Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-30
2002-05-21
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S783000, C530S324000, C530S350000, C530S378000, C530S412000, C530S422000, C435S069100
Reexamination Certificate
active
06391848
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is soybean proteins having chemopreventive effects.
BACKGROUND
The concept that dietary factors play an important role in the etiology of different kinds of cancer is well supported by epidemiological data (World Cancer Fund, 1997). For instance, there is much evidence to suggest that diets containing large amount of soybean products are associated with overall low cancer mortality rates, particularly for cancers of the colon, breast and prostate, which has given impetus towards identifying specific compounds in soybean that could be responsible for its cancer preventive effects (Messina and Barnes, 1991; Kennedy, 1995).
A soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI) has been shown to be a particularly effective chemopreventive agent (Kennedy, 1998). BBI has been characterized as a protein of 8 kD of defined sequence and structure (reviewed by Birk, 1985), however most studies demonstrating the efficacy of BBI have used BBIC, a soybean extract enriched in BBI. BBIC is highly effective in suppressing carcinogenesis (1) induced by several different carcinogens, (2) in three different in animal model systems (rats, mice and hamsters) and in in vitro transformation systems (Kennedy et al, 1993), (3) in several tissues/organs (colon, liver, lung, esophagus and oral epithelium, (4) when administered to animals in several different routes (ip,iv, topical,dietary), (5) involving different kinds of tumors (squamous cell carcinomas, adenocarcinomas, angiosarcomas,etc, (6) in different cell types (epithelial cells in liver, colon, lung, esophagus and cheek pouch as well as connective tissue cells (fibroblasts both in vitro as well as in liver which give rise to angiosarcomas. Thus, the chemopreventive ability of BBIC has been demonstrated in a variety of different carcinogenesis assay systems, achieving Investigational New Drug status from the FDA in 1992 (IND no.34671) and now in human clinical trials.
LITERATURE CITED
Birk (1985) The Bowman-Birk Inhibitor. Int J Peptide Protein Res 25:113-131
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Da Silva Conceicao A, and Krebbers E. (1994). A cotyledon regulatory region is responsible for the spatial expression patterns of Arabidopsis 2S albumin genes. Plant J. 5:493-505.
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Erickson, H. P.(1997). FtsZ, a tubulin homologue in prokaryote cell division. Trends in Cell Biol. 7:362-367.
Galvez A F and de Lumen B O (1999) A soybean cDNA encoding a chromatin-binding peptide inhibits mitosis of mammalian cells. Nature Biotechnology 17:495-500.
Galvez A F, Revilleza M J and de Lumen B O (1997) A novel methionine-rich protein from soybean cotyledon: cloning and characterization of cDNA (Accession No. AF005030) Plant Gene Register. Plant Physiol 114:1567.
Harlow E and Lane D (1988) Antibodies: A lab manual. p. 342. Cold Spring Harbor Lab.
Hassig C A, Fleischer T C, Billin A N, Schreiber S L and Ayer D E (1997) Histone deacetylase is required for full transcriptional repression by mSin3A. Cell 89:341-347.
Hauxwell A J, Corke F M K, Hedley C L and Wang J. (1990). Storage protein gene expression is localized to regions lacking mitotic activity in developing pea embryos: An analysis of seed development in
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Kennedy A R (1993a) Cancer prevention by protease inhibitors. Preventive Med 22:796-811.Kennedy A R (1993b) Potential mechanisms of antitumorigenesis by protease inhibitors. in. Antimutagenesis and Anticarcinogenesis Mechanisms III, pp. 301-307. G. Bronzetti et al (eds). Plenum Press, New York.
Kennedy A R (1994) Prevention of carcinogenesis by protease inhibitors. Cancer Res (Suppl) 54:1999S-2005S.
Kennedy A R (1995) The evidence for soybean products as cancer preventive agents. J Nutr 125:733S-743S.
Kennedy A R (1998) The Bowman-Birk inhibitor from soybeans as an anticarcinogenic agent. Am J Clin Nutr 68 (suppl):1406-1412S.
Kennedy A R and Little J B (1978) Protease inhibitors suppress radiation induced malignant transformation in vitro. Nature (Lond) 276:825-826.
Kennedy A R, B F Szuhaj, P Newberne and Billings P C (1993) Preparation and production of a cancer chemopreventive agent, Bowman-Birk inhibitor concentrate. Nutr Cancer 19:281-302.
Laherty C D, Yang W M, Sun J M, Davie J R, Seto E and Eisenman R N (1997) Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89:349-356.
Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain J P, Troalen F, Trouche D and Harel-Bellan A.(1998) Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391:601-605.
Messina M and Barnes S (1991) The role of soy products in reducing risk of cancer. J Natl Cancer Institute 83:541-546.
Odani, S., Koide, T and Ono, T. 1987. Amino acid sequence of a soybean (Glycine max) seed polypeptide having a poly(L-aspartic acid) structure. J. Biol. Chem. 262, 10502-10505.
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Yavelow J, Collins M, Birk Y, Troll W and Kennedy A R (1985) Nanomolar concentrations of Bowman-Birk protease inhibitor suppress X-ray induced transformation in vitro. Proc Natl Acad Sci USA 82:5395-5399.
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SUMMARY OF THE INVENTION
The invention provides methods and comprisitions for delivering effective amounts of lunasin as a nutraceutical. The general formulation comprises a composition comprising an active unit dosage of a lunasin polypeptide and a pharmaceutically acceptable excipient, said composition comprising at least 50% by polypeptide weight said lunasin polypeptide and less than 10% by polypeptide weight Bowman-Birk Inhibitor polypeptide. In other embodiments, the composition comprises at least 70%, preferably at least 90%, more preferably at least 98%, most preferably 100% by polypeptide weight said lunasin polypeptide and less than 2%, preferably less than 0.5%, more preferably less than 0.1%, most preferably 0% by polypeptide weight Bowman-Birk Inhibitor polypeptide. The formulations may be delivered or administered by any of a wide variety of convenient delivery methods well known in the art, (see, e.g. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition) including oral ingestion, by topically contacting skin using well known techniques for dermal delivery, by introducing into a retained physiological fluids such as blood, synovial fluid, interstitial fluid, etc.
The invention also provides methods for making the subject formulations by purifying lunasin polypeptides to the requisite purity, and combining said lunasin polypeptide with a pharmaceuitcally acceptible excipient in an orally active unit dosage. The lunasin source material may be soybeans, a recombinant lunasin polypeptide expression system, a synthetically produced lunasin, or extract or fraction thereof. Suitable excipients and dosages are readily determined emperically as guided by existing BBIC data.
REFERENCES:
patent: 5614198 (1997-03-01), Kennedy et al.
patent: 6107287 (2000-08-01), de Lumen et al.
Odani et al., The Journal Of Biological Chemistry, vol. 262, No. 22, pp. 10502-10505, Aug 5, 1987.*
Yavelow et al.,Proc. Natl. Acad. Sci. USA.,vol. 82, pp
de Lumen Benito O.
Galvez Alfredo F.
Low Christopher S. F.
Mohamed Abdel A.
Osman Richard Aron
The Regents of the University of California
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