Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Reexamination Certificate
1999-02-02
2004-09-07
Devi, S. (Department: 1645)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
C530S350000, C530S351000, C424S185100, C424S085500
Reexamination Certificate
active
06787634
ABSTRACT:
The interferons (IFN) constitute a group of secreted proteins which exhibit a wide range of biological activities and are characterized by their capacity to induce an antiviral state in vertebrate cells (I. Gresser and M. G. Tovey Biochem Biophys. Acta 516:231, 1978). There are three antigenic classes of IFN: alpha (&agr;), beta (&bgr;) and gamma. IFN&agr; and IFN&bgr; together are known as the type I interferon.
Natural type I human interferon comprises 12 or more closely related proteins encoded by distinct genes with a high degree of structural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol. Biol. 33:251, 1986).
The human IFN&agr; locus comprises two subfamilies. The first subfamily consists of 14 non allelic genes and 4 pseudogenes having at least 80% homology. The second subfamily, &agr;II or omega (&ohgr;), contains 5 pseudogenes and 1 functional gene which exhibits 70% homology with the IFN&agr; genes (Weissmann and Weber 1986).
The subtypes of IFN&agr; have different specific activities but they possess the same biological spectrum (Streuli et al. PNAS-USA 78:2848, 1981) and have the same cellular receptor (Agnet M. et al. in “Interferon 5” Ed. I. Gresser p. 1-22, Academic Press, London 1983).
The interferon &bgr; (IFN&bgr;) is encoded by a single gene which has approximately 50% homology with the IFN&agr; genes.
The interferon &agr; subtypes and interferon &bgr; bind to the same receptor on the cell surface.
The interferon gamma (IFN gamma) is also encoded by a single copy, which has little homology with the IFN&agr; and IFN&bgr; genes. The receptor for IFN gamma is distinct from the receptor of the &agr; and &bgr; interferons.
For the purpose of the present invention the receptor of &agr; and &bgr; classes of IFN will be designated IFN-R. This represents natural type I receptor. The group of proteins forming natural interferon &agr; will be designated IFN&agr;, and type I-IFN will represent both natural IFN&agr;, IFN&ohgr;, and IFN&bgr;.
Despite the fact that interferon is a potent antiviral agent, there is considerable evidence to suggest, that many of the characteristic symptoms of acute virus diseases such as upper respiratory tract infections are caused by an overproduction of interferon alpha. Furthermore, IFN alpha has been shown to contribute to the pathogenesis of certain chronic virus infections in experimental animals and the available evidence suggests that this is also the case for certain human chronic virus diseases such as those due to measles virus.
The interferons &agr; are also potent immuno-regulatory molecules which stimulate polyclonal B-cell activation, enhance NK cell cytotoxicity, inhibit T-cell functions, and modulate the expression of the major histocompatibility complex (MHC) class 1 antigens, all of which are implicated in the induction of autoimmunity and in graft rejection. The abnormal production of interferon &agr; is associated with a number of autoimmune diseases and inflammatory disorders including systemic lupus erythematosus (SLE), type I diabetes, psoriasis, rheumatoid arthritis, multiple sclerosis, Behcet's disease, aplastic anemia, the acquired immunodeficiency syndrome (AIDS) and severe combined immunodeficiency disease. The presence of interferon &agr; in the serum of patients with systemic lupus is correlated with both the clinical and humoral signs of increased disease activity. The production of interferon &agr; in HIV positive subjects is also highly predictive of disease evolution.
Administration of interferon &agr; has been reported to exacerbate underlying disease in patients with psoriasis and multiple sclerosis and to induce a SLE like syndrome in patients without a previous history of autoimmune disease. Interferon &agr; has also been shown to induce glomerulonephritis in normal mice and to accelerate the outset of the spontaneous autoimmune disease of NZB/W mice.
Interferon &agr; is also produced during the course of graft-versus-host disease (GVHD) in parallel with the enhanced NK cell activity characteristic of systemic GVDH. Interferon &agr; is the principal modulator of NK cell cytotoxicity and administration of interferon &agr; has been shown to enhance the intestinal consequences of GVDH in normal mice.
The object of the present invention is to provide new antagonists against the biological activities of the human type I-IFN. These antagonists could be used for therapeutical, including prophylaxis purposes, in cases where the type I-IFN (IFN &agr;/&bgr;) is abnormaly produced and when this abnormal production is associated with pathological symptoms. Such antagonists could also be used for the diagnosis of various diseases or for the study of the evolution of such diseases.
In order to define such antagonists, the inventors have taken into account the fact that the human natural type I-IFN is in fact constituted of a mixture of interferons (subspecies) and the fact that the composition of this association of different subtypes of interferons varies both quantitatively and qualitatively.
Some natural interferons, such as the ones secreted by Namalwa cells (Namalwa interferon) or leukocyte (leucocyte interferon) have been studied in detail (N. B. Finter and K. H. Fautes, Interferon 2, 1980, p. 65-79 I. Gresser Editor Academic Press; K. Cantell et al, Interferon 1, 1979 p. 2-25, I. Gresser Editor Academic Press) and were used by the inventors to define natural type I interferons.
In some pathological cases, like AIDS, interferons having some special properties have been described (O. T. Preble et al, Annals of New-York Academy of Sciences p. 65-75). This interferon involved in pathological cases like AIDS nevertheless binds to the same receptor, as described above.
One object of the present invention is to provide an antagonist of the type I-IFN, which would be able to inhibit or neutralize, to a determined extent, the biological properties of the human type I-IFN, that is to say, to neutralize in vivo a mixture of &agr;, &bgr;, &ohgr; subspecies.
Accordingly the inventors have defined antibodies, especially monoclonal antibodies, which have the property of being antagonists to the type I-IFN. These antibodies are directed against the human type I-IFN receptor.
The invention thus also concerns the use of the monoclonal antibodies for the preparation of pharmaceutical compositions, useful for the treatment of symptoms associated with the abnormal production of type I-IFN. These monoclonal antibodies are also appropriate for the preparation of diagnosis reagents.
A monoclonal antibody according to the present invention is directed against the human type I-interferon receptor (IFN-R) and is characterized by the following properties:
it recognizes the extracellular domain of the human IFN-R, and
it has a neutralizing capacity against the biological properties of the human type I-IFN.
The ability to neutralize the biological properties of type I-IFN can be estimated as a function of the capacity of the monoclonal antibody to neutralize the antiviral activity of the type I-IFN. Such a test is relevant in order to determine whether the antibody assayed is included within the scope of the invention, although it is clear that the biological properties of type I-IFN are not limited to its antiviral properties. Detailed procedures are given in the examples in order to enable to perform such a test of the antiviral activity. The cells tested can advantageously be Daudi-cells, which affinity for the type I-IFN is well known. The main steps of such a test would consist in:
incubating a determined concentration of human cells responsive to human type I-IFN, with human type I-IFN in the presence of a determined concentration of monoclonal antibodies to be assayed, for a time sufficient to allow the formation of a complex between the monoclonal antibodies and the IFN-R of the human cells and/or between the type I-IFN and the IFN-R of the human cells;
infecting the incubated cells with a determined virus, in a determined concentration,
washing the cells,
resuspending the cells in culture medium,
incubating for a
Benoit Patrick
Maguire Debborah
Meyer Francois
Plavec Ivan
Tovey Michael G.
Devi S.
Medisup International N.V.
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