Expression enhancer for protein synthesis inhibitory genes

Details Expression enhancer for protein synthesis inhibitory genes Expression enhancer for protein synthesis inhibitory genes

2001-09-26

2004-08-10

Andres, Janet (Department: 1646)

Drug, bio-affecting and body treating compositions

Lymphokine

C424S085100, C424S085400, C514S002600, C530S351000, C530S350000

Reexamination Certificate

active

06773701

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel expression enhancer for protein synthesis inhibitory genes, more particularly, to an expression enhancer for protein synthesis inhibitory genes, which comprises as effective ingredients interferon-&agr;2 and interferon-&agr;8 subtypes of human interferon-&agr; (hereinafter the terms “interferon”, “interferon-&agr;”, “interferon-&agr;2 subtype of human interferon-&agr;”, and “interferon-&agr;8 subtype of human interferon-&agr;” may be abbreviated as “IFN”, “IFN-&agr;”, “IFN-&agr;2” and “IFN-&agr;8”, respectively).
BACKGROUND ART
The term IFN(s) is the generic name for a group of proteins having anti-virus activity secreted extracellularly from vertebrate animal cells when externally stimulated by virus infections or antigenic stimulants. Based on the antigenicity of IFNs, they are roughly classified into three types of IFN-&agr;, IFN-&bgr; and IFN-&ggr;. IFNs have been known to have anti-virus activity and other diversified physiological activities such as cell growth-inhibitory activity and anti-tumor activity. The isolation and identification of receptors against IFNs have been progressed and, for example, as disclosed in “
The Cytokine FactsBook
”, edited by Robin E. Callard and Andy J. H. Gearing, published by Academic Press, pp. 148-162 (1994), it is known that IFN-&agr; and IFN-&bgr; have a common receptor and that IFN-&ggr; has another different acceptor. Similarly as in the case of other cytokines, the expression of physiological activities of IFNs is caused by different changes in IFN-susceptive cells induced by IFN stimulations in such a sequential manner of the binding of IFNs to their receptors expressed on the cell surfaces, the actuation of intracellular information transmission system, and the intracellular expression of specific genes. The isolation and identification of molecules relating to the above intracellular information transmission system has been in a rapid progress in these days.
There are different types of genes whose gene expressions are induced as a result of cell stimulation by IFNs. For example, Table 2 in chapter 18 of “
The Cytokine Handbook
”, 3rd edition, edited by Angus Thomson, published by Academic Press (1998) shows products or proteins as gene expression products, induced by the stimulation of IFN-&agr; and IFN-&bgr;, such as 2′, 5′-oligoadenylate synthetase (abbreviated as “2-5A” hereinafter), double-stranded RNA dependent protein kinase (hereinafter abbreviated as “PKR”), Mx protein, class I and class II MHC molecules, &bgr;-2 macroglobulin, guanylate bound proteins, and metallothionein. Most of the above products or proteins can be also induced by IFN-&ggr;. Among these gene expression products induced by IFNs, 2-5A synthetase and PKR as protein synthesis inhibitory enzymes, and Mx protein play a direct role in inhibiting abnormality of cells received with abnormal conditions such as tumorigenic transformation and virus infection. While MHC molecules and &bgr;-2 macroglobulin are proteins responsible for the function of immune system of living bodies, and indirectly relate to the elimination of tumors and viruses from the bodies through the action of immune system in vivo. As regards guanylate bound proteins and metallothionein, their correlations with the expression of physiological activities by IFN(s) have not been revealed yet.
At the beginning of the discovery, IFN was once called “a novel dream medicine” and had been greatly expected for use as a pharmaceutical, however, there found no sufficient therapeutic effect on some types of diseases as it had been expected. As one of the causes thereof, it may be speculated that although there exist specificities on the actions and levels to be exerted depending on the conditions of the types and subtypes of IFNs used, for example, the types of cells to be treated and of viruses being infected to the cells and the combination of IFNs used, it has not yet been completely revealed the optimum conditions for sufficiently exerting the desired actions in respective conditions.
As regards the comparison among the gene expression enhancing actions by IFN-&agr;, IFN-&bgr; and IFN-&ggr;, for example, as found in “
Journal of Biological Response Modifiers
”, Vol. 5, No. 6, pp. 562-570 (1986) by PL. Triozzi, and “
Journal of Interferon Research
”, Vol. 8, No. 1, pp. 113-127 (1988) by EM. Coccia et al., it was reported that IFN-&ggr; was inferior to IFN-&agr; and IFN-&bgr; in expression inductivity of 2-5A synthetase gene and PKR gene. On the contrary, unlike IFN-&bgr; and IFN-&ggr;, IFN-&agr; has at least ten or more subtypes, however, there has been no report on research aiming at revealing the action conditions of IFN-&agr; to effectively exert its gene expression enhancing action, particularly, the optimization of combination use of IFN-&agr; subtypes.
DISCLOSURE OF INVENTION
Under the above background, the present inventors focused their attention on the fact that there has not yet been studied a research on products, which are expressed by protein synthesis inhibitory genes through the induction by IFNs and which directly relate to exert some actions by IFNs, nor a research on the optimization of the combination use of IFN-&agr; subtypes in inducing the expression of the genes. Based on this, they speculated that, if an appropriate combination of IFN-&agr; subtypes that greatly enhances the expression of the genes were found, more effective medical uses of such IFNs would be attained.
Thus the object of the present invention is to specify the combination use of IFN-&agr; subtypes that outstandingly enhances the expression of protein synthesis inhibitory genes, and to provide a gene expression enhancer comprising, as effective ingredients, the above IFN-&agr; subtypes used in combination and uses thereof.
To attain the above object, using isolated human IFN-&agr; subtypes, the present inventors widely studied the action of the subtypes on cells when used alone or in combination, and then compared the results each other. As a result, the present inventors found the following completely novel phenomenon: When IFN-&agr;2 and IFN-&agr;8 subtypes of human IFN-&agr; are allowed to act on cells in combination, they synergistically enhance the expression level of protein synthesis inhibitory genes such as 2-5A synthetase intracellularly. This phenomenon was evidenced by the fact that the phenomenon was also observed as a synergism when examined with an index of anti-virus activity to which 2-5A synthetase would directly correlate. The present invention was made based on the above completely novel finding by the present inventors.
The present invention solves the above objects by providing an expression enhancer for protein synthesis inhibitory genes which comprises as effective ingredients IFN-&agr;2 and IFN-&agr;8 subtypes of human IFN-&agr;, and uses thereof including pharmaceuticals.
BEST MODE OF THE INVENTION
The present invention relates to an expression enhancer for protein synthesis inhibitory genes (may be referred to as “the expression enhancer of the present invention” or “the expression enhancer”, hereinafter) which comprises as effective ingredients IFN-&agr;2 and IFN-&agr;8 subtypes of human IFN-&agr; (the term “IFN-&agr;2 and IFN-&agr;8 subtypes of human IFN-&agr;” may be briefly called “subtypes”). The terms “IFN-&agr;2” and “IFN-&agr;8” as referred to as in the present invention mean proteins which contain substantially the same amino acid sequences of the subtypes containing the N-terminal signal sequences as shown in SEQ ID NOs: 1 and 2 in the present specification, registered for SWISSPROT, a protein database produced by Amos Bairoch, Switzerland, under the primary accession numbers of P01563 and P32881, respectively, and which are confirmed to have anti-virus activity when determined in the later described appropriate assay systems, independently of their higher-order structures and carbohydrate chains other than their amino acid sequences. The term “substantially the same amino acid sequences” as referred to as

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