250 (1993); Polterak, et al.,
J. Biol. Chem.
, 272:7151-7158 (1997)). Human VEGF isoforms consists of monomers of 121, 145, 165, 189, and 206 amino acids, each capable of making an active homodimer (Polterak et al.,
J. Biol. Chem
, 272:7151-7158 (1997); Houck, et al.,
Mol. Endocrinol.
, 8:1806-1814 (1991)). The VEGF
121
and VEGF
165
isoforms are the most abundant. VEGF
121
is the only VEGF isoforms that does not bind to heparin and is totally secreted into the culture medium. VEGF
165
is functionally different than VEGF
121
in that it binds to heparin and cell surface heparin sulfate proteoglycans (HSPGs) and is only partially released into the culture medium (Houck, et al.,
J. Biol. Chem.
, 247:28031-28037 (1992); Park, et al.,
Mol. Biol. Chem.
, 4:1317-1326 (1993)). The remaining isoforms are entirely associated with cell surface and extracellular matrix HSPGs (Houck, et al.,
J. Biol. Chem.
, 247:28031-28037 (1992); Park, et al.,
Mol. Biol. Chem.
, 4:1317-1326 (1993)).
VEGF receptor tyrosine kinases, KDR/Flk-1 and/or Flt-1, are mostly expressed by EC (Terman, et al.,
Biochem. Biophys. Res. Commun.
, 187:1579-1586 (1992); Shibuya, et al
Klagsbrun Michael
Soker Shay
Children's Medical Center Corporation
Nickol Gary B.
Nixon & Peabody LLP
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