Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-12-20
2000-09-19
Mertz, Prema
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 530330, 530331, 530332, A61K 3806, A61K 3807
Patent
active
061212407
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the fields of ligands of the urokinase plasminogen activator receptor, and methods for using and preparing the same.
BACKGROUND OF THE INVENTION
Urokinase-type plasminogen activator (uPA) is a multidomain serine protease, having a catalytic "B" chain (amino acids 144-411), and an amino-terminal fragment ("ATF", aa 1-143) consisting of a growth factor-like domain (4-43) and a kringle (aa 47-135). The uPA kringle appears to bind heparin, but not fibrin, lysine, or aminohexanoic acid. The growth factor-like domain bears some similarity to the structure of epidermal growth factor (EGF), and is thus also referred to as an "EGF-like" domain. The single chain pro-uPA is activated by plasmin or other proteases, cleaving the chain into the two chain active forrn, which is linked together by a disulfide bond.
uPA binds to its specific cell surface receptor (uPAR). The binding interaction is apparently mediated by the EGF-like domain (S.A. Rabbani et al., J Biol Chem (1992) 267:14151-56). Cleavage of pro-uPA into active uPA is accelerated when pro-uPA and plasminogen are receptor-bound. Thus, plasmin activates pro-uPA, which in turn activates more plasmin by cleaving plasminogen. This positive feedback cycle is apparently limited to the receptor-based proteolysis on the cell surface, since a large excess of protease inhibitors is found in plasma, including .alpha..sub.2 antiplasmin, and PAI-1.
Plasmin can activate or degrade extracellular proteins such as fibrinogen, fibronectin, and zymogens, particularly of the matrix metalloproteinases. Plasminogen activators thus can regulate extracellular proteolysis, fibrin clot lysis, tissue remodeling, developmental cell migration, inflammation, and metastasis. Accordingly, there is great interest in developing uPA inhibitors and uPA receptor antagonists. E. Appella et al., J Biol Chem (1987) 262:4437-40, determined that receptor binding activity is localized in the EGF-like domain, and that residues 12-32 appear to be critical for binding. The critical domain alone (uPA.sub.12-32) bound uPAR with an affinity of 40 nM (about 100 fold less than intact ATF).
Recent studies have shown that the invasiveness of human tumor cell lines in vitro correlates with surface bound urokinase, and that urokinase production itself is an independent prognostic indicator in human breast cancer (W. Schlechte et al., Cancer Comm (1990) 2:173-79; H. Kobayashi et al., Br J Cancer (1993) 67:537-44; J. A. Foekens et al., Cancer Res (1992) 52:6101-05). It has also been shown in both breast and colon cancer that urokinase is often made by stromal cells (fibroblasts and macrophages), whereas the urokinase receptor is found on tumor cells (C. Pyke et al., Cancer Res (1993) 53:1911-15; C. Pyke et al., Am J Path (1991) 138:1059-67). UPAR has independently been identified as a monocyte activation antigen, Mo3, whose expression is induced in these inflammatory cells upon activation (H.Y. Min et al., J Immunol (1992) 148:3636-42), as well as an activation antigen on human T lymphocytes (A. Nykjxr et al., J Immunol (1994) 152:505-16). Urokinase plasminogen activator "knock-out" mice (in which the uPA gene is inactivated or deleted throughout the body) have been developed, and their macrophages are deficient in extracellular matrix degradation in vitro (P. Carmeliet et al., Fibrinolysis (1993) 7 Suppl. 1:27-28). In addition, these mice show greatly reduced smooth muscle cell migration/proliferation after arterial wounding, suggesting a possible role for uPA/uPAR in post-angioplasty restenosis.
The induction of urokinase and its receptor by agents known to be angiogenic in vivo, such as bFGF, vEGF, and TNF.alpha., suggests a role for cell surface urokinase in angiogenesis (P. Mignatti et al., J Cell Biol (1991) 113:1193-202; L. E. Odekon et al., J Cell Physiol (1992) 150:258-63; M. J. Niedbala et al., Blood (1992) 79:678-87). Although many factors are likely to be angiogenic in pathological conditions, degradation of extracellular matrix by capillary endotheli
REFERENCES:
patent: 4708871 (1987-11-01), Geysen
patent: 4833092 (1989-05-01), Geysen
patent: 5194392 (1993-03-01), Geysen
patent: 5536853 (1996-07-01), Spellmeyer et al.
Appella et al., "The Receptor-binding Sequence of Urokinase", J Biol Chem (Apr. 5, 1987) 262:4437-40.
Behrendt et al., "Binding of the Urokinase-type Plasminogen Activator to Its Cell Surface Receptor is Inhibited by Low Doses of Suramin", J Biol Chem (Mar. 15, 1993) 268:5985-89.
Carmeliet et al., "Biological Effects of Inactivation of the Genes for Tissue-type Plasminogen Activator, Urokinase-type Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Mice", Fibrinolysis (1993) 7 Suppl. 1:27-28.
Cekuoliene et al., "Oxamido and Succinamidotetraacetic Acids and Their Derivatives", Chemical Abstracts (1974) 80:382, Abstract No. 145348F.
Crowley et al., "Prevention of Metastasis by Inhibition of the Urokinase Receptor", Proc Natl Acad Sci USA (Jun., 1993) 90:5021-25.
Foekens et al., "Prognostic Value of Urokinase-type Plasminogen Activator in 671 Primary Breast Cancer Patients", Cancer Res (Nov. 1, 1992) 52:6101-05.
Goodson et al., "High-affinity Urokinase Receptor Antagonists Identified With Bacteriophage Peptide Display", Proc Natl Acad Sci USA (1994) 91:7129-7133.
Kobayashi et al., "Saturation of Tumour Cell Surface Receptors for Urokinase-type Plasminogen Activator by Amino-terminal Fragment and Subsequent Effect on Reconstituted Basement Membranes Invasion", Br J. Cancer (1993) 67:537-44.
Mignatti et al., "Expression of the Urokinase Receptor in Vascular Endothelial Cells is Stimulated by Basic Fibroblast Growth Factor", J Cell Biol (Jun., 1991) 113:1193-202.
Min et al., "cDNA for Mo3, A Monocyte Activation Antigen, Encodes the Human Receptor for Urokinase Plasminogen Activator", J Immunol (Jun. 1, 1992) 148:3636-42.
Niedbala et al., "Tumor Necrosis Factor Induction of Endothelial Cell Urokinase-type Plasminogen Activator Mediated Proteolysis of Extracellular Matrix and Its Antagonism by .gamma.-Interferon", Blood (Feb. 1, 1992) 79:678-87.
Nykj.ae butted.r et al., "An Activation Antigen in Human T Lymphocytes", J Immunol (1994) 152:505-16.
Odekon et al., "Urokinase-type Plasminogen Activator Mediates Basic Fibroblast Growth Factor-Induced Bovine Endothelial Cell Migration Independent of Its Proteolytic Activity", J Cell Physiol (1992) 150:258-63.
Ossowski et al., "Antibodies to Plasminogen Activator Inhibit Human Tumor Metastasis", Cell (Dec., 1983) 35:611-19.
Ossowski, "In Vivo Invasion of Modified Chorioallantoic Membrane by Tumor Cells: the Role of Cell Surface-bound Urokinase", J Cell Biol (Dec. 1988) 107:2437-45.
Ploug et al., "Ligand Infection between Urokinase-Type Plasminogen Activator and Its Receptor Probed with 8-Anilino-1-naphthalenesulfonate. Evidence for a Hydrophobic Binding Site Exposed Only on the Intact Receptor", Biochemistry (1994) 33:8991-97.
Pyke et al., "Urokinase-type Plasminogen Activator is Expressed in Stromal Cells and Its Receptor in Cancer Cells at Invasive Foci in Human Colon Adenocarcinomas", Am J Path (May, 1991) 138:1059-67.
Pyke et al., "Receptor for Urokinase is Present in Tumor-associated Macrophages in Ductal Breast Carcinoma", Cancer Res (Apr. 15, 1993) 53:1911-15.
Rabbani et al., "Structural Requirements for the Growth Factor Activity of the Amino-terminal Domain of Urokinase", J Biol Chem (Jul. 15, 1992) 267:14151-56.
Schlechte et al., "Invasion of Extracellular Matrix by Colon Cancer Cells: Dependence on Urokinase Receptor Display", Cancer Comm (1990) 2:173-79.
Takano et al., "Suramin, an Anticancer and Angiosuppresive Agent, Inhibits Endothelial Cell Binding of Basic Fibroblast Growth Factor, Migration, Proliferation, and Indution of Urokinase-type Plasminogen Activator", Cancer Res (May 15, 1994) 54:2654-60.
Weinstat-Saslo et al., "Angiogenesis and Colonization in the Tumor Metastatic Process: Basic and Applied Advances", FASEB J (Apr., 1994) 8:401-407.
Martin Eric J.
Rosenberg Steven
Spear Kerry L.
Blackburn Robert P.
Chiron Corporation
Fujita Sharon
Mertz Prema
Pak Michael
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