Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Patent
1997-11-10
1999-12-21
Degen, Nancy
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
435 6, 4353201, 435377, 435455, 514 44, 536 231, 536 241, 536 245, C07H 2104, C12N 1511, C12N 1585
Patent
active
060048131
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a nucleotide sequence, which is able to inhibit the IL-6 activity, its use in therapy as well as pharmaceutical compositions containing it.
BACKGROUND OF THE INVENTION
IL-6 is a protein belonging to the group of cytokines, which proved to play a key role in the organism's immune response and haematopoiesis stimulation.
Many biological functions have, in fact, been found for IL-6 in the hematopoietic and lymphoid system, in the liver and in other target organs and cells. Some of these functions are beneficial, while others are related to pathological states. Among the latter functions, IL-6 has been found to be a growth factor for multiple myeloma cells; anti-IL-6 antibodies were shown to transiently block myeloma cell proliferation in a leukemic patient (see for example Klein et al., Blood, 78, (5), pp.1198-1204, 1991 and Lu et al., Eur. J. Immunol., 22, pp. 2819-24, 1992).
Elevated IL-6 levels have been correlated with autoimmune and inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, psoriasis, and Castelman's disease (see for example Graeve et al., Clin. Investig., 71, pp.664-71, 1993). IL-6 has also been shown to play a direct role in bone loss and hypercalcemia (see for example Poli et al., Embo J., 13, (5) pp. 1189-96 and Yoneda et al., Cancer Res., 53, pp. 737-40, February 1993).
The development of inhibitors of IL-6 activity has therefore been the subject of active research. For this purpose, different approaches have been pursued, including the use of antibodies against IL-6 (as reported by Klein et al. above), gp130 or gp80; the use of soluble gp130; or the use of muteins for IL-6, or IL-6 Receptor.
Since these approaches might be associated with specific unwanted effects in clinical applications (as reported by Lu et al., above), the setting-up of additional strategies to inhibit IL-6 activity would be useful.
The Applicant has, therefore, investigated a different approach to inhibit IL-6 activity: by blocking the intracellular proteins mediating the IL-6 signal.
The transduction of the IL-6 signal in responsive cells has been intensively investigated. Fowlkes et al. (PNAS USA, 81, pp. 2313-6, 1984) first suspected DNA responsive elements specific for IL-6 flanking the rat fibrinogen genes.
Later on, Kunz et al. (Nuc. Ac. Res., 17, (3), 1121-37, 1989) showed a responsive element with a core sequence identical to that of rat fibrinogen genes (CTGGGA) to respond to IL-6 in the rat .alpha..sub.2 -macroglobulin gene.
DNA responsive elements with sequences related to those above-mentioned have also been defined in the genes coding for the human C Reactive Protein (CRP) (see Toniatti et al., Mol. Biol. Med, 7, pp. 199-212, 1990), human haptoglobin (see Oliviero et al., Embo J. 6, (7), pp. 1905-12, 1987) and in other genes coding for additional acute phase proteins induced by IL-6 (see Heinrich et al., Biochem. J., 265, pp. 621-36, 1990), leading to the definition of a core consensus sequence CTGGGAW or CTGGRAA, where W stands for A or T, and R stands for A or G.
Hocke et al. (Mol. Cell. Biol., 12, (5), pp. 2282-94, 1992) indicated that multiple related core sequences, similar to the core sequence mentioned above, might be present in regulatory regions of wild-type genes responding to IL-6 and that this multiplicity leads to amplification of the response, as functionally analyzed with a reporter gene assay.
Wegenka et al. (Mol. Cell. Biol., 13, (1), pp. 276-88, 1993) have recently indicated an enlarged version of the core consensus sequence as the Acute Phase Response Element (APRE), active in hepatoma cells that can be represented by the formula KTMYKGKAA, wherein M stands for C or A, K stands for T or G, Y stands for C or T.
By Yuan et al. (Mol. Cell. Biol., 14, (3), pp. 1657-68, 1994) it has been shown that such APRE-like sequences bind a protein transcription factor having a molecular weight of about 90 KD, called APRF which has been recently cloned (see Akira et al., Cell, 77, pp. 63-71, 1994). In practice, the bindin
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Pezzotti Annarita
Serlupi-Crescenzi Ottaviano
Applied Research Systems ARS Holding N.V.
Degen Nancy
McGarry Sean
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