Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Patent
1996-09-24
1999-12-28
Fitzgerald, David L.
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
424 854, A61K 3821
Patent
active
060078057
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the treatment or prophylaxis of viral infections with interferons (IFNs).
Type I interferons (IFN) are a family of closely related glycoproteins containing many IFN-.alpha. subtypes and one IFN-.beta. subspecies. At least 23 different human IFN-.alpha. subtypes have been identified by analysis of human CDNA libraries and by protein analysis of the IFNs produced by stimulated lymphoblastoid cells. The reasons for this heterogeneity are not yet known. Previous studies have suggested that all Type I IFNs bind to an identical receptor and therefore have identical effects. However a mutant cell line that responds only to IFN-.beta. but not IFN-.alpha. has been identified showing that these two IFN subspecies bind to a different receptor and may therefore have different effects. Studies on the recently identified transmembrane human IFN receptor have shown that if this receptor is transfected into murine cells the cells respond only to some IFN subtypes, showing that a second receptor component is required to allow cells to respond to IFN and that the murine equivalent of this component is able to distinguish between different IFN subtypes. Molecular analysis of the human Type I IFN receptor thus suggests that the receptor may be able to distinguish between different IFN subtypes, but whether the different subtypes do, in fact, have different effects is not yet clear. A number of studies have compared the effects of different IFN-.alpha. subtypes on the antiviral activities of human cell lines. Zoon et al (J. Biol. Chem. 267: 15210-16 (1992) studied IFNs that were obtained from HPLC purification of natural IFN and found no gross differences in their antiviral activities. However, Sperber et al, J. Interferon. Res. 12 363-368 (1992) examined the effects of different recombinant IFN-.alpha. subtypes on cells infected with the human immunodeficiency virus (HIV) and found marked differences in their antiviral properties.
Whereas the investigations of Sperber et al were confined to the effect of different subtypes of IFN-.alpha. against a particular virus (HIV-1), it has now been found that the antiviral effect of subtypes of IFN-.alpha. is dependent on the type of cell infected with the virus. Further, it appears that certain subtypes of IFN-.alpha. act as partial agonists to antivirally effective IFNs-.alpha.. Therefore, by virtue of the invention, the use of specific subtypes of IFN-.alpha. for the treatment of each cell type is indicated.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1A is a graph showing the relative ED50 for various interferon subtypes in HuH7 cells;
FIG. 1B is a graph showing the relative ED50 for various interferon subtypes in SHSY cells; and
FIG. 1C is a graph showing the relative ED50 for various interferon subtypes in A549 cells.
DESCRIPTION OF THE INVENTION
According to the invention, there is provided the use of a single interferon-.alpha. (IFN-.alpha.) subtype in the preparation of a medicament for preventing or treating viral infections of a particular organ or cell type.
The cell type will generally not be T-lymphocytes, in view of the prior work of Sperber et al. However, nothing in the Sperber et al publication referred to above suggests that IFNs-.alpha. exhibit cell-type specific antiviral activity.
A particularly preferred IFN-.alpha. subtype is IFN-.alpha..sub.8. This is particularly suitable for treating or preventing viral infections of the liver. In addition to its potent antiviral effects in normal cell lines, IFN-.alpha..sub.8 is also active in a mutant cell line (11,1 (Pellegrini et al, Mol. Cell. Biol. 9: 4605-4612 (1989))) that does not respond to other .alpha. IFN subtypes.
The particular IFN-.alpha. subtype to be used in clinical practice will depend on the cell type which is infected. Preferred subtypes for a particular cell type may be those which not only have potent antiviral activity for that particular cell type but also have relatively low activity in respect of other cell types, so as to reduce the possibility of side effects.
For exampl
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Foster Graham Russell
Thomas Howard Christopher
Fitzgerald David L.
Imperial College of Science and Technology
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