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
2000-05-01
2002-12-31
Caputa, Anthony C. (Department: 1642)
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...
C435S331000
Reexamination Certificate
active
06500932
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel monoclonal antibody to human thymidylate synthase and also to a hybridoma capable of producing the same.
BACKGROUND ART
Thymidylate synthase (EC2.1.1.45, hereinafter called “TS”) is an enzyme that catalyzes a reaction in which thymidylic acid is formed from deoxyuridylic acid, plays a role to supply thymine which is a base specific to DNAs, and is one of principal rate-limiting enzymes for a DNA precursor supply pathway. Accordingly, its activity is known to become higher in thymi or tumor tissues where cell growth is active.
On the other hand, fluoropyrimidine antitumor drugs such as 5-fluorourasil and 5-fluorodeoxyuridine act against TS as a target enzyme, and for example, 5-fluorodeoxyuridine changes into fluorodeoxyuridylic acid in vivo and inhibits TS. In particular, fluoropyrimidine antitumor drugs are known to show high therapeutic effect and significant life prolongation for patients with a low level of TS expression in tumor cells but to exhibit low therapeutic effect for patients with TS in a high level [“Gan to Kagaku Ryoho (Cancers and Chemotherapy)”, 24(6), 705-721 (1997)]. The measurement of TS is therefore important, for example, an advance measurement of the expression of TS in an excised tumor upon treatment for a cancer patient gives indications for the determination of a treatment method and for the selection of an antitumor drug.
An object of the present invention is therefore to provide an anti-human TS monoclonal antibody useful for the immunological measurement of human TS and also a hybridoma capable of producing the same.
DISCLOSURE OF THE INVENTION
With the foregoing circumstances in view, the present inventors have proceeded with various investigations. As a result, novel anti-human TS monoclonal antibodies have been obtained and moreover, these monoclonal antibodies have been confirmed to be useful for the immunological measurement of human TS, leading to the completion of the present invention.
The present invention therefore provides an anti-human TS monoclonal antibody capable of recognizing an epitope which exists in a region of 187th to 313th amino acids from an N-terminus in human TS, an anti-human TS monoclonal antibody capable of recognizing an epitope which exists in a region of from an N-terminus to a 61st amino acid in human TS, and also hybridomas capable of producing these monoclonal antibodies.
Incidentally, the recognition regions by the human TS monoclonal antibodies according to the present invention have been determined in accordance with the amino acid sequence of human TS described, for example, in Nucleic Acids Research, 13(6), 2035-2043 (1985) or the like.
REFERENCES:
patent: 92/19650 (1992-11-01), None
Proceedings of the American Association for Cancer Research 90th Annual Meeting, vol. 40, issued Mar. 1999, Okabe, H. et al., “Preparation and epitope analysis of monoclonal antibodies to recombinant human thymidylate synthase, and their application to clinical studies”, #2647 (Copy submitted to USPTO by WIPO).
Database BIOSIS on Dialog, No. 199800321040, Behan, K.A. et al., “Epitope mapping of a series of human thymidylate synthase monoclonal antibodies”, Cancer Research, vol. 58, No. 12, 2606-2611, Jun. 15, 1998 (Copy submitted to USPTO by WIPO).
Proceedings of the American Association for Cancer Research 88th Annual Meeting, vol. 38, issued Mar. 1997, Behan, K. et al., “Epitope mapping of a series of human thymidylate synthase monoclonal antibodies”, (TS106, TS109 and TS110), #3180.
Cancer Research, vol. 51, No. 24, issued Dec. 15, 1991, Patrick G. Johnston et al., “Production and Characterization of Monoclonal Antibodies That Localize Human Thymidylate Synthase in the Cytoplasm of Human Cells and Tissue”, pp. 6668-6676.
Biochemistry, vol. 24, No. 3, issued Jan. 29, 1985, Malgorzata M. Jastreboff et al., “Isolation and Functional Effects of Monoclonal Antibodies Binding to Thymidylate Synthase”, pp. 587-592.
XP-002156191-Johnston, et al., “Immunological Quantitation of Thymidylate Synthase Using the Monoclonal Antibody TS106 in 5-Fluorouracii-Sensitive and-Resistant Human Cancer Cell Lines”, Cancer Research, vol. 52, No. 16, Aug. 15, 1992.
International Search Report.
Fukushima Masakazu
Okabe Hiroyuki
Caputa Anthony C.
Davis Natalie
Taiho Pharmaceutical Co. Ltd.
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