Colon cancer KH-1 and N3 antigens

Details Colon cancer KH-1 and N3 antigens Colon cancer KH-1 and N3 antigens

1998-01-13

2001-05-29

Ungar, Susan (Department: 1642)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

C424S193100, C424S194100, C424S130100, C424S137100, C424S138100, C424S278100, C424S283100

Reexamination Certificate

active

06238668

ABSTRACT:

Throughout this application, citations for various publications are provided. The disclosures of these publications are hereby incorporated in their entirety by reference into this application in order to more fully describe the state of the art to which this invention pertains.
FIELD OF THE INVENTION
The present invention is in the field of tumor-specific cell-surface antigens. In particular, the present invention relates to processes for the preparation of KH-1 and N3 antigens and analogues thereof which are useful as anticancer therapeutics. The present invention also provides novel compositions of matter which serve as intermediates for preparing the KH-1 and N3 antigens.
BACKGROUND OF THE INVENTION
The function of carbohydrates as structural materials and as energy storage units in biological systems is well recognized. By contrast, the role of carbohydrates as signaling molecules in the context of biological processes has only recently been appreciated. (M. L. Phillips, E. Nudelman, F. C. A. Gaeta, M. Perez, A. K. Singhal, S. Hakomori, J. C. Paulson,
Science,
1990, 250, 1130; M. J. Polley, M. L. Phillips, E. Wagner, E. Nudelman, A. K. Singhal, S. Hakomori, J. C. Paulson,
Proc. Natl. Acad. Sci. USA,
1991, 88, 6224; T. Taki, Y. Hirabayashi, H. Ishikawa, S. Kon, Y. Tanaka, M. Matsumoto,
J. Biol. Chem.,
1986, 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
Chem. Int. Ed. Engl.,
1982, 21, 155; Schmidt, R. R., Angew.
Chem. 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., Faser-Reid, B.,
Can. J. Chem.,
1965, 43:1460; Lemieux, R. U., Morgan, A. R.,
Can. J. Chem.,
1965, 43, 2190; Thiem, J., Karl, H., Schwentner, J.,
Synthesis,
1978, 696; Thiem. J. Ossowski, P.,
Carbohydr. Chem.,
1984, 3, 287; Thiem, J., Prahst, A., Wendt, T.
Liebigs Ann. Chem.,
1986, 1044; Thiem, J., in
Trends in Synthetic Carbohydrate Chemistry
, Horton, D., Hawkins, L. D., McGarvey, G. L., eds., ACS Symposium Series #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 and 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, E. Nudelman, F. C. A. Gaeta, M. Perez, A. K. Singhal, S. Hakomori, J. C. Paulson,
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 might find applications at the diagnostic level, as resources in drug delivery or ideally in immunotherapy. (Toyokuni, T., Dean, B., Cai, S., Boivin, D., Hakomori, S., and Singhal, A. K.,
J. Am. Chem Soc.,
1994, 116, 395; Dranoff, G., Jaffee, E., Lazenby, A., Golumbek, P., Levitsky, H., Brose, K., Jackson, V., Hamada, H., Paardoll, D., Mulligan, R.,
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 use of synthetic carbohydrate conjugates to elicit antibodies was first demonstrated by Goebel and Avery in 1929. (Goebel, W. F., and Avery, O. T.,
J. Exp. Med.,
1929, 50, 521; Avery, O. T., and Goebel, W. F.,
J. Exp. Med.,
1929, 50, 533.) Carbohydrates were linked to carrier proteins via the benzenediazonium glycosides. Immunization of rabbits with the synthetic antigens generated polyclonal antibodies. Other workers (Allen, P. Z., and Goldstein, I. J.,
Biochemistry,
1967, 6, 029; Rude, E., and Delius, M. M.,
Carbohvdr. Res.,
1968, 8, 219; Himmelspach, K., et al.,
Eur. J. Immunol.,
1971, 1, 106; Fielder, R. J., et al.,
J. Immunol.,
1970, 105, 265) developed similar techniques for conjugation of carbohydrates to protein carriers. Most of them suffered by introducing an antigenic determinant in the linker itself, resulting in generation of polyclonal antibodies. Kabat (Arakatsu, Y., et al.,
J. Immunol.,
1966, 97, 858), and Gray (Gray, G. R.,
Arch. Biochem. Bioshys.,
1974, 163, 426) developed conjugation methods that relied on oxidative or reductive coupling, respectively, of free reducing oligosaccharides. The main disadvantage of these techniques, however, is that the integrity of the reducing end of the oligosaccharide was compromised. In 1975 Lemieux described the use an 8-carbomethoxy-1-octanol linker (Lemieux, R. U., et al.,
J. Am. Chem. Soc.,
1975, 97, 4076) which alleviated the problem of linker antigenicity and left the entire oligosaccharide intact. Equally effective in producing glycoconjugates was the allyl glycoside method described by Bernstein and Hall. (Bernstein, M. A., and Hall, L. D.,
Carbohydr.
Res., 1980, 78, C1.) In this technique the allyl glycoside of the deblocked sugar is ozonized followed by a reductive workup. The resultant aldehyde is then reductively coupled to a protein carrier with sodium cyanoborohydride.
In the mid-70's and early 80's Lemieux and his collaborators made contributions to antibody production stimulated by synthetic glycoconjugates (Lemieux, R. U., et al.,
J. Am. Chem. Soc.,
1975, 97, 4076) and to conformational issues (Lemieux, R. U., et al.,
Can. J. Chem.,
1979, 58, 631; Spohr, U., et al.,
Can. J. Chem.,
1985, 64, 2644; Vandonselaar, M., et al.,
J. Biol. Chem.,
1987, 262, 0848) important in the interactions of the blood group determinants (and analogues thereof) with the carbohydrate binding proteins known as lectins. More recently, workers at Bristol-Myers Squibb reported the X-ray crystal structure of the Lewis y epitope complexed with the antibody BR96. (Jeffrey, P. D., et al.,
Nature Structural Biol.,
1995, 2, 466.) Two main components appear to govern recognition between carbohydrates and most antibodies. The first is multiple hydrogen bonding between the sugar hydroxyls and the amino acid residues of Asp, Asn, Glu, Gln, and Arg. The second major interaction is stacking between the sugar-ring faces and aromatic side chains, which occurs most frequently with tryptophan. In the complex with BR96 the most significant interactions involve the latter; additional hydrogen bonding occurs between the sugar hydroxyls and the indole nitrogens. Most antibody binding sites can support about 6 linear carbohydrate residues in a groove or cavity shaped binding site.
Glycoconjugates may be used in direct im

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