Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1998-10-29
2000-10-24
Fitzgerald, David L.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
4241331, 53038822, 5303873, 536 2353, 4353201, 435328, 435334, 435346, 435 724, 436531, A61K 39395, C07K 1628, C12N 1513, C12N 520
Patent
active
06136309&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to antibodies directed against the ligand-binding component of the interferon-.alpha./.beta. receptor which are capable of selectively modulating the activity of various Type I interferons.
EP publication No. 588,177 describes a soluble IFN-.alpha. receptor, having a molecular weight of about 40,000, which was identified by cross-linking with .sup.125 I-IFN-.alpha.2 and immunoprecipitation with anti-IFN-.alpha. monoclonal antibodies. When obtained from serum, this species had a molecular weight of 50K. It also describes the aforesaid 40,000 IFN-.alpha. binding protein, (hereinafter "IFNAB-BP" or ("IFNAB-BPII") obtained from urine in a homogenous state and having a sequence that differs from any other known protein. The IFNAB-BP binds to and blocks the activity of a variety of IFN-.alpha. subtypes, as well as the one of IFN-.beta..
EP publication No 676,413 describes cloning and sequencing of two cDNA molecules coding for precursors of IFNAB-BP. Both are probably derived from the same gene, e.g., by alternative splicing. Production of two recombinant proteins, designated IFNAB-BPI and IFNAB-BPII in mammalian and other host cells is also described. Polyclonal and monoclonal antibodies directed against IFNAB-BP and useful for blocking the IFN receptor, for immunoassays and immunopurification of IFNAB-BPI and IFNAB-BPII are also disclosed.
In the present invention there are described two groups of neutralizing antibodies made against IFNAB-BPII which bind to the Type I interferon receptor on human cells. One group of the antibodies is capable of blocking the activity of both IFN-.alpha. subtypes as well as the activity of IFN-.beta.. Another group of antibodies is capable of selectively blocking the activity of various subtypes of interferon-.alpha. in human cells, without affecting the activity of interferon-.beta.. Thus, one group of said antibodies may inhibit undesired effects of IFN-.alpha. with very little effect on the activity of IFN-.beta..
BACKGROUND OF THE INVENTION
Type I interferons (IFNs) (IFN-.alpha. IFN-.beta. and IFN-.omega.) constitute a family of structurally related cytokines, usually defined by their ability to confer resistance to viral infections. Many other biological activities of type I IFNs have been reported, including inhibition of cell proliferation, induction of class I MHC antigens and several other immuno-regulatory activities (1). IFN-.alpha. and IFN-.beta. are useful for the treatment of several viral diseases, including hepatitis-C (2,3) and viral warts (4,5), as well as certain malignancies such as hairy cell leukemia (6), chronic myelogenous leukemia (7) and Kaposi's sarcoma (8).
IFN-.alpha. was detected in sera of various patents having autoimmune diseases such as systemic lupus erythematosus (9), as well as AIDS patients (10). IFN-.alpha. was implicated in the progression of juvenile diabetes (11). Further, IFN-.alpha. therapy has been shown in some cases to lead to undesired side effects, including fever and neurological disorders (12). Hence there are pathological situations in which neutralization of IFN-.alpha. activity may be beneficial to the patient.
As in the case of other cytokines, IFN-.alpha. exerts its biological activities by binding to a cell surface receptor, which is specific for all IFN-.alpha. subtypes, as well as for IFN-.beta. (13). A human IFN-.alpha. receptor (IFNAR) was identified and cloned from Daudi cells (14). The cloned receptor has a single transmembrane domain, an extracellular and an intracellular domain. When expressed in murine cells, this receptor confers responsiveness to human IFN-.alpha.B but not significantly to other IFN-.alpha. and IFN-.beta. species, indicating that additional components may be involved in the response to IFN-.beta. and to various IFN-.alpha. subtypes.
Several other studies indicate that there are additional components or receptor subunits involved in the binding of IFN-.alpha. and IFN-.beta. (15-17). Nevertheless, it was reported that the already described
REFERENCES:
Croze, E., et al. (1996). "The Human Type I Interferon Receptor." J. Biol. Chem. 271: 33165-68, Dec. 1996.
Platanias, L. C., et al. (1996). "Differences in Interferon .alpha. and .beta. Signaling." J. Biol. Chem. 271: 23630-33, Sep. 1996.
Benoit, P., et al., "A Monoclonal Antibody to Recombinant Human IFN-.alpha. Receptor Inhibits Biologic Activity of Several Species of Human IFN-.alpha., IFN-.beta., and IFN-.sup.1, " The Journal of Immunology 150-3:707-716 (1993).
Colamonici, O.R., et al., "Identification of a Novel Subunit of the Type I Interferon Receptor Localized to Human Chromosome 21," The Journal of Biological Chemistry 268-15:10895-10899 (1993).
Novick, D., et al., "The Human Interferon .alpha./.beta. Receptor: Characterization and Molecular Cloning," Cell 77:391-400 (1994).
Novick, D., et al., "Soluble and Membrane-Anchored Forms of the Human IFN-.alpha./.beta. Receptor," Journal of Leukocyte Biology 57:712-718.
Constantinescu, S.N., et al., "Role of Interferon .alpha./.beta. Receptor Chain 1 in the Structure and Transmembrane Signaling of the Interferon .alpha./.beta. Receptor Complex," Proc. Natl. Acad. Sci. USA 91:9602-9606 (1994).
Colamonici, O.R., et al, "Characterization of Three Monoclonal Antibodies that Recognize the Interferon .alpha.2 Receptor," Proc. Natl. Acad. Sci. USA 87:7230-7234 (1990).
Novick Daniela
Rubinstein Menachem
Fitzgerald David L.
Yeda Research and Development Co. Ltd.
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