Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1999-08-12
2002-10-08
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C514S012200, C514S002600, C424S094640
Reexamination Certificate
active
06461610
ABSTRACT:
FIELD OF THE INVENTION
A novel intracellular signalling activity of coagulation factor VII (FVII) in cells expressing tissue factor (TF) has been described. The present invention relates to use of FVIIa or another TF agonist, or FVIIai or another TF antagonist for the preparation of a medicament for modulation of FVIIa-induced activation of the MAPK signalling pathway in a patient. Moreover the present invention relates to a method of treatment, and a method of detecting the activity of compounds, in particular drug candidates, that interact with the FVIIa mediated intracellular signalling pathway.
BACKGROUND OF THE INVENTION
The extrinsic pathway of blood coagulation is initiated when FVIIa circulating in plasma binds to the integral-membrane protein, tissue factor (TF). The role of TF in blood coagulation has been extensively studied (Camerer, E., A. B. et al.
Thromb. Res
. 81:1-41, (1996)). The involvement of FVIIa as a proteolytic enzyme in the blood coagulation cascade is believed to be confined to the extracellular leaflet of TF expressing cells. An intracellular activity of FVIIa was first implied when the sequence of TF showed homology to the cytokine/interferon- or heamatopoietic receptor superfamily (Bassoon, J. F.
Proc. Natl. Acad. Sci. USA
87: 6934-6938, (1990)). The subclass I of the heamotopoietic receptor family includes receptors for growth hormone, prolactin, interleukins 1 to 7, granulocyte-macrophage colony stimulating factors, erythropoitin and thrombopoitin. Subclass II includes TF and receptors for interferon a and b (Wells, J. A., and De Vos, A. M.
Annu. Rev. Biomol. Struct
. 22: 329-351, (1993)).
The resemblance of TF to this class of receptors was further substantiated with the appearance of the crystal structure (Harlos, K., D. M. A. et al.
Nature
370: 662-666, (1994), Mueller, Y. A., M. H. et al.
Biochemistry
33: 10864-10870 (1994) ). Characteristic of this class of cytokine receptors that includes receptors for interferon b and g and IL-10 (Mott, H. R. and Campbell, I. D.
Curr, Opin, Struct, Biol
. 5: 114-121, (1995)) is that their activation lead to rapid tyrosine phosphorylation of the receptors themselves, as well as a subset of intracellular proteins. Within minutes after the initial tyrosine phosphorylation an array of mitogen-activated (Ser/Thr) kinases (MAPK) is activated (Whitmarsh, A. J. and Davis, R. J.
J. Mol. Med
. 74:589-607, (1996)). These kinases are arranged in several parallel signalling pathways (David, M. et al. Science 269, 1721 (1996); Current opin. immunol. 8, 402-11 (1996)). Thorough studies of the putative intracellular signalling capacity of FVIIa have shown that it induces mobilization of intracellular free calcium (Ca
2+
) in the human bladder carcinoma cell line, J82, which constitutively expresses TF and in umbelical vein endothelial cells which were pre-treated with interleukin-1 to express TF (Rottingen, J.-A. et al.
J. Biol. Chem
. 270: 4650-4660, (1995)), but have failed to show any cytokine-like activation of intracellular tyrosine kinases (Camerer, E., et al.
J. Biol. Chem
. 271: 29034-29042, (1996)). In conclusion FVIIa is believed, in a TF dependent manner, to induce mobilization of intracellular Ca
2+
through activation of phospholipase C (Camerer, E., et al.
J. Biol. Chem
. 271: 29034-29042, (1996)). The mechanism by which FVIIa activates phospholipase C is not known, but Camerer et al. specifically ruled out tyrosine kinase activation.
SUMMARY OF THE INVENTION
The present invention relates to usage of FVII and/or FVIIa and/or another TF agonist and/or FVIIai and/or another TF antagonist in therapeutic treatment of pathological conditions that can be related to or treated by specific activation or inhibition of the FVIIa mediated intracellular signalling pathway.
In accordance with the present invention it has been shown that binding of FVIIa to its receptor TF induces activation of the mitogen-activated protein kinase (MAP kinase) pathway including phosphorylation of tyrosines in MAPK/Erk1. TF is known to play a pertinent role in the pathogenesis of a number of diseased states where regulatory interference at the intracellular level is believed to be beneficial.
Thus, diseased states which may be treated are pathological conditions such as mechanical injury of blood vessels, atherosclerosis, ischemia/reperfusion, bacterial infection, tumour deposition, or stimuli induced by “stress factors” such as cytokines, smoking, high blood pressure, high lipids- or glucose levels, advanced glycosylation end-products, and bacterial lipopolysaccarides.
In another aspect, the invention encompasses methods for modifying cell motility or migration, which are carried out by contacting a tissue factor(TF)-expressing cell with a motility modifying-effective amount of a Factor VIIa; a Factor VIIa agonist; or a Factor VIIa antagonist, under conditions that result in modification of motility or migration. TF-expressing cells include, without limitation, fibroblasts, monocytes, macrophages, smooth muscle cells, endothelial cells, and tumor cells. To cause an increase in cell motility, Factor VIIa or an agonist thereof may be used. To cause a decrease, a Factor VIIa antagonist may be used, including, without limitation, Dansyl-Phe-Pro-Arg chloromethyl ketone-Factor VIIa; Danyl-Glu-Gly-Arg chloromethyl ketone-Factor VIIa; Dansyl-Phe-Phe-Arg chloromethyl ketone-Factor VIIa; or Phe-Phe-Arg chloromethyl ketone-Factor VIIa. These methods find utility in detection of effective treatments for pathological conditions involving inappropriate cell migration.
In yet another aspect, the invention provides methods for inhibiting cell migration in a patient suffering from a pathological condition associated with undesired cell migration, which are carried out by administering to the patient a migration-inhibitory-effective amount of a Factor VIIa antagonist. Administration may be via any appropriate route, including, without limitation, intravenous, intramuscular, and subcutaenous injection or by via direct injection into a tumor.
REFERENCES:
patent: 5753446 (1998-05-01), Johnson
patent: 0 244 221 (1987-11-01), None
patent: WO 94/05328 (1994-03-01), None
patent: WO 96/12800 (1996-05-01), None
patent: WO 96/40276 (1996-12-01), None
patent: WO 97/22717 (1997-06-01), None
Sato et al., “Tissue Factor Induces Migration of Cultured Aortic Smooth Muscle Cells” (1996) Thromb. Haemost. 75(3), 389-392.*
Sato et al., “Tissue Factor Pathway Inhibitor Aortic Smooth Muscle Cell Migration Induced by Tissue Factor/Factor VIIa Complex”, Sep. 01, 1997, Thromb. Haemost. 78(3), pp. 1138-1141.*
Sato et al., “Tissue Factor Induces Migration of Cultured Aortic Smooth Muscle Cells”, Aug. 1, 1996, Thromb. Haemost. 75(3), pp. 389-392, in EMBASE, AN 96104512.*
Versteeg et al., “Factor VIIa/Tissue Factor-induced Signalling via Activation of Src-like Kinases, Phosphatidylinositol 3-Kinase, and Rac”, Sep. 15, 2000, J. Mol. Biol., 275(37), pp. 28750-28756.*
Sato et al., “Overexpression of Tissue Factor Pathway Inhibitor in Aortic Smooth Muscle Cells Inhibits Migration Induced by Tissue Factor/Factor VIIa Complex”, Jun. 15, 1999, Thromb. Res., 94(6), pp. 401-406.*
Ott et al., “A Role for Tissue Factor in Cell Adhesion and Migration Mediated by Interaction with Actin-binding Protein 280”, Mar. 9, 1998, J. Cell Biol., 140(5), pp. 1241-1253.*
Masuda et al., (1996) Eur. J. Immunol. 26:2529-2532.
Abstract Medline Accession No. 09277431.
Abstract Medline Accession No. 08687034.
Abstract Medline Accession No. 09499002.
Abstract Medline Accession No. 09462465.
Røttingen et al., (1995) J. of Biological Chem. 270(9):4650-4660.
Orthner et al., (1995) Blood 86(2) :436-443.
Bergenhem Niels
Ezban Mirella
Foster Don
Kongsbak Lars
Petersen Lars Christian
Green, Esq. Reza
Novo Nordisk A S
Weber Jon P.
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