Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1993-02-17
2002-11-05
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S350000, C530S351000, C435S069100, C435S325000, C435S007210, C435S069510, C435S069700, C424S085400, C424S143100, C536S023500
Reexamination Certificate
active
06475983
ABSTRACT:
The present invention relates to new water-soluble polypeptides, DNA sequences, new cells, the preparation process of said polypeptides, their use as medicaments and the compositions containing them.
&agr; and &bgr; interferons form a group of secreted proteins endowed with diverse biological properties and characterized by their ability to induce, in the cells of vertebrates, an antiviral and anti-proliferative state (I. Gresser and M. G. Tovey, Biochem. Biophys. Acta 516:23/1978).
&agr; interferon has significant effects on the immune, cellular and humoral system, in particular on the polyclonal activation of B cells (M. Peters, J. Immunol., 137:3153/1986), the inhibition of the T cell functions (J. Knop et al, J. Immunol., 133:2412/1984) and the modification of the expression of histocompatibility antigens (M. Fellous et al, Eur. J. Immunol., 9:446/1979). All these processes are involved in the development of auto-immunity.
Although interferon is considered as a beneficial factor for the organism, an abnormal production of interferon may contribute to the pathology of certain illnesses and in fact is associated with various so-called auto-immune illnesses. For example, high levels of interferon are present in the serum or tissues of patients suffering from various illnesses, such as lupus erythematosus, rheumatoid arthritis, Behcet's syndrome, diabetes mellitus, multiple sclerosis, aplasia of the marrow and a serious multiple immuno-deficiency illness. A direct correlation exists between the levels of this interferon and the poor prognosis of the development of the AIDS illness (E. Buimovivi-Klein et al; AIDS Res., 2:99/1986).
It has been shown that in a specific mouse strain (NZB) suffering from a spontaneous illness, which illness serves as an animal model of lupus erythematosus in man, the administration of &agr; or &bgr; interferon aggravates the progression of the illness (H. Heremans et al, Infect. immun., 21:925/1978; C. Adam et al, Clin. Exp. Immunol., 40:373/1980).
In young mice, the administration of large quantities of interferon induces a growth-inhibition syndrome, necrosis of the liver and death (I. Gresser et al, Nature, 258:76/1975). Also, infection by certain viruses (such as the viruses of Pichinde lymphocytic choriomeningitis, or rheovirus) during the neonatal period of the female mouse is accompanied by the production of large quantities of endogenic interferon which brings about the same lethal syndrome. The administration of an &agr; or &bgr; anti-interferon antibody protects the young mice infected at birth by the viruses of this syndrome mentioned above (Y. Riviere et al, Proc. Natl. Acad. Sci. USA, 74:2135/1977; Y. Riviere et al, J. Exp. Med., 152:633/1980; T. Clark et al, J. Virol, 59:728/1986). This experiment represents a convincing argument for the harmful role of interferon in the pathogenesis of this illness.
Furthermore, the activation of NK cells and the modification of the expression of histocompatibility antigens are both regulated by &agr; or &bgr; interferon and play an important role in the rejection of bone marrow grafts (C. Ohien et al, Science, 246:66/1989). In fact, it was demonstrated that the production of &agr; or &bgr; interferon is one of the essential elements in the resistance of F1 hybrid mice to a graft of the parental marrow (Afifi et al, J. Immunol., 134:3739/1985). Thus the treatment of F1 mice or also of allogenic mice by a murine &agr; or &bgr; anti-interferon serum allows the grafting and proliferation of the parental or allogenic marrow (Afifi et al, 1985).
It is also known that the biological effects of interferons and their sub-types are generated by their interaction with a specific receptor which has a high affinity for the cell surface (M. Aguet et K. E. Mogensen, Academic Press, London, 1983).
At present no effective therapy exists for auto-immune illnesses and for other illnesses such as multiple sclerosis, which is suspected of having a connection with auto-immune illnesses. The present treatments for auto-immune type illnesses are unsatisfactory and have toxic effects. Those used in “anti-rejection” therapies inhibit the manifestations of these pathologies but not their causes and have a very high toxicity. It would therefore be highly desirable to have available medicaments having therapeutic effects and a reduced toxicity for auto-immune illnesses and organ rejections.
It would therefore be very desirable to block the action of (&agr; or &bgr;) interferon by injection of an antagonist which in this way could be therapeutically beneficial for auto-immune type illnesses and for preventing the rejection of grafts. However, such an approach based on the injection of foreign immunoglobulin which has proved its effectiveness is not practical in a therapeutic treatment in man.
That is why the present Application relates to a new approach which is based on the use of a soluble form of the specific receptor of &agr; interferon as antagonist to block the action of &agr; or &bgr; interferon. These variants of the natural receptor, prepared by genetic engineering techniques, retain the ability to fix the endogenic &agr; interferon either circulating or locally, and are deprived of the part which fixes them to the cell surface; they can circulate freely and due to their specificity only link up with &agr; or &bgr; interferon.
By fixing &agr; or &bgr; interferon, they are capable of blocking—as an antibody would—the action of &agr; or &bgr; interferon in the organism.
It would therefore be desirable to have available a product capable of blocking the activity of &agr; and/or &bgr; interferon.
That is why a subject of the present Application is a water-soluble polypeptide, characterized in that it has a high affinity for &agr; and &bgr; interferons.
By “high affinity” is meant a dissociation constant of less than 10
−9
M.
By “water-soluble” is meant that the said polypeptide is capable of circulating ,in an organism such as the human body then of fixing itself to a cell.
In the present Application, and in what follows, by “hybrid” is meant the product resulting from the fusion (or conjugation) of a water-soluble polypeptide according to the present invention (“soluble” part of the natural receptor, modified complete receptor, or “soluble” part of the natural receptor modified for example by substitution) and of another molecule, in particular of polypeptide type, such as an immunoglobulin or an immunoglobulin fragment.
By “soluble receptor of &agr; and &bgr; interferons” (or of interferon) is meant one of the water-soluble polypeptides as defined above.
In order to simplify the wording, in what follows, “interferon receptor” will generally be referred to instead of “receptor for &agr; and &bgr; interferons”.
Among the polypeptides as defined above, a particular subject of the invention is a water-soluble polypeptide, characterized in that it corresponds to the formula given in annex 1.
This polypeptide corresponds to the extra-cellular soluble part of the natural native receptor of &agr; or &bgr; interferon.
Of course polypeptides other than the polypeptide described above retain a high affinity for the said interferons. It is thus that the polypeptide given in annex 1 could be replaced in particular by substitution or deletion variants which are also part of the subject of the present Application.
With regard to the deletions, one or more amino acids of the polypeptide corresponding to
FIGS. 1A-1B
could be suppressed without unfavourably modifying the affinity vis-à-vis the &agr; and &bgr; interferons.
Deletions could also relate to the complete and native receptor, in particular at the level of its soluble part, in such a way for example as to make it lose its ability to fix itself to the cell membrane and therefore make it available in the circulation.
If one starts with the sequence of the native and complete receptor of interferon given in annex 2, the trans-membrane and cytoplasmic sections of its sequence could for example be suppressed.
The deletion of the 437-457 residues corresponding to the tran
Eid Pierre
Gresser Ion
Lutfalla Georges
Meyer Francois
Mogensen Knud Erik
Andres Janet L
Medisup International N.V.
Spector Lorraine
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