WO2004047856A1 - Inhibiteur de metastase cancereuse - Google Patents

Inhibiteur de metastase cancereuse Download PDF

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Publication number
WO2004047856A1
WO2004047856A1 PCT/JP2003/014979 JP0314979W WO2004047856A1 WO 2004047856 A1 WO2004047856 A1 WO 2004047856A1 JP 0314979 W JP0314979 W JP 0314979W WO 2004047856 A1 WO2004047856 A1 WO 2004047856A1
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WO
WIPO (PCT)
Prior art keywords
protein
adamts
cancer metastasis
equivalent variant
homologous polypeptide
Prior art date
Application number
PCT/JP2003/014979
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Bannai
Kunitaka Hirose
Kouji Kuno
Original Assignee
Kureha Chemical Industry Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kureha Chemical Industry Co., Ltd. filed Critical Kureha Chemical Industry Co., Ltd.
Priority to AU2003284663A priority Critical patent/AU2003284663A1/en
Publication of WO2004047856A1 publication Critical patent/WO2004047856A1/fr

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    • 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)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

Definitions

  • the present invention relates to a cancer metastasis inhibitor.
  • ADAMTS-1 protein is an extracellular matrix-bound MMP, and ADAMTS-1 protein appears to be involved in the metabolism of extracellular matrix components.
  • ADAMTS-1 protein has an activity to degrade aggrecan (a g g r e a c a n), which is the main component of proteoglycan in joints.
  • Non-Patent Document 1 “The Journal of Biological Chemistry” (USA), 1 997, 272, p. 556-562
  • Non-Patent Document 2 “FEBS Letters”, (UK), 2000, 478th, ⁇ 241 -245
  • Non-patent Document 3 “Science”, (USA), 2002, Vol. 295, p. 2387-2392 Disclosure of Invention
  • ADAMTS-1 protein was transferred to the experimental lung metastasis system in mice. It was found that metastasis of the introduced cancer cells to the lung was significantly suppressed compared to the control, and ADAMTS-1 protein was found to be useful as an anti-metastatic agent for cancer.
  • the present invention is based on such knowledge.
  • An object of the present invention is to provide a novel cancer metastasis inhibitor.
  • the present invention relates to (1) ADAMTS-1 protein or functionally equivalent variant or homologous polypeptide thereof,
  • the present invention also provides: (A) (1) ADAMTS-1 protein or a functional equivalent variant or homologous polypeptide thereof,
  • composition for inhibiting cancer metastasis comprising a pharmaceutically or veterinarily acceptable carrier or diluent.
  • the present invention also provides (1) ADAMTS-1 protein, a functionally equivalent variant thereof, or a homologous polypeptide, (2) a polynucleotide encoding ADAMTS-1 protein or functionally equivalent variant or homologous polypeptide thereof, or
  • the present invention relates to a use for producing a cancer metastasis inhibitor or a pharmaceutical composition for inhibiting cancer metastasis.
  • FIG. 2 is a graph showing the results of suppression of lung metastasis of mouse ADAMTS-1 transgenic mouse Lewis lung cancer strain.
  • ADAMTS a homologous polypeptide of one protein
  • ADAMTS a recombinant vector containing a polynucleotide encoding a functionally equivalent variant of 1 protein, or
  • At least one of the active ingredients is administered in an effective amount to a subject that needs to inhibit cancer metastasis.
  • At least one of the active ingredients is used for producing a cancer metastasis inhibitor or a pharmaceutical composition for cancer metastasis inhibition.
  • AD AM TS-1 protein refers to human ADAMTS-1 protein disclosed in JP-A-11-46781 and various animals corresponding to this human A DAMTS-1 protein.
  • Protein for example, mouse ADAMTS-1 protein ( ⁇ B iol. Cem., 272, 55 6-562, 1 997). That is, it means the natural ADAMTS-1 protein of various animals including humans.
  • the human ADAMTS-1 protein is composed of 727 amino acid residues, and the amino acid sequence thereof is disclosed in the above-mentioned JP-A-11-46781.
  • the shape of the AD AM TS-1 protein or functionally equivalent variant thereof contained in the cancer metastasis inhibitor of the present invention is not particularly limited as long as the cancer metastasis inhibitory activity is maintained.
  • it can be the native ADAMTS-1 protein itself, or it can be a fusion protein of ADAMTS-1 protein or a functionally equivalent variant thereof and a fusion partner (eg, protein or peptide). You can also.
  • ADAMTS-1 protein homologous polypeptide means 70% or more homology with the amino acid sequence of native ADAMTS-1 protein (preferably 80 o / o or more, more preferably 90 ⁇ A polypeptide having an amino acid sequence of 1 ⁇ 2 or more, more preferably 95% or more, more preferably 98% or more, particularly preferably 99% or more), and having the same activity as the natural ADAMTS-1 protein. means.
  • the term “homology” refers to B LAST (Basic Ioca Ia II ngmentsearchtool; AI tschu I, S. F. et al., J. Mo, B iol., 215, 403-41 0, 1 990) means the value obtained.
  • polypeptide By obtaining a polynucleotide to be expressed, expressing the polynucleotide using an appropriate expression system, and confirming whether the expressed polypeptide has the same activity as the native ADAMTS-1 protein.
  • the desired polypeptide can be obtained.
  • the polynucleotide encoding ADAMTS-1 protein or functional equivalent variant or homologous polypeptide thereof, which can be used as an active ingredient of the cancer metastasis inhibitor of the present invention is ADAMTS-1 protein or functional equivalent variant thereof.
  • ADAMTS-1 protein or functional equivalent variant thereof is ADAMTS-1 protein or functional equivalent variant thereof.
  • it is not particularly limited as long as it can encode a homologous polypeptide, for example, a naturally occurring ADAMTS-1 gene, or an ADA MTS-1 protein or a functionally equivalent variant thereof, or And a polynucleotide chemically synthesized based on the amino acid sequence of the homologous polypeptide.
  • polynucleotide J includes both DNA and RNA.
  • oral preparations such as powders, fine granules, granulated powders, tablets, capsules, suspensions, emulsions, syrups, extracts or pills
  • parenteral preparations such as injections, external preparations, ointments, suppositories, topically applied creams, and eye drops.
  • oral preparations include, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean lecithin, sucrose, fatty acid ester, talc , Magnesium stearate, Polyethylene glycol, Magnesium silicate, Caustic anhydride, Synthetic aluminum silicate, etc.
  • Excipients Binders, Disintegrants, Surfactants, Lubricants, Fluidity promoters, Diluents, Preservation It can be produced according to a conventional method using an agent, a colorant, a fragrance, a corrigent, a stabilizer, a humectant, a preservative, or an antioxidant.
  • parenteral administration methods include injection (subcutaneous, intravenous, etc.), or rectal administration. Of these, the injection is most preferably used.
  • a water-soluble solvent such as physiological saline or Ringer's solution, vegetable oil
  • a water-insoluble solvent such as a fatty acid ester, an isotonic agent such as glucose or sodium chloride, a solubilizer, a stabilizer, a preservative, a suspending agent, or an emulsifier can be optionally used.
  • cancer metastasis inhibitor of the present invention may be administered using a method of sustained release preparation using a sustained release polymer or the like.
  • the cancer metastasis inhibitor of the present invention can be incorporated into a pellet of an ethylene vinyl acetate polymer and surgically transplanted into the tissue to be treated or prevented.
  • the cancer metastasis inhibitor of the present invention is not limited to this, but ADAMTS-1 protein or a functionally equivalent variant or homologous polypeptide thereof is 0.1 to 99% by weight, preferably 0. It can be contained in an amount of 1 to 80% by weight.
  • the dosage in the case of using the cancer metastasis inhibitor of the present invention can be appropriately determined according to, for example, the type of illness, the age, sex, weight, symptom of the patient, or administration method, and orally. Or it can be administered parenterally.
  • a polynucleotide encoding ADAMTS-1 protein, a functionally equivalent variant thereof or a homologous polypeptide is used as an active ingredient.
  • a nucleotide or a recombinant vector containing the same the polynucleotide or the recombinant vector alone, or optionally with an ordinary carrier or diluent that can be used for gene therapy, an animal, preferably Can be administered to mammals, particularly humans.
  • a method of administering a recombinant vector in which the polynucleotide is incorporated is exemplified.
  • vectors that can be used to prepare the recombinant vector include vectors that can be generally used for gene therapy, such as adenovirus vector, adeno-associated virus vector, lentivirus vector, helper. Virus vectors, vaccinia virus vectors, retrovirus vectors, and the like. By using these virus vectors, administration can be efficiently performed.
  • the administration method is not particularly limited as long as it is administered in such a way that an effective amount reaches the affected area.
  • systemic administration for example, intravenous administration, intraarterial administration, subcutaneous administration, muscle, Internal administration, or oral administration
  • local administration transmucosal administration
  • intestinal administration for example, administration methods combined with catheter techniques or surgical operations.
  • Example 2 in the experimental lung metastasis system of mice, when ADAMTS-1 gene is introduced into cultured cells derived from lung cancer, metastasis to the lung depends on the expression level of ADAMTS-1 gene. Suppressed. Considering that ADA MTS-1 protein is extracellular matrix-bound MMP, as described above in the prior art section, the expression of ADAMTS-1 gene introduced into cultured cells leads to the A DAMTS-1 protein is produced outside the cell. In Example 2, it is considered that this extracellular ADAMTS-1 protein suppressed cancer metastasis to the lung.
  • Mouse A DAM TS-1 expression vector J. B iol. C chem., 273, 1 391 2— 1 391 7, 1 998 or control vector [pc DN A 3; Invitrogen (San Diego, California, The mouse Lewis lung cancer strain in a commercially available transfection reagent [I ipofectin; I fe Techno Iogie s3 ⁇ 4 (. Aa ⁇ thersburg, Maryland, USA)].
  • L LC ATCC C RL-1 642).
  • G-418 (Lif te c h no l o g i es (G a te r s b ur g, Maryland, USA)) was added and cultured so that the final concentration was 200 ⁇ g ZmL. Three weeks later, G-418-resistant transfectant was isolated and cultured.
  • ADAMTS-1 gene is weakly expressed ⁇ Lance fuectan ⁇ L LCZ ADAMTS— 1 ZC— 1 3 and AD AMTS— 1 gene is strongly expressed L LC / ADAM TS-1ZC-1 2 and control vector-introduced transfectant LL CZVe ctor were selected and used in the following mouse lung metastasis experiments.
  • Figure 1 shows the results of Northern hybridization for the three types of selected transformants.
  • cancer metastasis inhibitor of the present invention cancer metastasis can be suppressed.
  • this invention was demonstrated along the specific aspect, the deformation

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Cell Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un inhibiteur de métastase cancéreuse contenant, en tant que principe actif, une protéine ADAMTS-1, sa modification équivalente sur la plan fonctionnel ou un homologue polypeptidique de celle-ci, un polynucléotide codant une telle protéine, sa modification équivalente sur la plan fonctionnel, un homologue polypeptidique de celle-ci, ou un vecteur de recombinaison contenant ce polynucléotide.
PCT/JP2003/014979 2002-11-25 2003-11-25 Inhibiteur de metastase cancereuse WO2004047856A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003284663A AU2003284663A1 (en) 2002-11-25 2003-11-25 Cancer metastasis inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002341207A JP2004175689A (ja) 2002-11-25 2002-11-25 癌転移抑制剤
JP2002-341207 2002-11-25

Publications (1)

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WO2004047856A1 true WO2004047856A1 (fr) 2004-06-10

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PCT/JP2003/014979 WO2004047856A1 (fr) 2002-11-25 2003-11-25 Inhibiteur de metastase cancereuse

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JP (1) JP2004175689A (fr)
AU (1) AU2003284663A1 (fr)
WO (1) WO2004047856A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071577A1 (fr) * 1999-05-25 2000-11-30 Human Genome Sciences, Inc. Polynucleotides et polypeptides meth1 et meth2
WO2001075109A2 (fr) * 2000-03-31 2001-10-11 Imclone Systems Incorporated Antagonistes d'anticorps de la ve-cadherine n'ayant pas d'effets defavorables sur la permeabilite vasculaire
WO2001088131A1 (fr) * 2000-05-19 2001-11-22 Fujichemico, Ltd. Regulation de l'activite de mt1-mmp
EP1197550A2 (fr) * 2000-08-25 2002-04-17 Pfizer Products Inc. Méthodes et compositions pour diagnostiquer et traiter des troubles associés à l'angiogenèse

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071577A1 (fr) * 1999-05-25 2000-11-30 Human Genome Sciences, Inc. Polynucleotides et polypeptides meth1 et meth2
WO2001075109A2 (fr) * 2000-03-31 2001-10-11 Imclone Systems Incorporated Antagonistes d'anticorps de la ve-cadherine n'ayant pas d'effets defavorables sur la permeabilite vasculaire
WO2001088131A1 (fr) * 2000-05-19 2001-11-22 Fujichemico, Ltd. Regulation de l'activite de mt1-mmp
EP1197550A2 (fr) * 2000-08-25 2002-04-17 Pfizer Products Inc. Méthodes et compositions pour diagnostiquer et traiter des troubles associés à l'angiogenèse

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LUQUE, A. ET AL: "ADAMTS1/METH1 Inhibits Endothelial Cell Proliferation by Direct Binding and Sequestration of VEGF165", J. BIOL. CHEM, vol. 278, no. 26, 2003, pages 23656 - 23665, XP002971183 *
MASUI, T. ET AL: "Expression of METH-1 and METH-2 in Pancreatic Cancer", CLIN. CANCER RES., vol. 7, 2001, pages 3437 - 3443, XP002976281 *
YASUNORI OKADA: "Hito Gan Saibo Shinjun. Ten'i ni okeru MMP no Bunshi Sayo Kiko", MITSUI SEIMEI KAGAKU KENKYU SHINKO ZAIDAN KENKYU HOKOKUSHU, vol. 16, 2000, pages 59 - 71, XP002976280 *

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JP2004175689A (ja) 2004-06-24
AU2003284663A1 (en) 2004-06-18

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