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WO2007037555A1 - Application therapeutique ou diagnostique du gene dusp15 - Google Patents

Application therapeutique ou diagnostique du gene dusp15 Download PDF

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Publication number
WO2007037555A1
WO2007037555A1 PCT/JP2006/320043 JP2006320043W WO2007037555A1 WO 2007037555 A1 WO2007037555 A1 WO 2007037555A1 JP 2006320043 W JP2006320043 W JP 2006320043W WO 2007037555 A1 WO2007037555 A1 WO 2007037555A1
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Prior art keywords
gene
antibody
protein
dus
cells
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Japanese (ja)
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WO2007037555A9 (fr
Inventor
Shinichirou Niwa
Yasutaka Makino
Tomoki Ikuta
Kazuya Arai
Takayuki Shindou
Hiromichi Ogura
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Link Genomics Inc
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Link Genomics Inc
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Publication of WO2007037555A9 publication Critical patent/WO2007037555A9/fr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/12—Dual-specificity kinases (2.7.12)
    • C12Y207/12001—Dual-specificity kinase (2.7.12.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to the gene 15 gene specifically amplified in cannabis and its therapeutic or diagnostic use.
  • non-small cell pulmonary canal GFR epidermal growth factor receptor
  • tyrosine kinase inhibitor generic name: Kehuitinif
  • WO 9 6 Z 3 3 9 8 0 tyrosine kinase inhibitor
  • the present inventors have found that there is a U S P 15 gene that has been intensively studied (especially the large intestine) and is frequently amplified.
  • the present inventors have been able to suppress the growth of cancer cells by inhibiting the expression of D US P 15 in cancer cell lines, particularly cervical cancellous cell lines, and have completed the present invention. That is, the present invention provides a screening method for a screening agent, a quinotocan for diagnosis of a candidate substance having an inhibitory action on a therapeutic agent.
  • a substance that inhibits the expression of DU SP 15 gene as an active ingredient (c) Te to DU SP 15 gene or a part thereof (d) DU SP 15 gene variant acting in a tiff manner on DU SP 15 gene or part thereof
  • a therapeutic agent that effectively comprises a DU S P 15 protein inhibitory substance comprising a substance selected from the group consisting of:
  • a therapeutic agent for epilepsy comprising the antibody according to (9) above.
  • Radioisotope Therapeutic protein A low-molecular-weight drug The above-mentioned (10 therapeutic agent further comprising a hector carrying a gene.
  • a can diagnosis agent comprising the antibody according to (9) above.
  • DU SP 15 gene expression inhibitor is an active ingredient SEQ ID NO: 5 SEQ ID NO: 6 SEQ ID NO: 8 SEQ ID NO: 9 or SEQ ID NO: 10
  • a canine therapeutic agent containing a chito having the nucleotide sequence of SEQ ID NO: 10 According to the present invention, a novel drug useful for the treatment of cans (eg, colon cane) If it is a quinoto and method, a method of screening a candidate compound is provided.
  • 01 is a histogram showing the frequency of the DU S P 15 gene with respect to the degree of amplification of two genes derived from colonic epilepsy.
  • 02 is an optical micrograph (phase contrast image) showing the results when s 1 RNA of the large intestine cane cell line Caco 2 and RKO E 65 gene is transfected.
  • 03 is a graph showing the results of quantitative evaluation of the RNA 1 effect when DU S P 15 residue A was transfected into the large intestinal cane cell line C a c o 2.
  • Figure 7 is a photograph showing the results of a no-sense experiment performed using various normal organ tissues.
  • 09 A and 09 B are the krafts of sera derived from (A) and (B) sera from healthy subjects analyzed by mass spectrometry.
  • 01 1 is a graph showing the results of verifying the RNA i effect when D US P 1 RNA was transfected into the cervical cancer cell line HeLa cell line.
  • 01 2 is an optical micrograph showing the results of detailed observation of the experiment of 01 1 according to the time series under a microscope (differential varieties, best mode for carrying out the invention). Specimen amplification was performed using specimens, and the number of genes specific to the large intestine was increased 15% (Dualspecificitypnosplike 1 5) of the regions where amplification occurred frequently in the specimen It was found that the sample was. Therefore, it is called dual specificity phosphatase (Dualsptyphosphatase (DSP)). Frotin phosphatase (P roteinphose) is divided into serine threonine specific phosphatase (P and) and thyronphosphatase (PTP) containing nostin residues. NK & N eel ⁇ G (1 9 9 6) C e 1 1 8
  • P T P is P T 1 B (C ha r b o n n e t a 1 (1 9 8 9) P r C N at l A c a d
  • DSP MAP kinasephose (MK P), which is dephosphorylated and inactivated from erogen activated protein Erk J nkp 3 8 (S axena, M & n T (2 0 0 0) Semin I mmu nol 1 2 9 6 A lonso A eta 1 (2 0 0 3) r Genet 5 3 3 3— 3 5 8).
  • MK P MAP kinasephose
  • MKP kinase targeting mo ti roof.
  • VH 1 derived from vaccinia virus (V accinis) or DSP (Guan KL (1 9 9 1) N ature 3 5 0, 3 5 9-3 6 2) ⁇ DU SP 3 (VHR) (I shibashi T
  • DU S P 1 5 (VH Y) is characterized by testis in normal anorexia. Detailed analysis shows that it is expressed in spermatocytes. In addition, it is localized to the membrane at the acid or binding site (clean residue) or at the N-terminus and is localized in the cell. Not directly related to DU S P 15
  • the present inventors can suppress the expression of the DU S P 15 gene by suppressing the expression of the DU S P 15 gene by suppressing the expression of the DU S P 15 gene by inhibiting RNA l. It is also possible to make a diagnosis of can by measuring DU S P 15, which will be described in detail below.
  • the present invention provides (1) a cannula therapeutic agent containing DU SP 15 gene expression inhibitor and (2) a cane therapeutic agent containing a DU SP 15 tft inhibitor as an active ingredient.
  • Middle “DU SP 1 5 gene” means that it means a human DU element (SEQ ID NO: 1) consisting of 1 3 8 3 bases registered as Accession No 0 6 1 1 in NC Chitote (A lonso A
  • the “DU SP 15 gene” to be used in the middle and the high-rise chain are known methods or examples such as molecular cloning (Molecullng T hird E dition JS a mb ra 1 C old S pr ing Harbor L as 2 0 0 1) According to the method described in the above or according to the instruction manual attached when using a commercially available life rally.
  • stringent conditions can be any of moderate conditions and conditions can be selected.“ Low stringent conditions are 5 XSSC 5 X Tenhard solution 0 5% SDS murmite 3 The condition is 2 ° C. Also, “medium string is 5 XSSC 5 X Tenhard ⁇ liquid 0 5 0% formamide ⁇ 4 2 ° C.“ High string condition ”is 5 XSSC 5 X Tenhard solution 0
  • inhibitor of gene expression refers to a gene that inhibits any one of a series of events (including transcription (mRNA generation) quality generation) from the gene. Inhibits the production of coated hazelnut.
  • DUS P 1 5 protein refers to P 1 5 protein (SEQ ID NO: 2) from 2 3 5 amino acid residues registered in Aceticion N 542 1 7 8 ) And the activity of the tannins (for example, the flothiin mouth non-phosphatase activity 14 selected from the threonine-specific phosphatase activity) and 1 amino acid residue relative to this amino acid sequence. Deletion, substitution, insertion, insertion, or addition / lifetime mutant protein.
  • such a mutant protein is composed of two rows of SEQ ID NO: about 70% or more 75% or more 80% or more 85% or more 9 1% or more 9 2% or more 9 3% or more 9 4% or more 9
  • Any portion having the same activity as the activity ft of the DUSP 15 protein described above may be used for the site consisting of the amino acid sequence that follows.
  • SEQ ID NO: 2 it consists of at least 20 amino acids residues, preferably at least 50 or at least 70, more preferably at least 1 or at least 200 amino acids.
  • this contains an acid sequence in the part involved in the activity of DUSP 15 protein.
  • the amino acid residue in the amino acid sequence used in the present invention is 1 or about 1 to 20 in the amino acid sequence, more preferably about 1 to 10 or about 1 to 5). Or deletion, addition, substitution, or modification.
  • the DUSP 15 protein used in the present invention can be prepared from the cells and tissues.
  • this material can be synthesized by a known hematopoietic synthesizer, or can be prepared by reversion using an appropriate host cell selected from eukaryotes.
  • DUSP 15 used in the present invention may be derived from either species. Preferably, it is derived from human. “Substantially the same quality of active life” indicates their activity or property.
  • the enzyme activity (flotinthyronone activity tt and serine threonine-specific phosphatase activity (for example, about 0 0 1 to 100 0 times preferably about 0 5 1) Whether it should be performed in accordance with the known method described in the document “Nanato” is measured according to the screening method described later.
  • the identity of the amino acid sequence and the base sequence is determined by the alcoholic B LAST T (proc N atl S ci U SA 8 7 2 2 64-2 2 6 8 1 9 9 0 at 1 A cad S ci USA 9 0 5 8 7 3 Determined based on B LAS T alcoholism
  • a fukuro crumb called BLASTX has been developed hu 1 SF, eta 1 J Mol Biol 0 3 1 9 9 0).
  • cancer treatment agent is used as an anticancer agent, a cancer cell aphotonos inducer, a cancer cell growth inhibitor, a cancer agent, an antiepileptic agent Used to mean including the like.
  • cancer and “tumor” in this application have the same meaning.
  • DUS ⁇ 1 5 containing an expression inhibitor of the gene The present invention is, in one embodiment, DUS ⁇ 1 5 Examples of substances from DU SP 15 gene to DU SP 15 mRNA
  • nucleic acid means RNA or DNA.
  • Nucleic acid includes such modifications as those having other heterocyclic bases decorated with furin and hydrin bases. The product consists of methylated and / or liminated furin and / or lyminylated and furanized furin. 1 Nucleic acids that have an inhibitory effect are used as active ingredients. What is RNA i? When a double-stranded RNA that is the same as or has the target gene sequence is introduced into a cell, the introduced external endogenous I gene is inhibited.
  • Double-stranded RNA that generates 9 to 30 bases
  • ds RNA double-stranded RNA
  • siRNA small inter RNA
  • sh RNA shorthairpin
  • SAAP r 3 0 9 9 9, 6 04 7-6 0 5 2 ⁇ 25 bases Most preferably 2 1-2 bases.
  • SAAP r 3 0 9 9 9, 6 04 7-6 0 5 2 ⁇ 25 bases Most preferably 2 1-2 bases.
  • antisense nucleic acid or “anti-leocyto” refers to having at least a small number of horinucleotide in a target DNA region, and having a high frequency with the horinucleotide or part of it.
  • the antisense nucleic acid which is a nucleic acid, is RNA DNA or modified NADA)
  • the antisense nucleic acid of the present invention is alternatively a modified nucleic acid (RNA DNA).
  • NA Single-stranded DNA Double-stranded RNA Double-stranded RNA may be NA hyphenated.
  • Modified nucleic acid ingredients Sulfur derivatives of nucleic acids thiophosphite derivatives It does not need to be a sequence complementary to the endogenous gene or a part of it, as long as it effectively suppresses the expression of the gene.
  • design of a complementary antisense sequence near the 5 'end of mRNA of DU S P 15 gene is gene translation.
  • the length of antisense nucleic acid is at least about 10 bases (about 40), preferably 15 bases or more, more preferably 0 bases or more. Is it possible to design a nucleic acid with a length of about 500 bases or less by referring to the publicly known literature? Hirashima and Inoue New Chemistry Laboratory 2 Nucleic acid IV gene Japanese Biochemical Society Tokyo Chemical Dojin 1 9 9 3 p 3 1 9 K awakam 1 eta 1 P harm T ech V ol 8 p 2 4 7 1 9 9 2 V ol 8 p 3 2 STC rookeeta 1 edse Research and Ap plicatio Press 1 9 9 3
  • DU SP 15 Some have active domains (tankaku nucleus 0 3 5 p 2 1 9 1). Note: Reversing note type FEBSL ett, 1 9 8 8, 2 2 8, p SL ett 1 9 8 8 2 3 9 p 2 8 5 Tanha 1 9 9 0 3 5 p 2 1 9 1 N ⁇ c 1 A cids 8 9 1 7 p 7 0 5 9 For example, N type 1 p 3 4 9 Nuc 1 A cids R es 1 9 9 1 7 5 1 Hiroshi Kikuchi Chemistry and Biology 1 9 9 2 3 0 p 1 Using such a rehothyme, it is possible to specifically inhibit the transcript of the original SP 15 gene.
  • the present invention can use the transcription activity of the DU S P 15 gene as an active ingredient. For example, it is a factor involved in the expression and transcription of the DUS P 15 gene.
  • a compound is a natural product, but a compound such as a synthetic compound can be obtained by the screening method described later.
  • 1 2 DU S P 1 5 Contains protein inhibitor of protein activity M
  • the present invention provides a therapeutic agent for epilepsy comprising a DU SP 15 inhibitory substance Excluding foreign bodies)
  • antibody means the full length of a protein or an antibody.
  • the form of the antibody of the present invention is not particularly limited as long as it binds to DU S P 15 protein, but also includes a human antibody, a recombinant antibody, an antibody fragment, and an antibody modification product in addition to the above-mentioned monoclonal antibody.
  • Antibodies that bind to D protein can be prepared by those skilled in the art. Anti-DU S P 15 will be described later.
  • DUS P 1 5 protein mutant with Tiff properties against DUS P 1 5 protein By expressing a glanced gene, the activity of endogenous ft field 5 protein is lost or reduced. (Kunihiro Tsuchida, Gene Activity Inhibition Experiment Method Tahira (2 0 0 1) 2 6-3 2 Natto).
  • a compound other than a mutant that binds to DU SP 1 5 protein can be used as an active ingredient as a substance to obtain DU SP 1 5 protein.
  • a compound that binds to Such compounds may be natural products. Such compounds can be obtained by the screening method described later.
  • One preferred embodiment is a method using DU S P 15 protein and exposure as indicators.
  • DU S P 15 tantalum compounds are expected to be effective in inhibiting the activity of DU S P 15 protein.
  • the compound is preferably bound to the DU S P 15 position.
  • the protein is further brought into contact with the test compound.
  • DU SP 1 5 In response to an indicator for detecting binding to a test compound
  • Example 1 5 Purified form of protein Intracellular or extracellular or bound to an affinity column For example, radiation knowledge, fluorescence knowledge, etc. can be given as necessary for the knowledge of compounds used as needed. In this method, the binding of DU SP 15 protein is detected next.
  • DU SP 1 5 protein The binding of DU SP 1 5 protein to the test compound depends on the knowledge attached to the test compound bound to Example 1 5 protein.
  • DU SP 1 is generated by the binding of the test compound to the protein that is expressed intracellularly or extracellularly. Select a test compound that inhibits activity.
  • the compounds separated by this method have an anti-epileptic effect and are useful as therapeutic agents.
  • the screen linking method is based on D U S P current.
  • the DUSP 15 gene is first expressed and contacted with a test compound. It is not limited to the origin of the “cell” used, whether it is a cell that can be used as a source of the cell.
  • a “cell expressing a gene” a cell having an endogenous DUSP 15 or a cell expressing or expressing an exogenous DUSP 15 gene can be used.
  • Cells expressing an exogenous gene are usually prepared by introducing the expression vector left in D U S P 15 into the Sukuo cells.
  • the expression vector can be produced by general genetic engineering techniques.
  • Natural or compounds organic compounds to motor Compound Tanhaku compound off compound Namihi to quality life Larry Gene Raifurari cell extract Cell culture ⁇ products of fermenting microorganisms marine raw extract or the like is not particularly limited test compounds to be used in the process Used.
  • Test compound in cells expressing DUSP 15 gene Normal culture of cells expressing DUSP 15 gene I will come.
  • the antibodies used for DU SP 15 may be detectable antibodies, specifically monoclonal antibodies or polyclonal antibodies.
  • the compound selected as a compound that decreases the expression level compared to a roll that is not contacted with a test compound is 3 1 Anti-DUS P 1 5 antibody
  • anti-DU SP 15 antibody includes antibodies that are DU SP 1 (including fragments (partial edge) or salts thereof).
  • the anti-DU SP 1 reclonal antibody used in the present invention may be a monoclonal antibody.
  • the class of the antibody is not particularly limited, and anti-preferably having IgA type such as IgGIgMD or IgE is preferably IgG or IgM, and more easily IgG, more preferably IgG.
  • antibody used herein is meant to include any antibody fragment or derivative, and includes, for example, Fab 2 CDR-humanized antibody, multifunctional antibody, and single-chain antibody.
  • Antibody production methods of the present invention are well known in the art, such as the production of antibodies by known methods (see, for example, E & Lane Danantibody Collaborative Laboratory Laboratory 8). .
  • the tanned USP 15 used as a sensitizing anti-IT or a salt thereof also includes a margin in its part. This is limited. For example, it is a fragment of the amino acid sequence of SEQ ID NO: 2, eg, 40 or more 60 or more 80 or more 100 or more amino acids
  • the part has a sequence part.
  • these Salt or organic acid for example, acetic acid, quinic acid, flohy, etc.
  • SP 15 Used as a sensitizing antigen for antibody acquisition, SP 15 is restricted to the animal species from which it is derived. Tanja or preferred Tancho or preferred.
  • the above-mentioned DUPSP 15 protein is administered to a mammal mouse as an antigen using the portion of the protein (in this specification, these are collectively referred to as 15 protein) as an antigen.
  • 15 protein the portion of the protein (in this specification, these are collectively referred to as 15 protein) as an antigen.
  • 15 protein the portion of the protein (in this specification, these are collectively referred to as 15 protein) as an antigen.
  • 15 protein is administered to a mammal mouse as an antigen using the portion of the protein (in this specification, these are collectively referred to as 15 protein) as an antigen.
  • 15 protein When no hunt is used per animal of antigen, 0 1 to 10 Omg is used, and when using no hunt, 1 to 100 ⁇ g is used.
  • Quantum immunity is limited by insertion into the subcutaneous or intraperitoneal cavity as an example of aluminum hydroxide cultivated. Not every few days to several weeks Good weekly intervals 1 to 10 times, preferably 2 to 5 times Immunization 1 to
  • Antibody-producing cells and myelo to obtain hyphenoma NS I / 1 -A g 4-1 S 0/1 and mouse mye YB 2 0 and myroma myeloma cell line are listed Next, cell fusion between the above myeloma cells and antibody producing cells Serum-free DMEM R PM I — 1 6 40 1 1 0 6 to 1 1 0 7 cells 111 1 and 2 X 1 0 5 to 2 X 1 0 6 cells and production of Zm l myeloma cells Cell ratio of cells to myeloma cells 2 1 to 3 1 Carry out fusion reaction in the presence of a cell fusion promoter Cell fusion promotion Average molecular weight 1 0 0 0 to 6 0 0 0 . It is also possible to fuse antibody-producing cells using commercially available cell fusion devices that utilize electrical stimulation (eg, electon).
  • electrical stimulation eg, electon
  • PM I-16 40 medium containing hyphritoma 10 medium culture medium or seeking culture medium culture medium for example, 3 7 ° C 5% 7 to 14 days
  • ascitic fluid is taken approximately 1 X 1 0 7 or administered Haifuri Tomah re Thoma mammalian the same species animal-derived myeloma cells to atmospheric and 1 after 2 weeks Collecting the above-mentioned antibodies If purification of the antibody is required, the ammonium sulfate salting-out method, ion raffi-el filtration, affinity chromatography method can be selected as appropriate, or these can be combined.
  • F ab or F ab 2 fragments can be prepared by digestion using conventional methods.
  • Humanized antibodies are described, for example, by Riec hma nn et al. (R in J Mol Biol Oct 5 20 3 (3) 1 9 8 8) and J ones et al. (J ones et al. Nat 1 5 2 2- 5 2 5 1 9 8 6) It is possible to use one of the methods described in 1).
  • Chimeric antibodies are, for example, “Experimental Medicine (Special issue 16, No 1 0 1 9 8 8”). Equity 3— 7 3 2 8 0 Human antibodies are, for example, “Nature Genetic 1 5, p 1 ⁇ 4 6-1 5 6 1 9 9 7 '' ⁇ Naturelcs Vol 7 p 1 3-2 1 1 9 9 4 '' Special 3 6 5 Gazette International Application Publication W 0 9 4 2 5 5 8 5 G Monthly Nos. 40 to 50, 1 9 9 5 "V ol 3 6 8, p 8 5 6-8 5 9, 1 9 9 4" An antibody that binds to SP 15 protein may be used for the purpose of suppressing cancer cell metastasis, etc.
  • the antibody DU SP 15 can be obtained using bioluminescent compounds as well as phycoerythrin and fluoride.
  • the presence of bioluminescent protein is measured by fluorescence. This knowledge is important for the biologically generated renoferrin, linofelase, and aequorin.
  • the antibody of the present invention is used to specifically detect P 15 protein etc. in a sample of body fluid. Used and also used to purify DU SP 1 5 protein etc. DU SP 1 5 protein in each fraction during purification Analyzes the behavior of DUS P 1 5 protein in cells I will come.
  • Anti-DUS P 15 antibody complex or anti-DU SP 15 antibody used in the present invention is an agent or a diagnostic agent itself or an agent having a neutralizing activity. Therefore, the present invention is used in another embodiment for use as an addictive therapy or addictive drug in the US. Complexes of P 15 antibody and other glazes are also provided. According to such an embodiment, the anti-DU SP 15 antibody of the present invention is used as a labeling agent for the determination of the therapeutic effect. Iodine-1 2 5 C 1 25 I) and iodine-1 3 1 As with the above elements, these radiohalogen elements can be widely used as diagnostic agents for radiation therapy and knowledge of antibodies and hefty. For example, 1 25 I or 1 can be conjugated to an antibody by a known method such as the chloramine T method.
  • tech m indium 1 1 1 and potassium 1 6 7 6 7 Ga for treatment use indium 1 90 ( 9 0 Y) rhenium 6 R e) or rhenium 1 1 8 8 ( 1 88 R e)
  • the metal chelating agent EDTA D nonionic compound cyclam and DOTA or other known chelating agents can be bound to the antibody in advance and then released, or the radioactive metal chelate can be formed and then bound to the antibody.
  • cytokine that activates is preferable. It is possible to use linonyanph toxin to directly kill colonic canal cells. For example, for therapeutic proteins, coat the antibody or antibody fragment. C. Coat the DNA. C. Connect the DNA to coat the fusion antibody.
  • Cyclophosphine alkylating agent 5 Flul meso trexase Antimetabolic agent Yunomainon Mitomycin C Yunolhinone Toxorhinone Hinkristin Hinfrastin Hintesin-like hormone agent Bed oncology (Japan Clinical Oncology Research Group 1 9 9 6 Years Cancer and / or Height Mouth Cochisson Fretonison's Steroline Intome Yunon's Non-Steroit Agent Gold Tiolamin's Immunomodulator Cyclophos Anti-inflammatory agents such as chlorfenilamine maleate, antihistamines, etc.
  • virus hector a virus hector modified so as to be capable of binding to anti-DU of the present invention is used.
  • Watenovirus hector Wang P et 5
  • Retrovirus Hector RK eta 1 (1 9 9 6) JV ir
  • Anti-DU SP 15 antibodies can be recognized as antigens (ie, D).
  • the anti-DUS P 15 antibody and the other drug can be conjugated to chemical W or.
  • chemical bonds include ionic bonds, covalent bonds, intermolecular forces, and hydrophobic interactions
  • genetic engineering bonds include, for example, a fusion protein consisting of a milk protein.
  • the antibody and the therapeutic protein will be bound.
  • a chemically acceptable carrier can be added according to a conventional method.
  • excipient coloring +4 flavor storage +4 stabilizer buffer f Latin Medium-chain fatty acid trichryslate Horio kinoechi
  • Examples of the dosage form of the therapeutic agent of the present invention are oral powders, pills, powders, condylar agents, fine granules, soft cuffs, tans, helenotes, sublinguals, stings, etc.
  • Plasters For liquids for external use, etc. use the optimal dosage form according to the route of administration and the subject of administration.
  • the activity of DUS P 15 protein as an active ingredient (15 gene expression) Inhibitors can be determined from 0 1 to 9 9 in the drug product.
  • the dosage of the active ingredient of the drug of the present invention varies depending on the subject of administration Subject administration method Oral administration In general (as 60 kg) More preferably, it is about 1 to 100 mg.
  • the single dose varies depending on the organ symptoms, administration method, etc.
  • the normal person for example, 6 kg
  • About 30 mg per day preferably about 0 About 1 to 20 mg
  • About 0 1 to 1 Omg should be administered by intravenous vaginal discharge
  • the type of dosage form Administration method ⁇ Considering the symptoms of the deaf, etc. It will come out.
  • Bladder canister Uterine canister eg cervical canine uterine canopy
  • the leaf preparation of the present invention contains a DUSP 15 protein activity inhibitor SP 15 gene expression inhibitor as an active ingredient. Cancer agent Cancer metastasis inhibitor Cancer cell phohotosin inducer, etc. The type of cancer is not specific.
  • the drug of the present invention contains both a DUSP 15 protein and a substance that inhibits the expression of the DUSP 15 gene.
  • the sense nucleic acid is used as a monochromic or retrovirus vector. After insertion into a viral hector, it should be administered according to known means.Antisense nucleic acid should be administered alone or physiologically, and administered via a gene-like catheter Come.
  • a combination of a combination of a recombinant fatenovirus particle and an anti-DUSP 15 antibody may be used independently in the treatment of cancer.
  • a pharmaceutical carrier As such a carrier, water, physiological saline, krucose-hytoalf isotonic solution or the like is preferably used as a carrier.
  • water, physiological saline, krucose-hytoalf isotonic solution or the like is preferably used as a carrier.
  • the number of administrations is 1 and the administration period may be 1 day to several months or more.
  • the viral hectare nucleic acid molecule used in the present invention can be used for diagnosis of a specific cell and / or disease state.
  • a detectable marker gene into the nucleic acid molecule of C, it is possible to detect and diagnose tumor cells by combining with the virus Hector USP 15 antibody obtained by transfecting cells or anti-DUSP 1 5 Can be used to detect and diagnose tumor cells by allowing detection by antibodies
  • the present invention also provides a diagnostic agent.
  • One preferred diagnostic agent of the present invention is (a) a DUSP 15 antibody or (b) a DUSP 15 gene or a part of it. Diagnostic agents and diagnostics using 5 1 anti-DUSP 15 antibody containing
  • subject-derived biological test includes subject-related or body fluid (for example, blood (including whole blood, plasma, serum, etc.), liquid, saliva, perspiration, elliptical fluid, etc.).
  • a “subject” is a human subject who is or is suspected of receiving or desired to receive a human subject. Examples of such cans include large intestine, stomach, and lungs. Gland or esophageal or liver or biliary or splenic or uterine canal (eg cervical or uterine canal) testis or spleen or urinary canal tumor Tumor or blood tumor is preferred.
  • the immunoassay for issuing DUSP 1 in a subject's unexplained biological test as described above is based on the binding of a single antibody from a biological sample collected from a subject with a risk of kan (eg, large intestine).
  • Antibody binding including measuring anti-DUSP 15 antibody and the amount of immunospecific binding by the antibody, under conditions to detect whether DUSP 15 protein or increased expression is detected. In this case, detection of increased D halite expression or disease state indications. If necessary, you can compare the DUSP 15 tanned reher to that without a cane.
  • One embodiment of the above immunoassay is, for example, a blood clot test +4 It can be determined appropriately by those skilled in the art.
  • One method of detectably labeling anti-DUS P 15 antibodies is to bind the antibody to an enzyme such as the enzyme Imnoanose (EIA) [Vo 1 1 er, immunoadsorbent by A] ('The E nz yme Li mu nosorbent A ssay) (ELISA) lagnostlc Horizons 2 1-7 JC lin Pathol 3 1 1 9 7 8 B utler by ological A ssociates Quartblication, Wa lkersvi 1 le MD r A Meth E 7 3 4 8 2 to 5 2 3 1 9 8 1] by JE. Fermentation with antibody Appropriate substrate Fluorophotometry is used to produce a chemical molecule that can be detected by fluorescence measurement with visible means.
  • IA Imnoanose
  • ELISA E nz yme Li mu nosorbent A ssay
  • Enzymes that can be used to provide detectable knowledge to antibodies include, but are not limited to, herokinase and alkaline properties. This detection can also be achieved by a colorimetric method using a chromogenic substrate. Other methods that can be used in the present invention include the race (RIA) Santoi immunoassay method, the immunometric method, the immunofluorescence assay method ( FIA) Time-resolved fluorescence RFIA) Enzyme immunoassay (EIA) Luminescence immunoassay Electrochemiluminescence immunoassay (ECLIA) Latinox As described above, it is possible to diagnose various diseases related to DUS P 15 dysfunction by utilizing the in vivo D-quantitative method using the antibody of the present invention. Example 1 If an increase in the concentration of brown sea urchin is detected, whether it is likely due to overexpression of the brown sea urchin (for example, kan) or is likely to be affected in the future? The
  • the anti-DU S P 15 antibody of the present invention may be i n v i v.
  • the preparation of antibody preparations that can be used here is well known in the art.
  • the antibody—Kireet NuclMedb Biol 1 9 9 0 1 7 2 is described.
  • An example of an antibody having a paramagnetic ion used for magnetic resonance is described in, for example, M ag e e s e a n c e e n Me c i c e e e 1 9 9 1 -342.
  • whether the DUS P 15 gene or the flow designed for the DUS P 15 gene is used is, for example, (a) the subject-based DUS P 15 gene or its fragment base A salt that can be swallowed up under the conditions of a streaky sunset in the array. And z or quantify.
  • the base sequence used as the flow can be 12 bases or more 15 bases or more 18 bases or more 2 14 bases or more 2 7 bases or more 30 bases or more, or even a nucleotide fragment. High and low stringent conditions may be used. Included in the base sequence of DU SP 15 gene or its fragment is also included in the base sequence of DU SP 15 gene or its fragment. For example, international publication number 8 9 Z0 6 6 9 8 EP—A 0 2 US Pat. No. 2 9 1 5 0 8 EP—A 0 0 6 3 8 7
  • the DU SP 1 5 gene is publicly detected by using a nucleocytofluorine or a flymer. Or come to quantify.
  • the mR quasigene of the cellular DU SP 15 (housekeeping gene (for example, Shape et al., JM mmary G land B iol N la 3 (1 9 9 8) 3 1 5-3 2 4 Wu YY s JLA cta der venere (2 0 0 0) 2-3) mRNA reherence, preferably by R, can also be compared.
  • Another embodiment of the diagnostic method of the present invention is a sputum during the test. By determining the intensity of the sample, it is possible to identify the individual amino acids of the protein and hemiform from the results of mass spectrometry.
  • ionization there are various types of ionization, such as matrix antheno tracer tetherization (MAL D I), electrosfray ionization, phase (E I C I) and field desorption (FD).
  • MAL D I matrix antheno tracer tetherization
  • E I C I phase
  • FD field desorption
  • MAL DI matrix antheno tracer tetherization
  • E I C I electrosfray ionization
  • FD field desorption
  • ion fraction compatible with ionization method For example MAL DI, time-of-flight type (ti me ght ToF) Mass spectrometer
  • ESI quadruple ion trough type Magnetic type mass
  • An analyzer or a quantity analyzer may be used in tandem.
  • M S MALD I — T ⁇ It is also possible to determine the amino acid sequence by another method for determining amino acid sequence, for example, one (eg,
  • the present invention also provides a quinoto for quantifying or quantifying a subject DU SP 15 protein or fragment thereof containing an anti-DU SP 15 antibody.
  • the base sequence of the gene or a part of it contains a base sequence that can be hyfitized under stringent conditions.
  • the term “can marker” refers to a subject's body fluid (such as urine phosphorus eight fluids, saliva, sweat, semen, etc.) or a cell that is not derived from cells or normal tissues, or is a molecule that is alternatively enhanced in expression. This suggests the presence of the molecule in the subject or in the tissue.
  • the quinoto of the first embodiment contains antigens (DUSP 15 protein and its components and edge or Z or components to be quantified in the body fluid test from the subject.
  • antigens DUSP 15 protein and its components and edge or Z or components to be quantified in the body fluid test from the subject.
  • DUS or ELISA tissue sections or body fluids such as blood or urine, such as blood or urine, are used to detect and Z or quantify antibodies such as radioactivity, fluorescence ratio
  • the quinoto of the present invention contains a labeled secondary antibody
  • the quinoto of the above second embodiment is a stringent high hyphenation sequence in the DUSP 15 gene or base sequence.
  • Article containing holynucleocytos having a base sequence that can be used as a chair.
  • the quinoto of the present invention may contain the above-mentioned holy fixed on DNA chinofu.
  • the quinoto of the present invention is a highly efficient anti-DUSP 15 antibody DUSP 15 having a stringent base sequence.
  • Example 1 Colonic Canine Specific Amplification by Array C GH Method
  • a colonic specimen specific gene amplification region was prepared in a sample of 20 samples of large intestine cannula and array C verification was performed.
  • DU S P 1 5 gene was found to be amplified in 5 60% of 2 0 0 individuals.
  • the frequency of the colon cane S was high and the amplification degree of the colon cane-derived cultured cell line was verified.
  • the cultured cell line used was Caco 2 E 6 which is a cell line derived from the large intestine.
  • Kenome DNA was extracted from the cultured cells according to the key phrase using BLOOD & CELLEDENAQ (Q IAGEN).
  • Table 3 shows the DU S P15 gene colony cell line ZR value). As shown, it was found that colonic undifferentiated cells BAC Clone R P 1 1-2 4 3 J 16 located in P 1 5 gene was amplified.
  • Table 4 shows the cell lines of DU S P15 gene with large intestine. The values are relative to the DNA of Akira (normal). In addition, we found that DUS P 15 inheritance was also observed in the colon cell line (Table 4).
  • RNA i analysis using KOE 6 was also amplified in the colon colony cell line (C aco 6), so that the cells were selected for functional analysis of the DUS P 15 gene in the canine.
  • RNA i analysis using KOE 6 was also amplified in the colon colony cell line (C aco 6) and its phenotype RNA 1 analysis>
  • s 1 RN A synthesized s l RNA that selectively selects specific 21 mer within the gene (Q I AGEN
  • RNA i FE CT QI AGEN
  • the number of viable cells was measured by measuring leaf counts using the Cranco2 cells and cells with sl RNA of DUS P 15 gene T ransfec on the 4th day. Relative amounts are shown. As a result of the determination, it was found that in Caco 2 cells, 1 type of DU SP 1 l RNA (c) was found in all 3 types of s 1 RNA of 15 genes (ab, c) in RKOE 6 cells N Compared to egative control (NC), it was a little less (04 AB). It was observed whether the number of cells was low. All the sl RNAs of the SP 15 gene were subjected to t test. By carrying out this study, we verified the specific effects of the suppressive effect of epilepsy genes.
  • the cell line used was CCD 18 Co, which was cleared from AT CC.
  • the s 1 RNA c sequence used was used.
  • L1 am ine 2200 (Invitrogen) was used.
  • the slRNA was introduced into the cell according to the attached protocol. g atl v e C o n t r o ls ⁇ RNA (Q I AG). After introduction, the cells were observed under an inverted microscope for 5 days.
  • RNA 1 of cell line C derived from normal large intestine of the large intestine of DU S ⁇ 15 gene is as follows.
  • DU SP 15 c indicates one type of DU SP 15 RNA (c sequence of Example 3), and NC indicates no call. As shown, no NC effect was observed by phenotypic observation (05).
  • ⁇ E 6 is DUSP 15 gene due to RNA i effect. Is the proliferation or suppression of the peritoneal cell markedly suppressed? Large intestinal vesicle strain C CD 1 8 It has been found that it can be a pharmacological gene with little effect on normal cells.
  • DUS P 15 gene is an organ such as a normal tissue or not was evaluated by the North Sun-Hifuri known in the art.
  • the gene amplification degree (G / R) or more than 1 or 2 tissue according to the FISH method known in the art using the array CGH method.
  • the heftito fragment 0 1 was separated by a -Precolumn cartridge (C 5 ⁇ 300 ⁇ 300 ⁇ id ⁇ 5 mm LC PACKINGS 163589) Nano column (C18 PepMap 3 m 100 A 75 mid PACKINGS 160321).
  • the HPLC apparatus was Ultim PACKINGS.
  • the flow rate is 200nL / min. 0 1% Chinoic acid (Wak containing 2% Acetonitrile (MERCK 1287229) and 0 1% Chitol containing concentration gradient or 0 57% / min linear clone is installed. A complete MS / MS analysis was performed. 3) Analysis
  • 01 0 A ⁇ indicates the correspondence between 09 determined by MS / MS analysis and amino acid (or amino acid sequence).
  • 01 1 shows the results of BiJ assay (MTT assay) in HeLa cells using cells on day 4 after sl RN fectlon of D US P 15 gene.
  • NC Neg siRNA (Qiagen)
  • 3 types of siRNA (abc) of DUSP 15 gene shown in 0 (abc) showed 26% growth-inhibiting effect (p ⁇ 0 01 t, further time-sequentially observed differential icing images under microscope) Specifically, HeLa cells were subjected to siRNA (13,4 days after ab fuc- noon), and the results were shown in 01 2.
  • the growth rate of NC is higher than that of NC using Negative control s lRNA. (Indicated by the sign of inhibition and cell death).
  • the present invention provides a therapeutic agent for cans, a diagnostic agent, a diagnostic method, and a kinoto used for treatment. Therefore, it is useful in fields such as the present invention or acupuncture.

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Abstract

L'invention concerne un agent thérapeutique du cancer contenant un inhibiteur d'expression ou un inhibiteur d'activité de la protéine DUSP15. L'invention concerne également un procédé de criblage d'un composé pouvant servir d'ingrédient actif d'un tel agent thérapeutique; un anticorps contre la protéine DUSP15; un agent diagnostique du cancer et un procédé de diagnostic du cancer utilisant ledit anticorps et analogue.
PCT/JP2006/320043 2005-09-30 2006-09-29 Application therapeutique ou diagnostique du gene dusp15 Ceased WO2007037555A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024740A2 (fr) * 2000-09-19 2002-03-28 Ceptyr, Inc. Phosphatase dsp-15 a double specificite
JP2003517836A (ja) * 1999-12-21 2003-06-03 スージェン・インコーポレーテッド 哺乳動物蛋白質ホスファターゼ
JP2004528805A (ja) * 2000-07-28 2004-09-24 インサイト・ゲノミックス・インコーポレイテッド タンパク質ホスファターゼ

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003517836A (ja) * 1999-12-21 2003-06-03 スージェン・インコーポレーテッド 哺乳動物蛋白質ホスファターゼ
JP2004528805A (ja) * 2000-07-28 2004-09-24 インサイト・ゲノミックス・インコーポレイテッド タンパク質ホスファターゼ
WO2002024740A2 (fr) * 2000-09-19 2002-03-28 Ceptyr, Inc. Phosphatase dsp-15 a double specificite

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALONSO A. ET AL.: "VHY, a Novel Myristoylated Testis-restricted Dual Specificity Protein Phosphatase Related to VHX", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 279, no. 31, 2004, pages 32586 - 32691, XP003011092 *

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