Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-10-12
2003-11-11
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C536S004100, C514S025000
Reexamination Certificate
active
06645935
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, citations for various publications are provided within parentheses in the text. 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.
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; 0. 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, N.Y., 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., McGarvvey, 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. Nudelamn, 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 immuno-therapy. (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)
Livingston et al. (
Curr. Opin. Immunol.,
1992, 4:624-629) discusses conjugate vaccines with T or sTn covalently attached to keyhole limpet hemocyanin (KLH) and other carriers currently under investigation in a number of laboratories. Vaccines containing synthetic T antigen covalently attached to KLH have resulted in IgM and IgG antibodies and delayed type hypersensitivity reactions against T antigen in the mouse as well as the recovery of mice with established tumors [Livingston et al.,
Vaccine Res.
1992, 1:99-109; Fung et al.,
Cancer Res
1990, 50:4308-4314]. Recently, production IgM and IgG antibodies against T antigen in man on administration of these vaccines has also been described [MacLean et al.,
J. Immunother
1992, 11:292-305]. MacLean's and Livingston's groups (unpublished data) have induced IgM and IgG antibodies against sTn in cancer patients after sTn-KLH vaccinations.
Livingston et al. (
Curr. Opin. Immunol.,
1992, 4:624-629) also indicated that the term immunological adjuvant refers to an agent that increases the specific immune response to antigens. The relative importance of depot effect (i.e. the sequestration of antigen for slow release and for phagocytosis by macrophages and other presenting cells), macrophage activation, and T-cell activation in augmenting immune responses following adjuvant use remains an open question and is probably dependent on the antigen used. Primarily because of the need for adjuvants to augment the immunogenicity of recombinant peptide and purified carbohydrate vaccines against infectious diseases, a number of potent new adjuvants have been prepared and are in various phases of preclinical and clinical testing. These include the following: pleuronic triblock copolymers such as L121 [Hunter et al.,
Vaccine
1991, 9:250-256], which are known to activate macrophages and facilitate attachment of antigen to lipid-aqueous interfaces; SAF-m, which contains a muramyl dipeptide analog, L121 and squalene [Allison et al.,
J Immunol Meth
1986, 95:157-168]; Derox which contains a monophosphyryl lipid A analog and mycobacterial cell wall skeletons [Mitchell et al.,
Cancer Res
1988, 48:5883-5893]; and QS21 which is a purified Quil A saponin fraction [Newman et al.,
J Immunol
1992, 148:2357]. Of these adjuvants, QS21 is unique in that it is able to induce CTL activity against peptide antigens in addition to the ususal Th-cell activity and antibody responses [Newman et al.,
J Immunol
1992, 148:2357]. Based on studies comparing the antibody titers and delayed type hypersensitivity responses to a variety of carbohydrate and protein antigens [Livingston et al.,
Vaccine Res.
1992, 1:99-109; Livingston et al., Vaccine 1992], Livingston et al. selected SAE-m and QS21 as particularly potent adjuvants suitable for study in man. Livingston et al. is conducting Phase I clinical trials with QS21 and SAF-m.
The use of synthetic carbohydrate conjugates to elicit antibodies was first demonstrated by Gobel 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, 3029; Rüde, E., and Delius, M. M.,
Carbohydr. 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 carbohydra
Behar Victor
Danishefsky Samuel J.
Lloyd Kenneth O.
Cooper & Dunham LLP
Fonda Kathleen K.
Sloan-Kettering Institute for Cancer Research
White John P.
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