Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-03-25
2003-12-09
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S008100, C514S023000, C514S025000
Reexamination Certificate
active
06660714
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of &agr;-O-linked glycopeptides. In particular, the present invention relates to methods for the preparation of &agr;-O-linked glycoconjugates with clustered glycodomains which are useful as anticancer therapeutics. The present invention also provides novel compositions comprising such &agr;-O-linked glycoconjugates and methods for the treatment of cancer using these glycoconjugates.
Throughout this application, various publications are referred to, each of which is hereby incorporated by reference in its entirety into this application to more fully describe the state of the art to which the invention pertains.
BACKGROUND OF THE INVENTION
The role of carbohydrates as signaling molecules in the context of biological processes has recently gained prominence. M. L. Phillips, et al.,
Science,
1990, 250, 1130; M. J. Polley, et al.,
Proc. Natl. Acad. Sci. USA,
1991 88, 6224: T. Taki, et al.,
J. Biol. Chem.,
1996, 261, 3075; Y. Hirabayashi, A. Hyogo, T. Nakao, K. Tsuchiya, Y. Suzuki, M. Matsumoto, K. Kon, S. Ando, ibid., 1990, 265, 8144; O. Hindsgaul, T. Norberg, J. Le Pendu, R. U. Lemieux,
Carbohydr. Res.
1982, 109, 109; U. Spohr, R. U. Lemieux, ibid., 1988, 174, 211). The elucidation of the scope of carbohydrate involvement in mediating cellular interaction is an important area of inquiry in contemporary biomedical research. The carbohydrate molecules, carrying detailed structural information, tend to exist as glycoconjugates (cf. glycoproteins and glycolipids) rather than as free entities. Given the complexities often associated with isolating the conjugates in homogeneous form and the difficulties in retrieving intact carbohydrates from these naturally occurring conjugates, the applicability of synthetic approaches is apparent. (For recent reviews of glycosylation see: Paulsen, H.; Angew.
Chemie Int. Ed. Engl.
1982, 21, 155; Schmidt, R. R., Angew.
Chemie Int. Ed. Engl.
1986, 25, 212; Schmidt, R. R.,
Comprehensive Organic Synthesis
,Vol. 6, Chapter 1(2), Pergamon Press, Oxford, 1991; Schmidt, R. R.,
Carbohydrates, Synthetic Methods and Applications in Medicinal Chemistry
,Part I, Chapter 4, VCH Publishers, Weinheim, New York, 1992. For the use of glycals as glycosyl donors in glycoside synthesis, see Lemieux, R. U.,
Can. J. Chem.,
1964, 42, 1417; Lemieux, R. U., Fraiser-Reid, B.,
Can. J. Chem.
1965, 43, 1460; Lemieux, R. U.; Morgan, A. R.,
Can. J. Chem.
1965, 43, 2190; Thiem, J., et al.,
Synthesis
1978, 696; Thiem, J. Ossowski, P.,
Carbohydr. Chem.,
1984, 3, 287; Thiem, J., et al.,
Liebigs Ann. Chem.,
1986, 1044; Thiem, J. in
Trends in Synthetic Carbohydrate Chemistry
, Horton, D., et al., eds., ACS Symposium Series No. 386, American Chemical Society, Washington, D.C., 1989, Chapter 8.)
The carbohydrate domains of the blood group substances contained in both glycoproteins and glycolipids are distributed in erythrocytes, epithelial cells and various secretions. The early focus on these systems centered on their central role in determining blood group specificities. R. R. Race; R. Sanger, Blood Groups in Man, 6th ed., Blackwell, Oxford, 1975. However, it is recognized that such determinants are broadly implicated in cell adhesion and binding phenomena. (For example, see M. L. Phillips, et al., Science 1990, 250, 1130.) Moreover, ensembles related to the blood group substances in conjugated form are encountered as markers for the onset of various tumors. K. O. Lloyd,
Am. J. Clinical Path.,
1987, 87, 129; K. O. Lloyd,
Cancer Biol.,
1991, 2, 421. Carbohydrate-based tumor antigenic factors have applications at the diagnostic level, as resources in drug delivery or ideally in immunotherapy. Toyokuni, T., et al.,
J. Am. Chem Soc.
1994, 116, 395; Dranoff, G., et al.,
Proc. Natl. Acad. Sci. USA
1993, 90, 3539; Tao, M -H.; Levy, R.,
Nature
1993, 362, 755; Boon, T.,
Int. J. Cancer
1993, 54, 177; Livingston, P. O.,
Curr. Opin. Immunol.
1992, 4, 624; Hakomori, S.,
Annu. Rev. Immunol.
1984, 2, 103; K. Shigeta, et al.,
J. Biol. Chem.
1987, 262, 1358.
The present invention provides new strategies and protocols for glycopeptide synthesis. The object is to simplify such preparations so that relatively complex domains can be assembled with high stereospecifity. Major advances in glycoconjugate synthesis require the attainment of a high degree of convergence and relief from the burdens associated with the manipulation of blocking groups. Another requirement is that of delivering the carbohydrate determinant with appropriate provision for conjugation to carrier proteins or lipids. Bernstein, M. A.; Hall, L. D.,
Carbohydr. Res.
1980, 78, Cl; Lemieux, R. U.,
Chem. Soc. Rev.
1978, 7, 423; R. U. Lemieux, et al.,
J. Am. Chem. Soc.
1975, 97, 4076. This is a critical condition if the synthetically derived carbohydrates are to be incorporated into carriers suitable for clinical application.
Antigens which are selective (or ideally specific) for cancer cells could prove useful in fostering active immunity. Hakomori, S.,
Cancer Res.,
1985, 45, 2405-2414; Feizi, T.,
Cancer Surveys
1985, 4, 245-269. Novel carbohydrate patterns are often presented by transformed cells as either cell surface glycoproteins or as membrane-anchored glycolipids. In principle, well chosen synthetic glycoconjugates which stimulate antibody production could confer active immunity against cancers which present equivalent structure types on their cell surfaces. Dennis, J.,
Oxford Glycostems Glyconews
, Second Ed., 1992; Lloyd, K. O., in
Specific Immunotherapy of Cancer with Vaccines,
1993, New York Academy of Sciences, pp.50-58. Chances for successful therapy improve with increasing restriction of the antigen to the target cell. For example, one such specific antigen is the glycosphingolipid isolated by Hakomori and collaborators from the breast cancer cell line MCF-7 and immunocharacterized by monoclonal antibody MBrl. Bremer, E. G., et al.,
J. Biol. Chem.
1984, 259, 14773-14777; Menard, S., et al.,
Cancer Res.
1983, 43, 1295-1300.
The surge of interest in glycoproteins (M. J. McPherson, et al., eds.,
PCR A Practical Approach,
1994, Oxford University Press, Oxford, G. M. Blackburn; M. J. Gait, Eds.,
Nucleic Acids in Chemistry and Biology,
1990, Oxford University Press, Oxford; A. M. Bray; A. G. Jhingran; R. M. Valero; N. J. Maeji,
J. Org. Chem.
1944, 59, 2197; G. Jung; A. G. Beck-Sickinger,
Angew Chem. Int. Ed. Engl.
1992, 31, 367; M. A. Gallop; R. W. Barrett; W. J. Dower; S. P. A. Fodor; E. M. Gordon,
J. Med. Chem.
1994, 37, 1233; H. P. Nestler; P. A. Bartlett; W. C. Still,
J. Org. Chem.
1994, 59, 4723; M. Meldal,
Curr. Opin. Struct. Biol.
1994, 4, 673) arises from heightened awareness of their importance in diverse biochemical processes including cell growth regulation, binding of pathogens to cells (O. P. Bahl, in
Glycoconjugates: Composition, structure, and function
,H. J. Allen, E. C. Kisailus, Eds., 1992, Marcel Dekker, Inc., New York, p.1), intercellular communication and metastasis (A. Kobata,
Acc. Chem. Res.
1993, 26, 319). Glycoproteins serve as cell differentiation markers and assist in protein folding and transport, possibly by providing protection against proteolysis. G. Opdenakker, et al.,
FASEB J.
1993, 7, 1330. Improved isolation techniques and structural elucidation methods (A. De; K. -H. Khoo,
Curr. Opin. Struct. Biol.
1993, 3, 687) have revealed high levels of microheterogeneity in naturally-produced glycoproteins. R. A. Dwek, et al.,
Annu. Rev. Biochem.
1993, 62, 65. Single eukaryotic cell lines often produce many glycoforms of any given protein sequence. For instance, erythropoietin (EPO), a clinically useful red blood cell stimulant against anemia, is glycosylated by more than 13 known types of oligosaccharide chains when expressed in Chinese hamster ovary cells (CHO) (Y. C. Lee; R. T. Lee, Eds.,
Neoglycoconjugates: Preparation and Applications,
1994, Academic Press, London). The efficacy of erythropoietin is heavily dependent on the type and extent of glycosylation (E. Wa
Chen Xiao-Tao
Danishefsky Samuel J.
Glunz Peter
Hintermann Samuel
Kuduk Scott
Choate Hall & Stewart
Herschbach Jarrell Brenda
Huff Sheela
Lagneau Nadege M.
Sloan Kettering Institute for Cancer Research
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