Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2000-03-22
2003-07-22
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S138100, C424S139100
Reexamination Certificate
active
06596276
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with angiogenesis broadly and with tumor angiogenesis directly; and is focused on means and methods for inhibiting tumor angiogenesis involving vascular endothelial growth factor (“VEGF”) and integrin heterodimer surface receptors found in the vasculature of a living subject.
BACKGROUND OF THE INVENTION
Angiogenesis, the formation of new capillaries and blood vessels, is a complex process first recognized in studies of wound healing and then with investigations of experimental tumors. Angiogenesis involves extracellular matrix remodeling, endothelial cell migration and proliferation, and functional maturation of endothelial cells into mature blood vessels [Brier, G. and K. Alitalo,
Trends Cell Biol.
6: 454-456 (1996)]. Although the process generally has been studied for more than 50 years, the existence and in-vivo effects of several discrete angiogenic factors have been identified just over a decade ago [Folkman, J. and M. Klagsburn,
Science
235: 444-447 (1985)]. Clearly, in normal living subjects, the process of angiogenesis is a normal host response to injury; and as such is an integral part of the host body's homeostatic mechanisms.
In distinction, tumor angiogenesis is the specific development in-vivo of an adequate blood supply for a solid tumor mass; and the growth of a tumor in-vivo beyond the size of a few millimeters in diameter is believed to be dependent upon the existence, maintenance, and continued development of sufficient and functional blood vasculature in-situ. In a variety of experimental tumor systems, tumor survival and growth has been linked with new capillary and new blood vessel formation. Histological examination of such neoplasms has revealed that tumor cells typically surround blood capillaries in a cylindrical configuration with a radius not exceeding about 200 micrometers—the critical travel distance for diffusion of molecular oxygen [Folkman, J.,
Cancer Res.
46: 467-473 (1986)]. Moreover, in the cancer patient, tumor angiogenesis originates at least in part from the sprouting of new capillaries and blood vessels directly from the pre-existing and functional normal vasculature; and possibly also from stem cells existing in the blood. Tumor angiogenesis thus involves endothelial cell penetration of the vascular basement membrane in a preexisting blood vessel; followed by endothelial cell proliferation; and then by an invasion of the extracellular matrix surrounding the blood vessel to form a newly created vascular spout [Vernon, R. and E. H. Sage,
Am. J. Pathol.
147: 873-883 (1995); Auspunk, D. H. and J. Folkman,
Microvasc. Res.
14: 53-65 (1977)].
A number of different biologically active and physiologically functional molecular entities appear to be individual factors of angiogenesis. Among these are the biologically active classes of substances known as vascular endothelial growth factor and the integrin protein family of cell surface receptors. Each of these two classes will be summarily reviewed as to their conventionally known properties and functions.
Vascular Endothelial Growth Factor
Vascular endothelial growth factor (hereinafter “VEGF”), also known as vascular permeability factor, is a 34-45 kilodalton dimeric glycoprotein; is a cytokine; and is a potent inducer of microvascular hyperpermeability. As such, VEGF is believed to be responsible for the vascular hyperpermeability and consequent plasma protein-rich fluid accumulation that occurs in-vivo with solid tumors and ascites tumors [Senger et al.,
Science
219: 983-985 (1983); Dvorak et al.,
J. Immunol.
122: 166 (1979); Nagy et al.,
Biochem. Biophys. Acta.
948: 305 (1988); Senger et al.,
Federation Proceedings
46: 2102 (1987)]. On a molar basis, VEGF increases microvascular permeability with a potency which is typically 50,000 times that of histamine [Senger et al.,
Cancer Res.
50: 1774-1778 (1990].
Vascular endothelial growth factor is also noted for its mitogenic effects on vascular endothelial cells (hereinafter “EC”). VEGF is a specific EC mitogen which stimulates endothelial cell growth and promotes angiogenesis in-vivo [Conn et al.,
Proc. Natl. Acad. Sci. USA
87: 2628-2632 (1990); Ferrara et al.,
Biochem. Biophys. Res. Comm.
161: 851-858 (1989); Gospodarowicz et al.,
Proc. Natl. Acad. Sci. USA.
86: 7311-7315 (1989); Keck et al.,
Science
264: 1309 (1989); Leung et al.,
Science
246: 1306 (1989); Connolly et al.,
J. Clin. Invest.
84: 1407-1478 (1989)]. In addition, VEGF exerts a number of other effects on endothelial cells in-vitro. These include: an increase in intracellular calcium; a stimulation of inositol triphosphate formation; a provocation of von Willebrand factor release; and a stimulation of tissue factor expression [Brock et al.,
Am. J. Pathol.
138: 213 (1991); Clauss et al.,
J. Exp. Med.
172: 1535 (1990)].
Vascular endothelial growth factor elicits potent angiogenic effects by stimulating endothelial cells through two receptor tyrosine kinases, Flt-1 and KDR/Flk-1 [Dvorak et al.,
Am. J. Pathol.
146: 1029-1039 (1995); Mustonen, T. and K. Alitalo,
J. Cell Biol.
129: 895-898 (1996)]. Although there are potentially numerous angiogenesis factors, considerable evidence has accumulated indicating that VEGF is a cytokine of importance both for neovascularization in the medically normal adult and for development of embryonic vasculature. VEGF angiogenic activity has been demonstrated in several experimental models including the chick chorioallantoic membrane [Whiting et al.,
Anat. Embryol.
186: 251-257 (1992)]; rabbit ischemic hind limb [Takeshita et al.,
J. Clin. Invest.
93: 662-670 (1994)]; tumor xenografts in mice [Potgens et al.,
Biol: Chem. Hoppe. Seyler
376: 57-70 (1995); Claffey et al.,
Cancer Res.
56: 172-181 (1996)]; and a primate model of iris neovascularization [Tolentino et al.,
Arch. Ophthalmol.
114: 964-978 (1996)]. Additionally, both infusion of exogenous VEGF and overexpression of VEGF endogenously were found to induce hypervascularization of avian embryos [Drake et al.,
Proc. Natl. Acad. Sci. USA
92: 7657-7661 (1995); Flamme et al.,
Dev. Biol.
171: 399-414 (1995)].
Evidence supporting the importance of VEGF for angiogenesis generally also has come from analyses of VEGF and VEGF receptor expression. These investigations have established that elevated expression of VEGF and its receptors correlate both temporally and spatially with vascularization during embryogenesis [Millauer et al.,
Cell
72: 835-846 (1993); Peters et al.,
Proc. Natl. Acad. Sci. USA
90: 8915-8919 (1993)]; and also with the angiogenesis associated with wound healing [Brown et al.,
J. Exp. Med.
176: 1375-1379 (1992)]; cancer [Brown et al.,
Cancer Res.
53: 4727-4735 (1993)]; rheumatoid arthritis [Fava et al.,
J. Exp. Med.
180: 341-346 (1994)]; psoriasis [Detmar et al.,
J. Exp. Med.
180: 1142-1146(1994)]; delayed-type hypersensitivity reactions [Brown et al.,
J. Immunol.
154: 2801-2807 (1995)]; and proliferative retinopathies [Aiello et al.,
N. Eng. J. Med.
331: 1480-1487 (1994); Pierce et al.,
Proc. Natl. Acad. Sci. USA
92: 905-909 (1995)]. Thus, VEGF appears not only to promote angiogenesis in a variety of experimental systems, but also appears to be overexpressed in a diversity of settings in which neovascularization is prominent.
VEGF is typically synthesized and secreted in-vivo by a variety of cultured tumor cells, transplantable animal tumors, and many different primary and metastatic human tumors [Dvorak et al.,
J. Exp. Med.
174: 1275-1278 (1991); Senger et al.,
Cancer Res.
46: 5629-532 (1986); Plate et al.,
Nature
359: 845-848 (1992); Brown et al.,
Am. J. Pathol.
143: 1255-1262 (1993)]. Solid tumors, however, must generate a vascular stroma in order to grow beyond a minimal size [Folkman, J. and Y. Shing,
J. Biol. Chem.
267: 10931
Claffey Kevin P.
Detmar Michael
Senger Donald R.
Beth Israel Deaconess Medical Center
Caputa Anthony C.
Nickol Gary B.
Prashker David
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