Monoclonal antibody which recognizes the oligosaccharide...

Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...

Reexamination Certificate

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C530S387100, C530S391300, C424S137100

Reexamination Certificate

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06429295

ABSTRACT:

TECHNICAL SECTOR
The present invention is related with the field of immunology and human medicine particularly with the generation and selection of a monoclonal antibody (Mab) against the N-glycolylated-galactose-glucose sialic acid olygosaccharide sequence that can be used for the diagnosis and treatment of certain neoplasic diseases.
PRIOR ART
The olygosaccharide structures can be found forming part of glycoproteins and glycolipids. They are both present in normal and pathological tissues.
The aberrant glycosilation has been described in approximately 100% of the malignant neoplasm. Frequent changes in the aberrant glycosilation are: the expression of neoantigens, variations in the composition of the olygosaccharide sequences, increase or decrease of the sialic acid molecules in the olygosaccharides and increase in the density of the molecules in the cell surface, among others (Hakomori S. H. et al.
Curr. Opin. in Immunol.
1991,(3) 646-653). In addition to the changes that can be found in the mechanism of the sialyl-tranferases, there are also variations in the activated sialic acid N-acetylated dependent hydroxilases.
Gangliosides are glycoesfingolipids that contain sialic acid in their structure and are characterized by being present in most cells of the vertebrates. These molecules are found in normal tissue and can have a higher expression in the tumors, with a different organization and conformation in the surface of malignant cells (Hakomori, S H., 1985, Cancer Res. 45: 2405-2414; Miraldi, F., 1989, Seminars in Nuclear Medicine, XIX,282-294).
The humoral immune response against carbohydrate antigens is generally of the IgM isotype. The olygosaccharide sequences bound to lipids are generally less immunogenic than the glycoproteins. Thus, the use of glycolipids as immunogen requires of its binding to transporting proteins or their incorporation to liposomes or to bacteria such as
Micobacterium tuberculosis
or R595 de
Salmonella minnesota.
The response generated against Gangliosides is thymus independent. This has been reported repeatedly by Livingston, et al., (Livingston, P. O. et al., 1982,
Proc. Natl. Acad. Sci.
USA 84: 2911-2915; Livingston, P. O. et al. 1989,
Cancer Res.
49: 7045-7050). The main characteristics of the antibodies generated against Gangliosides when studied in the serum of different species are their low affinity, considerable cross reactivity and short life (Livingston, P.O. 1991,
Immunology and Allergy Clinics of North America,
11: 401-423; Portoukalian, J. et al, 1991,
Int. J. Cancer,
49: 893-899).
The expression of the N-glycolylated form in the olygosaccharides is common in normal and pathological tissues of all the species of vertebrates, except for chickens and humans in which it is only found in fetal and tumoral tissue. The normal tissues of these two last species posses only the N-acetylated variant (Nishimakit et al. 1979,
J. Immunology,
122: 2314; Higashi H. et al, 1985,
Cancer Res.,
45: 3796).
The study of the olygosaccharide composition in some human tumors demonstrate the presence of the N-glycolylated form both in glycolipids and glycoproteins of melanoma tumoral cells (Hirabayashi, Y, et al. 1987,
J. Cancer Res.,
78, 614 -620; Saida T. et al. 1991
Arch. Dermatol. Res.
282(3): 179-182; Kawashima I. et al. 1993,
J. Biochem
(Tokio) (2) 186-193; Kawachi S. et al., 1992,
J. Dermatol
(11): 827-830), as well as in colon tumors, especially in glycolipids (Miyoshi, I., et al, 1986,
Mol. Immunol.
23
(6): 631; Higashi H., et al, 1985,
Cancer Research,
45: 3796-3802). Additionally, studies have been performed to demonstrate the presence of the N-glycolylated form of the Gangliosides in tumoral samples of liver, teratoma, lymphoma, etc, (Kawai T. et al. 1991
Cancer. Res.
(51) 1242-1246). Although in the former cases the concentration of the N-glycolylated variant of glycolipids was less than 0,05% of the total sialic acid, Marquina and collaborators found in breast tumors values of approximately 10% of the sialic acid bound to lipid (Marquina, G. et al, 1996,
Cancer Res.
56: 5165-).
The generation of monoclonal antibodies against the N-glycolylated variant of the gangliosides has provided until now, antibodies of the IgM isotype that generally recognize more than one gangliosides molecule, for example, the human monoclonal antibodies 2-39 M and 32-27 M (Furukawa K., et al, 1988,
J. Biological Chemistry,
263: 18507) and the murine antibodies GMR8 and GMR3 (Ozawa H. et al, 1992,
Biochem. Biophys.,
2(294):427). Other authors have reported the generation of a specific species of anti N-glycolylated gangliosides antibodies, always of IgM isotype, among which are the monoclonal antibodies Y-2-HD1, against NGcGM
2
(Samai Y. et al, 1988,
Bioch Biophys. Act.,
958, 368) and MK2-34 against the same molecule (Miyake, M. et al, 1990,
Cancer Res.
48, 6154).
Nevertheless, Watarai (Watarai, S. et al. 1995.
J. Biochem.
117, 1062) generated the monoclonal antibody SHS-1 against the i-active N-glycolylated gangliosides and Nakumara obtained the monoclonal antibody YK-3 against the (NGc-NGc) GD1c (Nakumara et al, 1995,
J. of Biolog. Chemist.,
8 (270):3876). Recently Vázquez, et al., (Vázquez, A. M. et al, 1995,
Hybridoma,
14, 6, 551) reported the generation of the monoclonal antibody P3, that recognizes most Ganglioside molecules containing the N-glycolylated form of the sialic acid, as well as the sulfated glycolipids.
Nagai et al., have generated the HMA1 monoclonal antibody against Gangliosides (Nagai Y. et al. U.S. Pat. No. 4,965,198). They obtained a specific monoclonal antibody against the Ganglioside NGcGM2 from mice bearing an autoimmune disease. Although, they reported several of these antibodies that additionally recognized other N-glycolylated Gangliosides designated as PyK, YH02, YH03, YH04, YH05, YH06 y YH07.
Moreover, Yamasaki, M. et al., in their U.S. Pat. No. 4,942,131 report the generation of the Mabs YH08, YH09, YH10 e YH11 against the 4-O-Acetyl-NGcGM3 Ganglioside, also in mice with an autoimmune disease.
Monoclonal antibodies against Gangliosides have also been obtained using these molecules as lactones or from cell lines containing Gangliosides (U.S. Pat. Nos. 5,308,614; 5,240,833; 5,389,530 y 5,500,215).
In the same manner, different monoclonal antibodies, both murine and human, have been obtained against GD3, GD2 y GM2 gangliosides, all of the N-acetylated form and most of them of the IgM and IgG3 subclasses (Pukel, C. S. et al. 1982,
J. Exp. Med.,
115: 1133-1147; Hirabayashi, Y. et al. 1985,
J. Biol. Chem.,
260: 13328-13333; Patent application WO 86/00909; Miyake, M. et al. 1988,
Cancer Res.,
48: 6154-6160; Kawashima, I. et al. 1992
, Molecular Immunology,
29, 625-632; Kotani, M. et al. 1992,
Biochimica et Biophysica Acta,
1117: 97-103).
The passive immunotherapy with monoclonal antibodies against gangliosides has been used in clinical trials for the treatment of some tumors such as melanomas and neuroblastomas. Treatment of melanomas have been intra lesion or systemic and although results seem to be encouraging, only a reduced number of patients showed total or partial remissions (Houghton, A. N. et al, 1985,
Proc. Natl.Acad. Sci. USA,
82: 1242; Dippold, W. G. et al, 1988,
J Cancer Clin. Oncol.,
24: 865; Vadhan-Raj, S. et al. 1988,
J. Clin. Oncol.,
6: 1636; Saleh M. N. et al. 1992,
Cancer Res.,
52: 4332-4347).
These antibodies showed effect in complement or cell mediated cytotoxicity studies (Ravindramath M. H. et al. 1991,
Inter. Rev. Immunol.,
7, 303).
Up to now, all the monoclonal antibodies obtained against N-glycolylated gangliosides are of the IgM isotype and the toxicity they provoke is mediated by complement.
IgM's generally have low antigen affinity and it is difficult to use them for diagnosis or treatment as radiolabeled Mabs. Although they fix complement well and guarantee a good cytotoxicity, the possibility of large-scale purification is much more complicated than with the IgG isotype.
Moreover, little has been reported on monoclonal antibodies against N-

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