Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2001-05-03
2004-02-10
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C530S351000
Reexamination Certificate
active
06689352
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention generally relates to a method for activating only the vascular endothelial growth factor receptor-3 (VEGFR-3) using mouse vascular endothelial growth factor-D (VEGF-D), and a method for promoting and maintaining lymphatic vascularization of tissue.
The two major components of the mammalian vascular system are the endothelial and smooth muscle cells. The endothelial cells form the lining of the inner surface of all blood vessels and lymphatic vessels in the mammal. The formation of new blood vessels can occur by two different processes, vasculogenesis or angiogenesis (for review see Risau, W.,
Nature
386: 671-674, 1997). Vasculogenesis is characterized by the in situ differentiation of endothelial cell precursors to mature endothelial cells and association of these cells to form vessels, such as occurs in the formation of the primary vascular plexus in the early embryo. In contrast, angiogenesis, the formation of blood vessels by growth and branching of pre-existing vessels, is important in later embryogenesis and is responsible for the blood vessel growth which occurs in the adult. Angiogenesis is a physiologically complex process involving proliferation of endothelial cells, degradation of extracellular matrix, branching of vessels and subsequent cell adhesion events. In the adult, angiogenesis is tightly controlled and limited under normal circumstances to the female reproductive system. However angiogenesis can be switched on in response to tissue damage. Importantly solid tumors are able to induce angiogenesis in surrounding tissue, thus sustaining tumor growth and facilitating the formation of metastases (Folkman, J.,
Nature Med.
1: 27-31, 1995). The molecular mechanisms underlying the complex angiogenic processes are far from being understood.
Lymphatic vessels are very different in structure from arteriae, veins and capillaries. Lymph vessels are characterized by an extremely permeable, thin endothelial lining devoid of a basal lamina. Simple end-to-end cell junctions and interdigitating and especially junctions between endothelial cells are a characteristic feature of lymphatic vessels. In addition, the lymphatics typically lack supporting cells, such as pericytes and smooth muscle cells (Leak, L.,
Microvasc Res
2: 361-391, 1970; Leak, L.,
J Cell Biol.,
50: 300-323, 1971; and Leak and Jamuar,
Am Rev Respir Dis.
128: S59-S65, 1983). The differences in the structure and cellular composition of lymphatic and non-lymphatic vessels suggest that the lymphatic endothelial cells may represent a very differentiated form of endothelial cells (Taiplae, J. et al.,
Cur. Topics Micro. Immunol.
237: 85-96, 1999).
A major function of the lymphatic system is to provide fluid return from tissues and to transport many extravascular substances back to the blood. In addition, during the process of maturation, lymphocytes leave the blood, migrate through lymphoid organs and other tissues, and enter the lymphatic vessels, and return to the blood through the thoracic duct. Specialized venules, high endothelial venules (HEVs), bind lymphocytes again and cause their extravasation into tissues. The lymphatic vessels, and especially the lymph nodes, thus play an important role in immunology and in the development of metastasis of different tumors. Unlike blood vessels, the embryonic origin of the lymphatic system is not as clear and at least three different theories exist as to its origin. Lymphatic vessels are difficult to identify due to the absence of known specific markers available for them.
Lymphatic vessels are most commonly studied with the aid of lymphography. In lymphography, X-ray contrast medium is injected directly into a lymphatic vessel. The contrast medium gets distributed along the efferent drainage vessels of the lymphatic system and is collected in the lymph nodes. The contrast medium can stay for up to half a year in the lymph nodes, during which time X-ray analyses allow the follow-up of lymph node size and architecture. This diagnostic is especially important in cancer patients with metastases in the lymph nodes and in lymphatic malignancies, such as lymphoma. However, improved materials and methods for imaging lymphatic tissues are needed in the art.
Angiogenesis is also involved in a number of pathologic conditions, where it plays a role or is involved directly in different sequelae of the disease. Some examples include neovascularization associated with various liver diseases, neovascular sequelae of diabetes, neovascular sequelae to hypertension, neovascularization in post-trauma, neovascularization due to head trauma, neovascularization in chronic liver infection (e.g. chronic hepatitis), neovascularization due to heat or cold trauma, dysfunction related to excess of hormone, creation of hemangiomas and restenosis following angioplasty.
Because of the crucial role of angiogenesis in so many physiological and pathological processes, factors involved in the control of angiogenesis have been intensively investigated. A number of growth factors have been shown to be involved in the regulation of angiogenesis; these include fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF&agr;), and hepatocyte growth factor (HGF). See for example Folkman et al.,
J. Biol. Chem.,
267: 10931-10934, 1992 for a review.
It has been suggested that a particular family of endothelial cell-specific growth factors, the vascular endothelial growth factors (VEGFs), and their corresponding receptors is primarily responsible for stimulation of endothelial cell growth and differentiation, and for certain functions of the differentiated cells. These factors are members of the PDGF/VEGF family, and appear to act primarily via endothelial receptor tyrosine kinases (RTKs). The PDGF/VEGF family of growth factors belongs to the cystine-knot superfamily of growth factors, which also includes the neurotrophins and transforming growth factor-&bgr;.
Eight different proteins have been identified in the PDGF/VEGF family, namely two PDGFs (A and B), VEGF and five members that are closely related to VEGF. The five members closely related to VEGF are: VEGF-B, described in International Patent Application PCT/US96/02957 (WO 96/26736) and in U.S. Pat. Nos. 5,840,693 and 5,607,918 by Ludwig Institute for Cancer Research and The University of Helsinki; VEGF-C or VEGF2, described in Joukov et al.,
EMBO J.,
15: 290-298, 1996, Lee et al.,
Proc. Natl. Acad. Sci. USA,
93: 1988-1992, 1996, and U.S. Pat. Nos. 5,932,540 and 5,935,540 by Human Genome Sciences, Inc; VEGF-D, described in International Patent Application No. PCT/US97/14696 (WO 98/07832), and Achen et al.,
Proc. Natl. Acad. Sci. USA,
95: 548-553, 1998; the placenta growth factor (PlGF), described in Maglione et al., Proc. Natl. Acad. Sci. USA, 88: 9267-9271, 1991; and VEGF3, described in International Patent Application No. PCT/US95/07283 (WO 96/39421) by Human Genome Sciences, Inc. Each VEGF family member has between 30% and 45% amino acid sequence identity with VEGF. The VEGF family members share a VEGF homology domain which contains the six cysteine residues which form the cystine-knot motif. Functional characteristics of the VEGF family include varying degrees of mitogenicity for endothelial cells, induction of vascular permeability and angiogenic and lymphangiogenic properties.
Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein that has been isolated from several sources. Alterative mRNA splicing of a single VEGF gene gives rise to five isoforms of VEGF. VEGF shows highly specific mitogenic activity for endothelial cells. VEGF has important regulatory functions in the formation of new blood vessels during embryonic vasculogenesis and in angiogenesis during adult life (Carmeliet et al.,
Nature,
380: 435-439, 1996; Ferrara et al.,
Nature,
380: 439-442, 1996; reviewed in Ferrara and Davis-Smyth,
Endocrine Rev.,
18: 4-25, 1997). The significance of the role played by VEGF has been demonstrated in studies showing that inac
Achen Marc
Stacker Steven
Crowell & Moring LLP
Jiang Dong
Ludwig Institute for Cancer Research
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