Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-01-31
2004-01-27
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S008100, C514S021800, C530S326000, C530S834000
Reexamination Certificate
active
06683050
ABSTRACT:
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The invention relates to compounds which exhibit anti-KS and anti-HIV activity, pharmaceutical compositions and method of treatment thereof.
(b) Description of Prior Art
Kaposi's sarcoma (KS) is the most common tumour in AIDS subjects which afflicts high mortality (Friedman-Kien A E et al., 1990
, J Am Acad Dermatol
22:1237-1250). Less aggressive forms can also occur in non-AIDS subjects of the Mediterranean area and equatorial Africa as well as in renal transplant patients following treatment with immunosuppressive drugs (Friedman-Kien A E et al., 1990
, J Am Acad Dermatol
22:1237-1250). The pathogenesis and therapy of KS remain enigmatic (Bais C. et al., 1998
, Nature
391:86). For unknown reasons, occurrence of KS is higher in males than in females. For example, in the West, approximately 95% of AIDS-KS subjects are men. Although, hormonal dependence of KS has been demonstrated in the case of glucocorticoid and retinoid (Guo W X et al., 1996
, Am J Pathol
148: 1999-2008; Guo W X et al., 1995
, Am J Pathol
146: 727-734; Guo W X et al., 1995
, Cancer Res
55: 823-829), sex steroids do not seem to be directly involved in KS pathogenesis. Recently, Lunardi-Iskandar et al. (Lunardi-Iskandar Y et al., 1995
, Nature
375: 64-68) reported that the placental hormone human chorionic gonadotropin (HCG), displays anti-KS activity and prevents tumours in immunodeficient mice. This preliminary finding could otentially have significant therapeutic impact as demonstrated in clinical trials (Gill PS et al., 1996
, New Engl J Med
335: 1261-1310; Gill P S et al., 1997
, J. Natl. Cancer Inst
. 89: 1797) and may shed light on basic understanding of this disease particularly regarding the sexual dimorphism issue. Though the role of HCG is principally to sustain pregnancy, it is becoming increasingly apparent that this hormone, possibly along with other active molecules, may be responsible for numerous other phenomena. The low transmission rate of HIV across the placenta (Prober C G et al., 1991
, Ped Infect Dis J
10: 684-695) as well as the low incidence of Kaposi Sarcoma in women including those previously infected with the virus has led to the suspicion that pregnancy and/or reproductive hormones (such as related LH, see Lunardi-Iskandar Y et al., 1995
, Nature
377: 21-22) may be involved in curtailing the propagation of the virus. Studies by Bourinbaiar (Bourinbaiar AS et al., 1995
, Immunol Lett
44: 13-18) indicate that the hormone HCG or its &bgr; subunit may have an anti-HIV effect. The action of HCG on gonadal cells is mediated by a G-protein coupled trans-membrane receptor which interacts with the dimeric hormone (&agr; and &bgr; complex) with very high affinity and specificity (review Segaloff D L et al., 1993
, Endocr Rev
14: 324-347). In such a system, it is very well known that either one of the individual &agr; and &bgr; subunits have extremely low reactivity towards the membrane bound receptor (Pierce J G et al., 1981
, Ann Rev Biochem
50: 465-495; Sairam M R, 1983
, In: Hormonal Proteins and Peptides
. Li C. H., ed., pages 1-79) but complete activity can be regained by appropriate (1:1) recombination of the two subunits. Lunardi-Iskandar's and Bourinbaiar's data (Lunardi-Iskandar Y et al., 1995
, Nature
375: 64-68; Bourinbaiar A S et al., 1995
, Immunol Lett
44: 13-18) suggest the involvement of an “unconventional” mode of action for HCG in KS. In fact, they reported a biological activity for the &bgr; HCG, a notion which contradicts the generally accepted paradigm that the dimeric form of the hormone is required for triggering hormonal responses in classical target tissues. While stirring a controversy (Lunardi-Iskandar Y et al., 1995
, Nature
377: 21-22; Berger P et al., 1995
, Nature
377: 21; Rabkin C S et al., 1995
, Nature
377: 21-22; Krown S E, 1996
, New Engl J Med
335: 1309-1310), these findings raise intriguing and potentially novel issues.
There is reported in Nature Medicine (Vol. 4, No. 7, July 1998) that the anti-KS activity of crude hCG preparations is still a mystery.
It would be highly desirable to be provided with compounds which would exhibit anti-KS and anti-HIV activity.
SUMMARY OF THE INVENTION
One aim of the present invention is to provide with compounds which would exhibit anti-KS and anti-HIV activity.
In accordance with one preferred embodiment of the present invention there is provided a compound having anti-KS and anti-HIV pharmaceutical activity which comprises an RCG-like inhibitory protein and fragments thereof, the protein and fragments thereof are isolated from a biologically active fraction of APL™-HCG (“APL™” is the commercial trade name of the clinical-grade HCG sold by Wyeth-Ayerst), wherein said protein has a molecular weight of about 3,500 or of about 13,000 Dalton, and wherein said protein and fragments thereof are adsorbed to polypropylene plastic supports, such as tubes or pipette tips among others.
A preferred polypropylene plastic tube includes those sold by Sarstedt (Numbreht, Germany) cat #57.512 and cat #68.752.
In accordance with another preferred embodiment of the present invention there is provided purified protein and derivatives and fragments thereof having anti-KS and anti-HIV pharmaceutical activity which is a HCG-like inhibitory protein and derivatives and fragments thereof which are adsorbed to polypropylene plastic supports, and wherein said protein has an amino acid sequence selected from the group consisting of:
Ser-Lys-Glu-Pro-Leu-Arg-Pro-Arg-Glu-Arg-Pro-Ile-Asn*-Ala-Thr-Leu-Ala-Val-Glu-Lys SEQ ID NO:1; and
Ala-Pro-Asp-Val-Gln-Asp-Lys-Phe-Thr-Arg-Gln-Ile-Met-Ala-Thr SEQ ID NO:2.
The purified protein of the present invention is referred to as HIP or HCG-like Inhibitory Protein.
In other embodiments, the derivatives contain one or more D-amino acids or non-natural amino acids.
In accordance with another preferred embodiment of the present invention there, is provided a pharmaceutical composition for the prevention and/or treatment of Kaposi's sarcoma (KS) and/or HIV which comprises a therapeutically effective amount of at least one compound of the present invention in association with a pharmaceutically acceptable carrier.
In accordance with another preferred embodiment of the present invention there is provided a pharmaceutical composition for the prevention and/or treatment of Kaposi's sarcoma (KS) and/or HIV which comprises a therapeutically effective amount of at least one protein of the present invention in association with a pharmaceutically acceptable carrier.
In other embodiments, the pharmaceutical composition is formulated as a controlled release formulation.
In accordance with another preferred embodiment of the present invention there is provided a pharmaceutical composition for the prevention and/or treatment of Kaposils sarcoma (KS) and/or HIV which comprises a therapeutically effective amount of a derivative of a protein having anti-KS and anti-HIV pharmaceutical activity which is a HCG-like inhibitory protein which is adsorbed to polypropylene plastic supports, and wherein said protein has an amino acid sequence selected from the group consisting of:
Ser-Lys-Glu-Pro-Leu-Arg-Pro-Arg-Glu-Arg-Pro-Ile-Asn*-Ala-Thr-Leu-Ala-Val-Glu-Lys SEQ ID NO:1; and
Ala-Pro-Asp-Val-Gln-Asp-Lys-Phe-Thr-Arg-Gln-Ile-Met-Ala-Thr SEQ ID NO:2
in association with a pharmaceutically acceptable carrier.
In accordance with another preferred embodiment of the present invention there is provided a method for the prevention, treatment and/or reduction of Kaposi's sarcoma and/or HIV expression in AIDS patients, which comprises administering to said patient a therapeutically effective amount of a compound of the present invention.
In accordance with another preferred embodiment of the present invention there is provided a method for the prevention, treatment and/or reduction of Kaposi's sarcoma and/or HIV expression in AIDS patients, which comprises administering to said patient a therapeutically effective amount of a protein of t
Antakly Tony
Sairam Ram M.
Altachem Pharma Ltd.
Sharpe Paul S.
Stucker Jeffrey
LandOfFree
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