Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1990-04-02
1993-03-23
Lee, Lester L.
Drug, bio-affecting and body treating compositions
Lymphokine
514 8, A61K 3704, A61K 3702
Patent
active
051961920
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to secondary uses for the gonadal hormones inhibin and activin and the .alpha. subunit of inhibin and to uses for antagonists for these hormones.
BACKGROUND ART
Inhibit is a gonadal glycoprotein which preferentially suppresses FSH secretion in vitro and is believed to have a key role in the physiological control of FSH in vivo. Recently, inhibin has been isolated from bovine (Robertson et al 1985 Biochem Biophys Res Comm 126:220; Robertson et al 1986, Mol Cell Endocrinol 44:217; Fukada et al 1986 Mol Cell Endocrinol 44:55), porcine (Miyamoto et al 1985 Biochem Biophys Res Comm 129:396; Ling et al 1985, Proc Nat Acad Sci (USA) 82:7217) and ovine (Leversha et al 1987 J. Endocrinol 113:213) ovarian follicular fluids (FF). The amino acid sequence or porcine (Mason et al 1985 Nature 318:639), bovine (Forage et al 1986 Proc Nat Acad Sci (USA) 83:3091), human (Mason et al 1986 Biochem Biophys Res Comm 135:957; Steward et al 1986 FEBS 206:329), ovine (Crawford et al 1987 Mol Endocrinol 1:699; Forage et al 1987 Serono Symposium 42:89) and rat (Esch et al 1987 Mol Endocrinol 1:388; Woodruff et al 1987 Mol Endocrinol 1:561) inhibin has been determined by cloning techniques. Inhibit in a dimer of two partially homologous subunits (.alpha. and .beta.) joined by disulphide bonds. Inhibin with two variants of the .beta. subunit (A and B) has been isolated from porcine FF (Ling et al 1985 Proc Nat Acad Sci (USA) 82:7217) and their mRNAs also identified in the human (Mason et al 1986 Biochem Biophys Res Comm 135:957; Steward et al 1987 FEBS 206:329) and rat (Esch et al 1987 Mol Endocrinol 1:949; Woodruff et al 1987 Mol Endocrinol 1:561). Inhibin has also been isolated as two molecular weight forms (58000D and 31-32000D) which differ in the extent of processing of the .alpha. chain (Robertson et al 1986 Mol Cell Endocrinol 44:271). Bovine 58 kD inhibin is cleave to 31 kD inhibin in the presence of serum but not follicular fluid (McLachlan et al 1986 Mol Cell Endocrinol 46:175) suggesting that processing of the .alpha. subunit is extragonadal. Inhibin has also been identified as a placental product in rats and humane (McLachlan et al 1985 Biochem Biophys Res Comm 140:485; Petraglia et al 1987 Science 237:187), suggesting that it plays a role in pregnancy.
Recently, several proteins have been isolated from gonadal and other tissues and found to be structurally related to inhibin particularly to the .beta. subunit, but with different biological activities. These proteins include activin-A and activin-AB (inhibin .beta.A.beta.A or .beta.A.beta.B subunit dimers, Vale et al 1986 Nature 321:776; Ling et al 1986 Nature 321:779) or erythroid differentiating factor (Eto et al 1987 Biochem Biophys Res Comm 142:1095); Mullerian inhibitory substance (Cate et al 1986, Cell 45:685) and transforming growth factor-.beta. (Sporn et al 1987 J Cell Biol 105:1039). TGF-` is a potent inhibitor of lectin-induced T lymphocyte proliferation in vitro, and many patients with glioblastomas, which secrete large amounts of TGF-.beta., display suppressed immune functions (Kherl et al 1986 J Exp Med 163:1037; Wrann et al 1987 EMBO 6:1633).
DISCLOSURE OF THE INVENTION
Definitions
As used throughout the specification and claims "host" refers to a vertebrate host, preferably a mammalian host, and more particularly a human host.
The term "inhibin" as used throughout the specification is not restricted to inhibit isolated from a particular source and may include inhibin A (.alpha..beta..sub.A) or inhibin B (.alpha..beta..sub.B). The inhibin used may be naturally occurring or a recombinant or synthetic or semi/synthetic inhibin. It is recognised that for human applications the inhibin of choice would be a human inhibin whereas for veterinary applications one would preferably choose an inhibin derived from the appropriate animal species, unless an immune response is desired in which case an inhibin derived from a species differing from the host would be desirable. Purification and characterisation of native inhibi
REFERENCES:
Hedger, M. P. et al., "Inhibin and Activin Regulate [.sup.3 H]Thymidine Uptake by Rat Thymocytes and 3T3 Cells in Vitro", Molecular and Cellular Endocrinology, 61: 133-138 (1989).
European Search Report and Annex.
International Search Report and Annex.
McLachlan, R. I. et al., "The Human Placenta: A Novel Source of Inhibin", Biochem. Biophys. Res. Comm. 140:485-490 (1986).
Petraglia, F. et al., "Localization, Secretion, and Action of Inhibin in Human Placenta", Science, 237:187-189 (1987).
McLachlan, R. I., et al., "The Radioimmunoassay of Bovine and Human Follicular Fluid and Serum Inhibin", Mol.-Cell. Endocrinol. 46:175-185 (1986).
Eto, Y. et al., "Purification and Characterization of Erythroid Differentiation Factor (EDF) Isolated from Human Leukemia Cell Line THP-1", Biochem. Biophys. Res. Comm. 142:1095-1103 (1987).
Crawford, R. J. et al., "Alpha-Inhibin Gene Expression Occurs in the Ovine Adrenal Cortex, and Is Regulated by Adrenocorticotropin", Mol. Endocrinol. 1:699-708 (1987).
Esch, F. S. et al., "Complementary Dioxyribonucleic Acid (cDNA) Cloning and DNA Sequence Analysis on Rat Ovarian Inhibins", Mol. Endocrinol. 1:388-396 (1987).
Woodruff, T. K. et al., "Rat Inhibin: Molecular Cloning of Alpha-Beta-Subunit Complementary Dioxyribonucleic Acids and Expression in the Ovary", Mol. Endocrinol. 1:561-568 (1987).
Cate, R. L. et al., "Isolation of the Bovine and Human Genes for Mu Inhibiting Substance and Expression of the Human Gene in Animal Cells", Cell 45:685-698.
Sporn, M. B. et al., "Some Recent Advances in the Chemistry and Biology of Transforming Growth Factor-Beta", J. Cell Biol. 105:1039-1045 (1987).
Kehrl, J. H. et al., "Production of Transforming Growth Factor-Beta by Human T Lymphocytes and Its Potential Role in the Regulation of T Cell Growth", J. Exp. Med 163:1037-1050 (1986).
Wrann, M. et al., "T Cell Suppressor Factor from Human Glioblastoma Cellsis a 12.5-kd Protein Closely Related to Transforming Growth Factor-Beta", EMBO 6:1633-1636 (1987).
Ueno, N. et al., "Isolated and Partial Characterization of Follistatin: A Single-Chain M 35,000 Monomeric Protein that Inhibits the Release of Follicle-Stimulating Hormone", Proc. Natl. Acad. Sci., U.S.A. 84:8282-8286 (1987).
Robertson, D. M. et al., "The Isolation of Polypeptides with FSH Suppressing Activity from Bovine Follicular Fluid Which Are Structurally Different to Inhibin", Biochem. Biophys. Res. Comm. 149:744-749 (1987).
Morein, B. et al., "Iscom, a Novel Structure for Antigenic Presentation of Membrane Proteins from Envelop to Viruses", Nature 308:457-460 (1984).
McLachlan, R. I. et al., "Circulating Immunoreactive Inhibin Levels During the Normal Human Menstrual Cycle", J. Clin. Endocrinol. Metab. 65:954-961 (1987).
Nerenberg, S. T. et al., "Hematological Response of Response of Rabbits to Chronic, Repetitive, Severe Bleedings for the Production of Antisera", J. Imm. Meths. 24:19-24 (1978).
Forage, R. G. et al., "Immunization Against An Inhibin Subunit Produced by REcombinant DNA Techniques Results in Increased Ovulation Rate in Sheep", J. Endocr. 114:R1-R4 (1988).
Findlay, J. K. et al., "Effects of Immunization Against Recombinant Bovine Inhibin Alpha Subunit on Circulating Concentrations of Gonadotrophins in Ewes", J. Endocrinology 120:59-65 (1989).
de Kretser David M.
Hedger mark P.
Robertson David M.
Biotechnology Australia Pty. Ltd.
Koh Choon P.
Lee Lester L.
Monash Medical Centre
Monash University
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