Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving transferase
Reexamination Certificate
1998-07-16
2001-07-31
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving transferase
C435S007100
Reexamination Certificate
active
06268163
ABSTRACT:
FIELD OF INVENTION
A novel intracellular signalling activity of coagulation factor VII (FVII) in cells expressing tissue factor (TF) has been descibed. 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 &agr; and &bgr; (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 &bgr; and &ggr; 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 induce mobilisation of intracellular free calcium (Ca
2+
) in the human bladder carcinoma cell line, J82, which constitutively express 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 mobilisation 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.
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Bergenhem Niels
Foster Don
Kongsbak Lars
Petersen Lars Christian
Thastrup Ole
Green, Esq. Reza
Novo Nordisk A S
Weber Jon P.
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