Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1999-04-29
2001-06-26
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C530S398000
Reexamination Certificate
active
06251402
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of hCG fragments or deglycosylated hCG in the treatment of Kaposi's sarcoma. In particular the invention relates to the use of hCG Beta-core in the treatment of Kaposi's sarcoma.
BACKGROUND ART
Kaposi's sarcoma (KS) is a neoplastic disease characterised by highly vascularized lesions, closely related with epidemic HIV and which occasionally occurs in patients who underwent transplantation, as a consequence of the immunosuppression. KS occurs more often in men than in women and HIV-associated KS has a high occurrence in homosexual men. Most cultures of KS tumours yield cells with properties of hyperplastic (not malignant) endothelial cells under the control of several cytokines.
hCG is a hormone secreted by the placenta as well as by a number of various other tissues, normal and neoplastic ones. It is secreted and acts so in both an endocrine and paracrine way. hCG is heterodimer consisting of an &agr;-subunit and a &bgr;-subunit.
Surprisingly, each of them shares a structural feature, the so called cystine-knot motif, with several growth factors (NGF, PDGF and others) that are otherwise unrelated to HCG or to the family of glycoprotein hormones, as it has been recently elucidated by crystal structure analysis of deglycosylated HCG. Until now, there is only one receptor known that binds with high affinity (≈0.01 &mgr;M) hCG, but also luteinising hormone (LH), that is almost identical to hCG, except for a C terminal extension in hCG.
This receptor, referred to as the LH/hCG-R, as well as those of the other glycoprotein hormones, has been recently cloned and results to belong to the superfamily of 7-transmembrane helix/G protein-coupled receptors, from which it is however distinct due to the long extracellular domain, acting as the ligand capturing element. Such kind of receptors is encoded by a mosaic gene, consisting of 10 exons, representing 11 of the so called leucine rich repeats (LRM), and a 11th exon, representing 3 LRM's and the entire transmembrane module. The ensemble of the 14 LRM's is currently thought to form a horse-shoe structure “embracing” the ligand. The receptor of glycoprotein hormones binds only the respective entire hormone, but not a single subunit. The circulating hormone is in the subnanomolar range, as are the affinity for the respective receptor. Only during early pregnancy, the blood levels of hCG rise up to suprananomolar levels, and a fraction (about ≈0.001) occurs also as free subunit.
Besides dissociated subunits, a variety of other metabolic forms of hCG, particularly in urine, can be found, such as glycosylation and sialylation variants (isoforms), nicked hCG and a particular fragment of &bgr; subunit called “Beta-core”. Such fragment has been purified by affinity extraction by using monoclonal antibodies (Birken et al., Endocrinology, 123: 572-583, 1988). The amino acid sequence of the fragment has been determined. Beta-core consists of two polypeptides, bound by disulphide bridges, which correspond to residues 6-40 and 55-92 of hCG &bgr;-subunit.
In addition to the above mentioned isoforms, deglycosylated hCG can be obtained by different chemical and/or biotechnological ways as described, for example, by Kalyan e Bahl, J. Biol. Chem. 258: 67-74, 1983.
Beta-core, as deglycosylated hCG or the single isolated subunits, does not show hCG-like biological activity, but represents a major form of immunoreactive hCG and can contaminate pharmaceutical preparation of urinary hCG.
Lunardi-Iskandar et al., Nature, 375: 64-68, 1995 have shown that hCG and the hCG &bgr;-subunit inhibit the growth of KS cell lines derived from Kaposi's sarcoma, and inhibit tumour production by such cell lines in nude mice. Regression of Kaposi's sarcoma has been shown in two women during pregnancy, when the level of such hormone is high.
REFERENCES:
patent: 5677275 (1997-10-01), Lunardi-Iskandar et al.
Sairam, M.R., “Hormonal Antagonistic Properties of Deglycosylated Pituitary Lutropin” in “Horm. Act. Brain Pept.: Struct. Funct”, McKerns et al., Ed., Plenum Press, NY, pp. 85-97, 1983.*
Birken et al., “Structure of the Human Chorionic Gonadotropin &bgr;-Subunit Fragment from Pregnancy Urine”, Endocrinology, 123(1), pp. 572-583, Jul. 1988.*
Kalyan et al., “Role of Carbohydrate in Human Chorionic Gonadotropin”, J. Biol. Chem., 258(1), pp. 67-74, Jan. 1983.*
Lunardi-Iskandar et al., Tumorigenesis and Metastasis of Neoplastic Kaposi's Sarcoma Cell Line in Immunodeficient Mice Blocked by a Human Pregnancy Hormone, Nature, vol. 375, pp. 64-68, May 1995.*
Schwarz et al., “Visualization of Differences in Receptor Iteraction Between Native, Deglycosylated and Asialo Human Chorionic Gonadotropin (hCG) by Monoclonal Antibodies”, ACTA Endocrinologica, vol. 122, Suppl. 1, p. 42, Mar. 1990.*
Samaniego et al., “&bgr;-Human Chorionic Gonadotropin (&bgr;HCG) Induces Programmed Cell Death in AIDS-Associated Kaposi's Sarcoma (AIDS-KS) Cells”, AIDS Res. Hum. Retrovir., vol. 10, Suppl. 3, p. S102, Abstr. 158, Sep. 1994.*
Sigma Catalog, pp. 264-265, 1994.
Applied Research Systems ARS Holding N.V.
Browdy and Neimark
Weber Jon P.
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