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WO2003074074A1 - Compositions comprenant la proteine nm23 a utiliser en tant qu'inhibiteur de la metalloproteinase matricielle et de l'angiogenese - Google Patents

Compositions comprenant la proteine nm23 a utiliser en tant qu'inhibiteur de la metalloproteinase matricielle et de l'angiogenese Download PDF

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Publication number
WO2003074074A1
WO2003074074A1 PCT/KR2003/000419 KR0300419W WO03074074A1 WO 2003074074 A1 WO2003074074 A1 WO 2003074074A1 KR 0300419 W KR0300419 W KR 0300419W WO 03074074 A1 WO03074074 A1 WO 03074074A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
angiogenesis
disease
mmp
macula
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2003/000419
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English (en)
Inventor
Min-Young Kim
Kong-Joo Lee
Eunhee Kim
Byung-Young Park
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Angiolab Inc
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Angiolab Inc
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 Angiolab Inc filed Critical Angiolab Inc
Priority to AU2003212677A priority Critical patent/AU2003212677A1/en
Publication of WO2003074074A1 publication Critical patent/WO2003074074A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)

Definitions

  • compositions comprising Nm23 protein for the use of matrix metalloproteinase inhibitor and angiogenesis inhibitor
  • the present invention relates to pharmaceutical compositions for the use of matrix metalloproteinase (MMP) inhibitor and angiogenesis inhibitor comprising Nm23 protein as an active ingredient;
  • MMP matrix metalloproteinase
  • Angiogenesis is the process of forming new capillary blood vessels from microvessels. Angiogenesis occurs only during embryonic development, wound healing and female cyclic menstruation with the corpus luteum, but not under normal conditions [Folkman and Cotran, Regulation of proliferation to tumor growth. Int.
  • a failure in the regulation of angiogenesis can lead to the following disorders: angioma; angiofibroma; blood vessel malformation; cardiovascular diseases such as arteriosclerosis, intravascular coagulation and edematous sclerosis; ophthalmological diseases such as cornea-implant angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal disorder; involutional macula, pterygium, degeneration of macula, retrolental fibroplasias and granula trachoma; chronic inflammatory diseases such as arthritis; and skin disorders such as the psoriasis, capillary extension, the pyogenic granuloma, seborrheic dermatitis and acne.
  • Angiogenesis plays very important role in growth and metastasis of cancer cells [D'Amato RJ and Adamis AP, Ophthamol 102:1261-1262, 1995; Arbiser JL, J Am. Acad. Derm. 34(3): 486-497, 1996; O'brien KD. et al. Circulation 93(4): 672-682, 1996; Hanahan D and Folkman J. Cell. 86:353-364, 1996].
  • Angiogenesis influences growth and proliferation of cancer by supplying nutrients and oxygen, and also promotes for the metastasis of cancer cells to the circulating system of the blood and thus to the other parts of the entire body through neovascularization [Polverini PJ. Critical Reviews in Oral Biology, 6(3): 230-247,
  • Abnormal angiogenesis thus underlies the origin and progression of a number of diseases.
  • Development of effective inhibitors of angiogenesis is important for the prevention and treatment of such diseases and is currently an active area of research.
  • MMPs matrix metalloproteinases
  • MMP-1, MMP-8 gelatinase
  • MMP-9 gelatinase
  • stromelysin e.g. MMP-3
  • membrane-type collagenase e.g. MMP-14.
  • Collagenase participates in bone-arthritis while gellatinase plays a role in growth and metastasis of cancer by degrading the basement membrane [Howell DS and Pelaetier JP. In Arthritis and Allied Conditions; McCarthy DJ and Koopman J. Eds; Lea and Febiger; Philadelphia, 12 th Ed. 2:1723, 1993].
  • MMPs are also involved in the development of many other diseases from overactivation of MMP, among them, re-stenosis, osteo-hypotropy, inflammatory disorders in CNS, skin diseases of aging such as wrinkles; dermatitis, rheumatoid arthritis, septicemia arthritis, corneal ulcer, abnormal wound healing, bone diseases, proteinuria, aneurysm, degenerative cartilage loss caused by traumatic articular injury, demyelinating disease in nervous system, cirrhosis of the liver, glomerular disease, embryonic membrane rupture, inflammatory bowel disease, periodontal membrane disease, age-related degeneration of macula, diabetic retinopathy, proliferated retina syndrome, premature infant's retinopathy, ophthalmia, cone cornea, Shogren's syndrome, myopia, and ophthalmo-tumor. MMPs are also involved in the rejection of corneal graft.
  • Nm23 an endogenous protein, has nucleoside diphosphate kinase (NDPK) activity [Biggs et al., A Drosphilia gene that is homologous to a mammalian gene associated with tumor metastasis codes for a nucleoside diphospahte kinase. Cell, 63:933-940, 1990]. Also, Nm23 has been shown to serve as a transcriptional factor, and cell differentiation inhibitor [Postel et al, Human c-myc transcription factor PuF identified as Nm23-H2 nucleoside diphosphate kinase, a candidate suprpressor of tumor metastasis. Science.
  • This inhibitory activity is shared by both the acidic Nm23-Hl isoform and the basic Nm23-H2 isoform in human, and both types were shown to inhibit cell invasion and metastasis [Rosengard et al: Reduced Nm23/Awd protein in tumor metastasis and aberrant Drosphilia development. Nature, 342:177-180, 1989; Charpin et al: Automated and quantitative immunocytochemical assays of Nm23/NDPK protein in breast carcinomas, Int. J. Cancer, 74:416-420, 1997].
  • Nm23 has not well understood, though its activities and effects as described above have been shown. Therefore, this protein has a limit in application and there is a need for clarifying the working mechanism of Nm23 so as to provide applicability in various diseases. Also, there is a great need for development of a drug effective in the prevention and treatment of many diseases induced by overexpression of MMP and abnormal angiogenesis.
  • the present inventors have studied the relationship between NM23 and the activity of MMP and angiogenesis to provide an effective composition for prevention and treatment of many diseases induced by overexpression of MMP and abnormal angiogenesis.
  • compositions comprising Nm23 as an active ingredient for inhibiting the matrix metalloproteinase (MMP) activity and angiogenesis.
  • MMP matrix metalloproteinase
  • angiogenesis-related diseases such as angioma, angiofibroma, diabetic retinopathy, premature infant's retinopathy, neovascular glaucoma, angiogenesis-related corneal disorder
  • involutional macula, pterygium degeneration of macula, retrolental fibroplasias,
  • Nm23 protein used herein includes all proteins containing amino acids encoded by the human Nm23 genes (US PAT. NO. 6,329,198), and derivatives and fragments thereof and showing the same functions.
  • the Nm23 protein used herein includes Nrn23 proteins encoded by the human Nm23-Hl genes and the human Nm23-H2 genes, and derivatives and fragments thereof and showing the same functions.
  • the Nm23 protein used herein applies to all forms of Nm23 protein whether obtained from natural sources or artificially prepared using a peptide synthesizer or by a genetic engineering.
  • the Nm23 protein used herein may be mass-produced by E. coli.
  • the product is preferably purified by ATP-sepharose column chromatography.
  • the present invention covers all compositions comprising proteins showing the same functions as human Nm23 protein, and derivatives and fragments thereof as an active ingredient alone.
  • the present invention covers all compositions comprising proteins showing the same functions as human Nm23 protein, and derivatives and fragments thereof as an active ingredient in combination with another active ingredient.
  • compositions comprising Nm23 according to the present invention may include at least one other pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier suitable for liquid formulation may include saline, sterile water, Ringer's solution, buffered saline, dextrose solution, malto dextrin solution, glycerol, ethanol or a mixture of one or more these and may be combined with other common additives, including, for example, anti-oxidants, a buffer solution, bacteriostatic agents and the like, as needed.
  • the active agent may be formulated as an i ⁇ jectible form (aqueous solution, suspension, emulsion and the like), a pill, a capsule, granule or tablet, by adding a diluting agent, a dispersing agent, a surfactant, a binder or a lubricant. Further, it may be variably formulated according to the diseases to be treated or prevented, by appropriate methods described in Remington's Pharmaceutical Science, Mack Publishing Company,
  • the formulation resulting from this invention may be administered by the intravenous (IV), intraperitoneal (IP), intramuscular (IM), intraarterial (IA), transdermal, intranasal, inspiration, focal, rectal, oral, intraocular or intradermal routes.
  • parenteral administration includes the intraveneous, intramuscular, intraperitoneal, intrastemal, transdermal and intraarterial injection and infusion.
  • An effective dose is preferably 0.05mg to 2g per a day, which may be administered all at once or in several smaller doses depending, among others, on the type of the disease to be treated or prevented, the types and contents of an active ingredient and the other ingredients contained in the formulation, the route, and duration of administration, the age, body weight, general health condition, sex and diet of the patient, duration of the treatment, co-treatment drug (for example, chemotherapeutics) .
  • composition described in the present invention has been confirmed to strongly inhibit MMP activity in a spectrofluorometric MMPinhibition assay.
  • composition described in the present invention has been confirmed to strongly inhibit angiogenesis in endothelial cells in a tube formation assay using a gelled Matrigel and an animal test using a mouse Matrigel model.
  • Fig. 1 Inhibition of MMP activity by Nm23-Hl and Nm23-H2;
  • Fig. 2 Tube formation in the HUNEC (Human umbilical vein endothelial cell);
  • Fig. 3 Inhibitory effect of ⁇ m23-Hl on the tube formation in endothelial cells on Matrigel;
  • Fig. 4 Inhibitory effect of Nm23-H2 on the tube formation in endothelial cells on Matrigel
  • Fig. 5 Inhibitory effect of Nm23-Hl and Nm23-H2 on angiogenesis in a mouse Matrigel model.
  • Nm23-Hl and Nm23-H2 were recombinant proteins which were prepared following their over-expression in E. coli, and purification to at least 99% purity by
  • MMPs were prepared from insect cells using the Baculo virus system by the genetic engineering technique.
  • Substrates for MMPs are as follows; 2,4-dinitrophenyl-Pro-Leu-Ala-Leu- T ⁇ -Ala-Arg (Calbiochem, San Diego, CA, No.444211) as substrate for MMP-1 ; 2,4- dinitrophenyl-Pro-Leu-Gly-Met-T ⁇ -Ser-Arg (Calbiochem, San Diego, CA, No.
  • Tyr-Trp-Met-Arg (Calbiochem, San Diego, CA, No.444220) as substrate for MMP-3.
  • Example 2 Inhibitory Effect of Nm23 on angiogenesis in vitro.
  • HUNEC Human umbilical vein endothelial cells
  • FIG. 2 shows the reticular tube formation by the HUVE cells cultured on
  • Matrigel which appeared as a stage of the angiogenesis.
  • Fig. 3 shows that reticular tube formation is interrupted in HUNE cells cultured on Matrigel, after treatment with ⁇ m23-Hl at a concentration of 125 ⁇ gM.
  • Fig. 4 shows that reticular tube formation is interrupted in the HUNE cells cultured on Matrigel, after treatment with ⁇ m23-H2 at a concentration of 125 g/m .
  • Example 3 Inhibitory Effect of Nm23 on angiogenesis in vivo.
  • compositions described in this invention comprising Nm23 as the active ingredient have inhibitory effect on MMP activity and hence have potential therapeutic use in the prevention and treatment of various conditions and diseases resulting from overexpression of MMP.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques comprenant Nm23 en tant que principe actif pour inhiber l'activité de la métalloprotéinase matricielle (MMP) et l'angiogenèse. Les préparations pharmaceutiques comprenant Nm23 peuvent être utilisées comme médicament pour la prévention et le traitement d'une grande variété de maladies médiées par la suractivité de MMP et/ou l'angiogenèse anormale.
PCT/KR2003/000419 2002-03-05 2003-03-05 Compositions comprenant la proteine nm23 a utiliser en tant qu'inhibiteur de la metalloproteinase matricielle et de l'angiogenese Ceased WO2003074074A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003212677A AU2003212677A1 (en) 2002-03-05 2003-03-05 COMPOSITIONS COMPRISING Nm23 PROTEIN FOR THE USE OF MATRIX METALLOPROTEINASE INHIBITOR AND ANGIOGENESIS INHIBITOR

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2002-0011500 2002-03-05
KR10-2002-0011500A KR100450578B1 (ko) 2002-03-05 2002-03-05 엔엠23 단백질을 유효성분으로 하는, 매트릭스메탈로프로테아제 활성 억제 및 혈관신생 억제용 조성물

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WO2003074074A1 true WO2003074074A1 (fr) 2003-09-12

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AU (1) AU2003212677A1 (fr)
WO (1) WO2003074074A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8535944B2 (en) 2009-06-11 2013-09-17 Minerva Biotechnologies Corporation Culturing embryonic stem cells, embryonic stem-like cells, or induced pluripotent stem cells with a Muc1 or Muc1* ligand
US8802434B2 (en) * 2003-12-05 2014-08-12 The University Of Birmingham Biological cell culture, cell culture media and therapeutic use of biological cells
US8859495B2 (en) 2005-03-30 2014-10-14 Minerva Biotechnologies Corporation Methods for stimulating or enhancing proliferation of non-tumorous cells expressing MUC1 receptors
US10703821B2 (en) 2005-03-30 2020-07-07 Minerva Biotechnologies Corporation Method for stimulating or enhancing proliferation of cells by activating the mucin 1 (MUC1) receptor
US11898160B2 (en) 2008-10-09 2024-02-13 Minerva Biotechnologies Corporation Method for maintaining pluripotency in cells
US12049618B2 (en) 2011-03-17 2024-07-30 Minerva Biotechnologies Corporation Method for making pluripotent stem cells

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GRYCZYNSKI ET AL.: "Evaluation of CD44 adhesion molecule, nm23 gene product expression and intensity of angiogenesis in patients with laryngeal cancer", OTOLARYNGOL. POL., vol. 54, no. 6, 2000, pages 669 - 674 *
LI ET AL.: "Angiogenesis and the expression of nm23-H(1) tumor metastatic suppressor gene in primary breast carcinoma and their relations to lymph node metastasis", ZHONG HUA WAI KE ZA ZHI, vol. 40, no. 3, March 2002 (2002-03-01), pages 177 - 179 *
MOUSA: "Angiogenesis inhibitors and stimulators: potential therapeutic implications", TEXAS, USA, 2000, pages 124 - 133 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802434B2 (en) * 2003-12-05 2014-08-12 The University Of Birmingham Biological cell culture, cell culture media and therapeutic use of biological cells
US8859495B2 (en) 2005-03-30 2014-10-14 Minerva Biotechnologies Corporation Methods for stimulating or enhancing proliferation of non-tumorous cells expressing MUC1 receptors
US10703821B2 (en) 2005-03-30 2020-07-07 Minerva Biotechnologies Corporation Method for stimulating or enhancing proliferation of cells by activating the mucin 1 (MUC1) receptor
US11898160B2 (en) 2008-10-09 2024-02-13 Minerva Biotechnologies Corporation Method for maintaining pluripotency in cells
US8535944B2 (en) 2009-06-11 2013-09-17 Minerva Biotechnologies Corporation Culturing embryonic stem cells, embryonic stem-like cells, or induced pluripotent stem cells with a Muc1 or Muc1* ligand
US12049618B2 (en) 2011-03-17 2024-07-30 Minerva Biotechnologies Corporation Method for making pluripotent stem cells
US12195728B2 (en) 2011-03-17 2025-01-14 Minerva Biotechnologies Corporation Method for making pluripotent stem cells

Also Published As

Publication number Publication date
KR20030071993A (ko) 2003-09-13
AU2003212677A1 (en) 2003-09-16
KR100450578B1 (ko) 2004-09-30

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