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WO1994004175A1 - Promoteur de la production du facteur de croissance des hepatocytes - Google Patents

Promoteur de la production du facteur de croissance des hepatocytes Download PDF

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Publication number
WO1994004175A1
WO1994004175A1 PCT/JP1993/001177 JP9301177W WO9404175A1 WO 1994004175 A1 WO1994004175 A1 WO 1994004175A1 JP 9301177 W JP9301177 W JP 9301177W WO 9404175 A1 WO9404175 A1 WO 9404175A1
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WO
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Prior art keywords
disease
hgf
prostaglandin
heparin
interleukin
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Ceased
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PCT/JP1993/001177
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English (en)
Japanese (ja)
Inventor
Toshikazu Nakamura
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1

Definitions

  • the present invention relates to an agent for promoting HGF (Hepatoc to Growth Factor, hepatocyte growth factor) production, and more particularly to a substance that promotes HGF production of HGF-producing cells.
  • HGF Hepatoc to Growth Factor, hepatocyte growth factor
  • HGF is a protein that the present inventors have found in regenerated liver rat serum as a factor for growing mature hepatocytes in vitro (Biochem Biophys Res Commun, 122, 1450, 1984). The present inventors have further succeeded in isolating HGF from rat platelets (Proc. Natl. Acad. Sci, 83, 6489, 1986, FFBS Letter, 22, 311, 1987), and identified the amino acid sequence of the same. Department decided. Furthermore, the present inventors performed human and rat-derived HGF cDNA cloning based on the elucidated HGF amino acid sequence, and recombined the cDNA into animal tissues to proliferate hepatocyte cells. The factor was successfully obtained as a protein (human HGF: Nature, 342, 440, 1989; rat HGF: Proc. Natl. Acad. Sci, 87, 3200, 1990).
  • HGF The molecular weight of HGF is 82-85 kD by SDS-polyacrylamide gel electrophoresis.
  • Rat HGF molecules have a heterodimer structure in which an ⁇ chain consisting of 463 amino acid residues and a 9 chain consisting of 233 amino acid residues are bridged by a single disulfide bond. Each chain has two darcosamine-type sugar chain binding sites.
  • Human HGF also has almost the same physiological activity. It consists of an ⁇ -chain consisting of 463 amino acid residues and a / chain consisting of 234 amino acid residues.
  • the ⁇ chain has four kringle structures similar to the fibrinolytic enzyme plasmin, and the amino acid sequence of the ⁇ chain is approximately 37% homologous to the ⁇ chain of plasmin, which has serine mouth opening activity. Having. The homology of the amino acid sequences of rat HGF and human HGF was 91.6%, Has a very high homology of 88.9%, and their activities are completely compatible.
  • HGF which was discovered as a factor that specifically proliferates hepatocytes, has been shown to show various activities in vivo based on recent research results by the present inventors and other researchers. Expectations are growing for its application not only as a drug but also as a therapeutic agent for humans and animals.
  • HGF acts not only on hepatocytes but also on epithelial cells as a growth factor, and have achieved several inventions.
  • HGF promotes the proliferation of renal proximal tubule cells, and thus aims to develop its application as a therapeutic agent for renal diseases.
  • HGF promotes the growth of normal epithelial cells such as melanocytes and keratinocytes, and is being developed as an epithelial cell promoting agent for the treatment of wounds, skin ulcers, and hair root cell proliferating agents. Fulfilled and disclosed the details.
  • HGF is more suitable for practical use because it does not have the canceration effect and cancer cell proliferation activity found in many other growth factors such as EGF.
  • EGF epidermal growth factor
  • the present inventors have disclosed in Japanese Patent Application No. 3-140812, cancer cells such as Hep G2 cell line derived from human liver cancer of HGF and IM9 cell line derived from lymphoblastoid cancer. Utilizing its growth inhibitory activity, it disclosed that it can be used as an anticancer agent.
  • HGF is useful as a side effect inhibitor for cancer therapy, which can reduce the damage to normal cells and tissues in cancer treatment and reduce or prevent side effects. It is disclosed that there is.
  • HGF is useful for the prevention and treatment of chronic and acute lung diseases such as pneumonia, emphysema, chronic obstructive pulmonary disease, pneumoconiosis, and swallowing pneumonia in Japanese Patent Application No. 4-298053. Is disclosed.
  • HGF may be an entity of a neural inducing factor that contributes to the developmental stage of the central nervous system, and that it is useful for central diseases and useful for eye diseases, that is, Its usefulness in tongue has been clarified.
  • HGF is involved in the formation of osteoclasts, it inhibits osteoclast resorption, promotes osteoblast formation, and is useful for bone diseases, and it promotes osteoarthritis through the promotion of proteogliin synthesis.
  • the usefulness of HGF as a drug has been clarified, and the potential of HGF as a drug is not only liver disease, but also kidney disease, skin disease, blood disease, eye disease, lung disease, stomach, duodenal disease, It is becoming clear that the disease is diverse, such as cancer and related diseases and bone diseases.
  • HGF histoneum growth factor
  • HGF-producing cells are not epithelial cells themselves, but mainly mesenchymal cells such as K upffer cells and sinusoidal vascular endothelial cells in the liver, capillary endothelial cells in the kidney, and alveolar macrophage vascular endothelial cells in the lung. It has been elucidated that it is produced by cells, and it has been clarified that the so-called paracrine mechanism, in which HGF is supplied from neighboring cells as needed, has been established.
  • HGF is supplied by the so-called endocrine mechanism: That is, substances that promote HGF production are secreted from the injured tissue. It is thought to reach the HGF-producing cells via blood and release HGF stored in the cells, or to initiate new production.
  • HGF is administered for the purpose of wound healing and renal regeneration, but if a substance that promotes HGF production is administered, the same effect is expected to be obtained with a smaller dose and the number of administrations.
  • administration of the HGF production promoting substance can maintain the blood concentration of HGF for a longer period of time. It is expected that the dose and frequency of administration can be reduced.
  • the substance that promotes HGF production has transdermal absorbability, it becomes possible to obtain a preparation that promotes HGF production by transdermal absorption. As formulation and use become easier, application can be expected to expand.
  • the HGF production promoting factor is useful not only for studying the function of compensating for organ damage such as liver and kidney and for studying the mechanism of HGF expression, but also for healing tissue and organ damage of living organisms having HGF receptor. However, it is clear that it is very useful as a therapeutic drug.
  • HGF production promoting factors that control the entire repair function of organ injury, not only parenchymal cells but also non-parenchymal cells, such as supporting tissues such as peri-sinusoidal connective tissue, can be regenerated throughout Will be accelerated and true restoration will be promoted.
  • the HGF production promoting factor can be used as a therapeutic agent, the injury will be treated much more mildly and promptly than the conventional use of various cell growth factors alone. And its usefulness is immense.
  • an object of the present invention is to provide a therapeutic agent for various diseases as described above by having an HGF production promoting action. Disclosure of the invention
  • the present invention relates to interleukin-1 ⁇ , interleukin-1 / 9, heparin or a derivative thereof, heparan sulfate, prostaglandin II , prostaglandin II 2 , prostaglandin I2, and these prostaglandins. And a prostaglandin or an inclusion compound of these derivatives as an active ingredient. Two or more of these active ingredients may be used in combination.
  • Another invention is a method for treating liver disease or the like, which comprises administering an effective amount of the above compound to a human.
  • FIG. 1 is a diagram showing the relationship between the concentration of interleukin-1 ⁇ and interleukin-11 ⁇ and the amount of HGF production in Example 1.
  • Hata indicates interleukin-1 ⁇ and ⁇ indicates Interleukin-1 1 S is shown.
  • FIG. 2 is a graph showing the relationship between heparin concentration and HGF production in Example 2.
  • FIG. 3 is a graph showing the relationship between prostaglandin (hereinafter referred to as PG) concentration and HGF production amount in Example 3.
  • PG prostaglandin
  • FIG. 4 is a diagram showing the relationship between the culture time and the amount of HGF production in Example 5.
  • Qin the presence of P GE 2, ⁇ indicates a control.
  • FIG. 5 is a graph showing a time-dependent change in LI (labeling index) when lmgZkg of heparin was administered to a rat in Example 6.
  • ⁇ indicates a system to which heparin was administered
  • ⁇ indicates a control.
  • FIG. 6 is a graph showing the change over time in blood HGF concentration when 1 mg / kg of heparin was administered to a rat in Example 6.
  • ⁇ indicates the system to which heparin was administered, and ⁇ indicates the control.
  • Interleukin-1a and interleukin-11 are known substances, which are the active ingredients of the HGF production promoter of the present invention, are isolated from mammalian tissues and the like according to a conventional method. Any of the above-mentioned substances may be used, such as those prepared by genetic engineering means, etc. Further, the above-mentioned substances may be substances in which a part of the amino acid sequence has been deleted or substituted with other amino acids, or other amino acid sequences. , A substance in which one or more amino acids are bound to the N-terminus and Z- or C-terminus, a substance in which a sugar chain is added, substituted or deleted, etc.
  • Heparin and heparan sulfate are also known substances, and those isolated from mammalian tissues or the like according to a conventional method can be used.
  • Heparin derivatives include low-molecular-weight heparin (average molecular weight of about 440,600) obtained by chemical treatment of heparin, and functional groups of heparin (for example, hydroxyl group). , Carboxyl group, etc.) and a chemical treatment (eg, acylation, alkylation, esterification, amidation, etc.) into which a substituent is introduced.
  • a salt thereof (e.g., alkali metal salts) may be in the form of £
  • the active ingredient of the present invention, PGE,? ⁇ 5 2 and ⁇ 1 2 is the substance of the publicly known, for example, can be used commercially.
  • the derivatives of these PGs include compounds that have been subjected to various chemical modifications in order to improve stability, enhance action, etc., and are PGs and derivatives thereof having a carboxyl group. In the case of a compound, it may be in the form of a pharmaceutically acceptable salt.
  • inclusion compounds of the above PGs and derivatives thereof include inclusion compounds of these compounds with ⁇ -cyclodextrin, ⁇ -cyclodextrin and the like.
  • Examples of the above PG derivatives and clathrate compounds include, for example,
  • the accelerator of the present invention can take various formulation forms (for example, liquids, solids, capsules, etc.), and generally, the active ingredients interleukin-1 ⁇ , interleukin-1 ⁇ , heparin or heparin Only one or two or more components selected from the group consisting of derivatives thereof, heparan sulfate, PGE PGE 2 PGI 2 , derivatives of these PGs, and clathrates of these PGs or derivatives thereof, or They are used as injections with conventional carriers, or as external drugs with conventional carriers.
  • the injection can be prepared by a conventional method.
  • the above active ingredient is dissolved in an appropriate solvent (eg, sterile water, buffer solution, physiological saline, etc.), and then filtered through a filter or the like. And then filled in a sterile container.
  • an appropriate solvent eg, sterile water, buffer solution, physiological saline, etc.
  • the content of the active ingredient in the injection is appropriately adjusted.
  • external preparations for example, they are formulated into ointments, gels, liquids, etc., and the active ingredient content in the preparations should be adjusted as appropriate according to the disease, site of application, etc. But it can.
  • a stabilizer is preferably added, and examples of the stabilizer include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like. Further, it may contain additives necessary for preparation, for example, excipients, solubilizers, antioxidants, soothing agents, tonicity agents and the like.
  • a liquid preparation it is desirable to store it after freezing or freezing it by lyophilization. The freeze-dried preparation is used after reconstitution by adding distilled water for injection at the time of use.
  • the accelerator of the present invention can be administered by an appropriate administration route depending on the form of the preparation.
  • it can be administered in the form of injection, intravenously, arterial, subcutaneously, intramuscularly and the like.
  • the dose is appropriately adjusted according to the patient's condition, age, weight, and the like.
  • the HGF production promoter of the present invention is, for example, a therapeutic agent for liver disease, a therapeutic agent for renal disease, or a therapeutic agent for wound as described above.
  • liver disease eg, hepatitis, cirrhosis, liver failure
  • renal disease eg, glomerulonephritis, renal failure, renal anemia, diabetic nephropathy, renal injury after drug administration, etc.
  • skin disease eg, vitiligo disease, burn
  • Floor rub skin ulcer, baldness, etc.
  • blood disease eg, thrombocytopenia, bone marrow transplant, etc.
  • eye disease eg, corneal ulcer, etc.
  • lung disease eg, corneal ulcer, etc.
  • pulmonary tuberculosis chronic obstructive pulmonary disease, pneumoconiosis, pulmonary fibrosis, etc.
  • gastroduodenal diseases e.g., gastritis, gastric ulcer, duodenal ulcer, etc.
  • cancer diseases and related diseases e.g., various cancers, Side effects from cancer therapy, such as prevention of hepatotoxicity, nephrotoxicity, nausea, vomiting, thrombocytopenia, hair loss, etc., bone diseases (eg, osteoporosis, osteodysplasia, osteoarthritis, etc.), central diseases (eg, It is useful for prevention and treatment of diseases such as neuropathy.
  • Industrial applicability e.g., pneumonia, emphysema, pulmonary tuberculosis, chronic obstructive pulmonary disease, pneumoconiosis, pulmonary fibrosis, etc.
  • gastroduodenal diseases e.g., gastritis, gastric ulcer,
  • HGF production can be promoted, Can promote the healing of injuries of tissues and organs, such as liver disease, kidney disease, skin disease, blood disease, eye disease, lung disease, gastroduodenal disease, cancer And its related diseases, bone diseases, central diseases and the like.
  • tissues and organs such as liver disease, kidney disease, skin disease, blood disease, eye disease, lung disease, gastroduodenal disease, cancer And its related diseases, bone diseases, central diseases and the like.
  • Human skin fibroblasts were seeded on a 24-well plate at a density of 5 ⁇ 10 4 cells / cm 2 and cultured for 24 hours. The medium was replaced with fresh DMEM (Dulbecco, modified Eagle's medium) supplemented with 1% fetal calf serum (FCS), and then interleukin-1 ⁇ or interleukin-1 ⁇ was added. Cultured for hours. The HGF produced by the culture was measured by an enzyme immunoassay using a perforated anti-human HGF polyclonal antibody according to a conventional method.
  • Figure 1 shows the results.
  • ⁇ indicates interleukin-1 1
  • ⁇ indicates interleukin-1 1 ⁇ .
  • FIG. 1 it was found that both interleukin-11 ⁇ and interleukin-11 ⁇ significantly promote HGF production even at low concentrations.
  • MRC-5 human embryonic lung fibroblasts were seeded on a 24-well plate at a density of 5 ⁇ 10 4 cells / cm 2 and cultured for 24 hours. After the medium was replaced with fresh DMEM supplemented with 1% FCS, heparin dissolved in phosphate buffer was added, and the cells were cultured for 24 hours. HGF produced by the culture was measured by an enzyme immunoassay using a rabbit heron anti-human HGF polyclonal antibody according to a standard method. Figure 2 shows the results. As shown in FIG. 2, heparin was found to significantly promote HGF production even at low concentrations.
  • Human skin fibroblasts were seeded on a 24-well plate at 5 ⁇ 10 4 cells / cm 2 and cultured for 24 hours.
  • the medium was replaced with 1% FCS new Korea was added DMEM, 1 0- 12 1 0- 6 M PG such (i.e., is a P GE, derivatives or inclusion compound of P GE 2 and PEI 2 0P2507 and ONO41483) were added and cultured for 24 hours.
  • the HGF produced by the culture was measured by an enzyme immunoassay using an anti-human rabbit HGF polyclonal antibody according to a conventional method.
  • FIG. 3 shows the results.
  • PGE P indicates PGE 2 port ⁇ ⁇ 2507 ⁇ indicates ON041483 respectively.
  • P GE, P GE 2 OP 2 5 07 and ⁇ _NO 4 1 4 8 3 are all 1 0- S HGF production promoting action from M was observed, with 1 0- 6 M Showed maximum promotion. Promoting production at this time, 3 0.6 times P GE 1 as compared to the control, 6.7-fold with PGE 2, 0 2 5 07 7 5.4 times, 0 N 04 1 4 8 3 2 It was 0.7 times.
  • Human skin fibroblasts and MRC-5 cells were seeded at 5 ⁇ 10 4 cells Z cm 2 on 24-well plates and cultured for 24 hours.
  • the medium was replaced with 1% FC S Fresh was added pressure of DMEM, PG such 1 0- 6 M a (PGE, PGE 2 0 2 5 07 and Rei_1 ⁇ 7 04 1 4 8 3) was added
  • the cells were cultured for 24 hours.
  • the HGF produced by the culture was measured by an enzyme immunoassay using a perforated anti-human HGF polyclonal antibody according to a conventional method. The results are shown in Table 1.
  • Human skin fibroblasts were seeded on a 24-well plate at 5 ⁇ 10 4 cells / cm 2 and cultured for 24 hours.
  • the medium after replaced with fresh DME M supplemented with 1% FCS, the presence or absence of PGE 2 in 1 0- 6 M (Control port Lumpur), 3, 6, 9, 1 2 and Cultured for 24 hours.
  • HGF produced in the culture system was measured by an enzyme immunoassay using a rabbit heron anti-human HGF polyclonal antibody according to a conventional method.
  • Figure 4 shows the results. In the figure, - is the presence of PGE 2, ⁇ is shows the control.
  • a part of the liver fixed with 70% ethanol was embedded in paraffin, and immunohistochemically stained with an anti-BrdU monoclonal antibody according to a conventional method. After staining, a photograph was taken in a 100-fold visual field, the ratio (%) of the number of stained cells in four randomly selected visual fields was determined, and the average was defined as a labeling index (hereinafter referred to as LI).
  • LI labeling index
  • Plasma was prepared from whole blood collected at the time of sacrifice and stored at 4 ° C.
  • the plasma was partially purified on a heparin-Sepharose column according to the procedure described below, and the HGF concentration was measured by an enzyme immunoassay using a polyclonal alfa ⁇ -rat HGF antibody.
  • Table 2 shows the relationship between the heparin dose and LI 24 hours later.
  • Figure 6 shows the time course of blood HGF concentration when heparin was administered at 1 mg / kg. As shown in FIG. 6, the control showed a peak after 12 hours, and then gradually decreased. In contrast, when heparin was administered, a significant increase in blood HGF concentration was similarly observed after 12 hours, and an increase in blood HGF concentration was also observed after 48 hours. The increase in blood HGF concentration is observed after administration of c . The two peaks are presumed to be due to the increase in blood HGF concentration due to different mechanisms of action (t) Example 7
  • Example 6 A test similar to that of Example 6 was performed using low-molecular-weight heparin [Fragmin IV (trade name), average relative molecular weight of about 5,000] instead of heparin.
  • Table 3 shows the LI values 24 hours and 36 hours after administration of lmgZkg of palin to the low molecule.
  • Example 6 A test similar to that of Example 6 was performed using PGs ( ⁇ P—2507, PGE,) instead of heparin.
  • the dosing method was subcutaneous administration to the back, PGs were administered immediately after hepatectomy and 12 hours later, and sacrificed 24 hours later.
  • Table 4 shows the LI value and the blood HGF concentration after 24 hours when PGs were administered at 100 g / kg or SOgZkg.

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Abstract

Promoteur de la production du facteur de croissance des hépatocytes, présentant une activité favorisant la guérison de blessures de tissus et d'organes d'organismes vivants. Ledit promoteur contient, comme ingrédient actif, au moins un élément choisi dans le groupe comprenant l'interleukine 1α, l'interleukine 1β, l'héparine et des dérivés de celle-ci (tels que l'héparine de faible masse moléculaire), l'héparane-sulfate, la prostaglandine E1, la prostaglandine E2, la prostaglandine I2, des dérivés des prostaglandines, et des clathrates des prostaglandines ainsi que des dérivés de ceux-ci. Ce promoteur est utile pour soigner des blessures ou de lésions grâce au fait qu'il stimule la production du facteur de croissance des hépatocytes dans les cellules produisant ledit facteur.
PCT/JP1993/001177 1992-08-24 1993-08-23 Promoteur de la production du facteur de croissance des hepatocytes Ceased WO1994004175A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP4/248736 1992-08-24
JP24873692 1992-08-24
JP35509492 1992-12-16
JP4/355094 1992-12-16
JP5/67509 1993-03-02
JP6750993 1993-03-02

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WO1994004175A1 true WO1994004175A1 (fr) 1994-03-03

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654404A (en) * 1992-09-16 1997-08-05 Genentech, Inc. Protection against liver damage by HGF
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03285693A (ja) * 1990-04-03 1991-12-16 Mitsubishi Kasei Corp ヒト肝実質細胞増殖因子の生産方法および該因子を産生する形質転換体
JPH0436189A (ja) * 1990-05-30 1992-02-06 Otsuka Pharmaceut Co Ltd 肝細胞増殖因子の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03285693A (ja) * 1990-04-03 1991-12-16 Mitsubishi Kasei Corp ヒト肝実質細胞増殖因子の生産方法および該因子を産生する形質転換体
JPH0436189A (ja) * 1990-05-30 1992-02-06 Otsuka Pharmaceut Co Ltd 肝細胞増殖因子の製造方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654404A (en) * 1992-09-16 1997-08-05 Genentech, Inc. Protection against liver damage by HGF
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment

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