Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1994-05-11
1997-07-15
Loring, Susan A.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
4241551, 4241741, 53038885, 5303888, A61K 39395, C07K 1618, C07K 1628, C07K 1630
Patent
active
056480784
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a monoclonal antibody against a peptide which imparts adhesion activity to human cancer cells when expressed on cell surfaces and also to a cell adhesion inhibitor making use of the monoclonal antibody.
BACKGROUND ART
Carcinoembryonic antigen (hereinafter abbreviated as "CEA") is a glycoprotein discovered in 1965 by Gold and Freedman as an antigen which is found in both human colon cancer and the digestive organs of a 2-6 months old human embryo and having a molecular weight of 180,000 to 200,000 [Gold, P. & Freedman, S. O., J. Exp. Med., 121, 439 (1965)]. Its usefulness in cancer clinic has been widely recognized. It is a tumor marker which is used most often these days.
Further, it became evident by subsequent research that substances similar to CEA, that is, CEA-related antigen also exists in normal human tissues.
The term "CEA-related antigen" is a generic term for a group of antigens which are extremely similar to CEA in both proteinchemistry and immunology. Known typical CEA-related antigens include a nonspecific cross-reactive antigen which is a glycoprotein found in the lungs and spleen of a normal human being and having a molecular weight of about 90,000 [hereinafter abbreviated as "NC"; von Kleist, S. et al., Proc. Natl. Acad. Sci. U.S.A., 69, 2492 (1972)], NCA-2 found in embryonic feces [Burtin, P. et al., J. Immunol., 111, 1926 (1973)], and NFA (normal fecal antigen) found in normal adult feces [Kuroki, M. et al., Cancer Res. 41, 713 (1981)].
They are however still unknown in many aspects, including their detailed molecular structures and their differences in molecular structure.
Keeping step with changes in the diets of Japanese in recent years, colon cancer patients are increasing. About 80% of colon cancer is said to metastasize to the liver, and colon cancer is also said to metastasize to other organs such as the lungs. Recently, there has also been reported the possibility that the cell adhesion activity of CEA may take part in the metastasis of colon cancer to the liver [Jessup, J. M. et al., Cancer and Metastasis Reviews, 8, 263 (1989)].
Using a molecular biological technique, the primary structure of peptide has recently been ascertained with respect to CEA [Oikawa, S. et al., B.B.R.C., 142, 511 (1987) and Japanese Patent Laid-Open No. 177794/1988]. NCA [Tawaragi, Y. et al., B.B.R.C., 150, 89 (1988)], BGPI [Hinoda, Y. et al., Proc. Natl. Acad. Sci. U.S.A., 85, 6959 (1988)] and W272 (CGM6) [Arakawa, F. et al., B.B.R.C., 166, 1063 (1990)].
According to the results of a cDNA analysis, CEA peptide is composed of 668 amino acids as shown, for example, in FIG. 3 of Japanese Patent Laid-Open No. 177794/1988.
As is evident from the figure, CEA peptide can be divided into five domains, that is, domain N (1-108) extending from the N terminal to the 108th amino acid, domain I (109-286), domain II (287-464) and domain III (465-642) having mutually very homogeneous repetitive structures and composed individually of 178 amino acids, and domain M (643-668) composed of twenty-six, primarily hydrophobic amino acids on the side of the C terminal. Domains I, II and III may each be divided further into sub-domains (which may also be called "domains") which consist of 92 amino acid residues and 86 amino acid residues, respectively. These individual sub-domains may also be referred to as "1A", "1B", "2A", "2B", "3A" and "3B", respectively.
These individual domains and CEA peptide constructed of them are schematically illustrated at the top in FIG. 1 of Japanese Patent Application No. 222379/1991.
Domain M was first considered to be anchored on a cell membrane. It is however known that, after translation, domain M is processed and PI-G (phosphatidylinositol glycan) is added instead and is anchored on a cell membrane [Hefta, S. A. et al., Proc. Natl. Acad. Sci. U.S.A., 85, 4648 (1988); Takami N. et al., J. Biol. Chem., 263, 12716 (1988)].
All 12 cysteine residues are found in domains I, II and III, each domain having 4 residues at the same positions as others. Two
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Hashino Junko
Nakanishi Toshihiro
Nakazato Hiroshi
Oikawa Shinzo
Loring Susan A.
Suntory Limited
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