WO2005060997A2 - Medicament comprising inhibitors of long pentraxin ptx3 - Google Patents

Medicament comprising inhibitors of long pentraxin ptx3 Download PDF

Info

Publication number
WO2005060997A2
WO2005060997A2 PCT/IT2004/000714 IT2004000714W WO2005060997A2 WO 2005060997 A2 WO2005060997 A2 WO 2005060997A2 IT 2004000714 W IT2004000714 W IT 2004000714W WO 2005060997 A2 WO2005060997 A2 WO 2005060997A2
Authority
WO
WIPO (PCT)
Prior art keywords
arthritis
ptx3
use according
bone
autoimmune
Prior art date
Application number
PCT/IT2004/000714
Other languages
French (fr)
Other versions
WO2005060997A3 (en
Inventor
Barbara Bottazzi
Paolo Carminati
Cecilia Garlanda
Alberto Mantovani
Original Assignee
Defiante Farmaceutica Lda.
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 Defiante Farmaceutica Lda. filed Critical Defiante Farmaceutica Lda.
Priority to EP04806879A priority Critical patent/EP1706144A2/en
Priority to BRPI0418017-8A priority patent/BRPI0418017A/en
Priority to US10/584,292 priority patent/US20070098722A1/en
Priority to CA002548452A priority patent/CA2548452A1/en
Priority to AU2004305341A priority patent/AU2004305341A1/en
Priority to JP2006546487A priority patent/JP2007517021A/en
Priority to MXPA06007080A priority patent/MXPA06007080A/en
Publication of WO2005060997A2 publication Critical patent/WO2005060997A2/en
Publication of WO2005060997A3 publication Critical patent/WO2005060997A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • C07K14/4737—C-reactive protein
    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • Medicament comprising inhibitors of long pentraxin PTX3
  • the invention described herein relates to the use of inhibitors of long pentraxin PTX3 for the preparation of a medicament for the treatment of autoimmune diseases and of degenerative diseases of bone and cartilage.
  • PTX3 is a glycoprotein capable of organising itself spontaneously in a homodecameric structure held together by disulphide bridges, which is expressed in various cell types (Bottazzi, et al., J. Biol. Chem., 1997; 272: 32817-32823), particularly in mononuclear phagocytes and endothelial cells after exposure to the inflammatory cytokines Interleukin lbeta (IL-lbeta) and Tumor Necrosis Factor alpha (TNF- alpha).
  • IL-lbeta Interleukin lbeta
  • TNF- alpha Tumor Necrosis Factor alpha
  • PTX3 consists of two structural domains, an N-terminal unrelated to any known molecule, and a C-terminal similar to the short pentraxins such as C-reactive protein (CRP).
  • CRP C-reactive protein
  • Both recombinant PTX3 and PTX3 expressed by primary cells are organised mainly in a decameric structure stabilised by disulphide bridges.
  • the single monomer of PTX3 has a molecular weight of approximately 45 kDa which can be obtained from the decameric protein through reduction of disulphide bridges and subsequent alkylation of the reduced cysteines involved in the inter-monomer interaction or through site-specific mutagenesis of the same ( Bottazzi, et al., J. Biol. Chem., 1997; 272: 32817-32823).
  • WO 03/086380 describes the use of an inhibitor of PTX3 gene expression for the treatment of autoimmune diseases, including rheumatoid arthritis.
  • WO 03/086380 differs from the present invention in that it envisages the use both of completely different compounds and of a completely different inhibition method compared to the compounds and inhibition method described in the present invention.
  • PTX3 antagonists are described that are capable of directly inhibiting the biological activity of the protein (PTX3).
  • inhibitors or antagonists of PTX3 can be used to prevent and treat autoimmune diseases and degenerative diseases of bone and cartilage.
  • PTX3 inhibitors according to the present invention are monoclonal or polyclonal anti-PXT3 antibodies, while a non-limiting example of PTX3 antagonists according to the present invention are monomeric PTX3 or its peptide or peptidomimetic derivatives.
  • the object of the present invention is therefore the use of inhibitors or antagonists of long pentraxin PTX3, which are capable of impeding the biological activity of long pentraxin PTX3, as agents useful for the preparation of a medicament for the treatment of autoimmune diseases selected from the group consisting of: systemic lupus erythematosus (SLE), multiple sclerosis (MS), arthritis, diabetes, thyroiditis, haemolytic anaemia, atrophic orchitis, Goodpasture's disease, autoimmune retinopathy, autoimmune thrombocytopenia, myasthenia gravis, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, dermatitis, chronic glomerulonephritis, Sj ⁇ gren's syndrome, Reiter's syndrome, myositis, systemic sclerosis and polyarthritis; and of degenerative bone and cartilage diseases selected from the group consisting of: osteoarthritis; osteoarthrosis; degenerative diseases of
  • inhibitors of long pentraxin PTX3 is any monoclonal or polyclonal antibody, irrespective of its natural (human or animal), recombinant or synthetic origin, which is capable of binding PTX3 and impeding its biological activity.
  • An example of the preparation of monoclonal antibodies according to the present invention is described by Godine, J.W., 1986, in Monoclonal Antibodies: Principle and Practice. Academic Press, San Diego, whereas an example of the preparation of polyclonal antibodies according to the present invention is described by Harlow E. and Lane D., in Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory, 1988; Cold Spring Harbor, NY.
  • monomeric pentraxin any monomeric pentraxin, irrespective of its natural (human or animal), recombinant or synthetic origin.
  • derivative of monomeric pentraxin is either a functional analogue of said monomeric pentraxin bearing at least one mutation and conserving the functional capability of selectively inhibiting PTX3 activity, or a peptide or peptidomimetic analogue capable of simulating linear or conformational domains of PTX3 and conserving the functional capability of selectively inhibiting PTX3 activity.
  • the preferred type of monomeric pentraxin is human monomeric pentraxin, the sequence of which is described in WO99/32516.
  • the autoimmune diseases related to abnormal activation of PTX3 are comprised in the group consisting of: systemic lupus erythematosus (SLE), multiple sclerosis (MS), arthritis, diabetes, thyroiditis, haemolytic anaemia, atrophic orchitis, Goodpasture's disease, autoimmune retinopathy, autoimmune thrombocytopenia, myasthenia gravis, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, dermatitis, chronic glomerulonephritis, Sj ⁇ gren's syndrome, Reiter's syndrome, myositis, systemic sclerosis and polyarthritis.
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • arthritis diabetes, thyroiditis, haemolytic anaemia, atrophic orchitis, Goodpasture's disease, autoimmune retinopathy, autoimmune thrombocytopenia, myasth
  • the degenerative bone and cartilage diseases related to abnormal activation of PTX3 are comprised in the group consisting of: osteoarthritis; osteoarthrosis; degenerative diseases of the joints; collagen deficiencies; cartilage or bone diseases characterised by endochondrial ossifications: primary arthritis, including, for example, rheumatoid arthritis, juvenile arthritis, undifferentiated chronic arthritis, and polyarthritis; secondary arthritis of autoimmune origin, including, for example, systemic lupus erythematosus arthritis, psoriasic arthritis, Crohn's disease arthritis; arthritis of dysmetabolic origin, including, for example, monosodium urate arthropathy, pyrophosphate arthropathy, calcium oxalate arthropathy; infectious arthritis, arthritis due to osteoporosis, aseptic osteonecrosis, benign and malignant bone tumours.
  • primary arthritis including, for example, rheumatoid arthritis, juvenile arthritis, undifferentiated chronic arthritis, and polyarthritis
  • PTX3-deficient mice were used in a murine model of collagen-induced arthritis (CIA) (Campbell, et al, Eur. J. Immunol, 2000; 30: 1568-75). The aim of the experiment was to evaluate the susceptibility of PTX3-/- mice to the induction of an arthritic phenotype.
  • CIA collagen-induced arthritis
  • 129 sv x C57 BL/6 PTX3-/- mice were treated with 100 ⁇ g of chicken type II collagen (SIGMA) in complete Freund's adjuvant added with 250 ⁇ g of heat-inactivated M. tuberculosis in a total volume of 100 ⁇ l by multiple intradermal injections in the region proximal to the tail.
  • SIGMA chicken type II collagen
  • results obtained indicate that the absence of PTX3 or its inhibition is useful for the prevention and treatment of inflammatory and/or degenerative diseases of bone and cartilage.
  • monomeric pentraxin PTX3 or its peptide or peptidomimetic derivatives or the anti-pentraxin PTX3 antibody will be in the form of a pharmaceutical composition in which the active ingredients are solubilised and/or vehicled by pharmaceutically acceptable excipents and/or diluents, such as sterile water, carboxymethyl-cellulose or other excipients known to the expert in the sector.
  • pharmaceutically acceptable excipents and/or diluents such as sterile water, carboxymethyl-cellulose or other excipients known to the expert in the sector.
  • compositions usable for the monomeric pentraxin are the same as those described for long pentraxin PTX3 in WO 99/32516.
  • the compounds according to the present invention can be administered by the enteral or parenteral routes, particularly preferred pharmaceutical forms being the slow-release implant or intr a- articular injection forms.
  • the daily dose will depend, according to the primary care physician's judgement, on the patient's weight, age and general condition.
  • compositions including the slow-release forms, can be done using routine techniques and instruments well known to pharmacists and to experts in pharmaceutical technology.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Environmental Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Plant Pathology (AREA)
  • Toxicology (AREA)

Abstract

The use of inhibitors of long pentraxin PTX3 for the preparation of a medicament for the prevention and treatment of autoimmune diseases and of degenerative diseases of bone and cartilage is described.

Description

Medicament comprising inhibitors of long pentraxin PTX3
The invention described herein relates to the use of inhibitors of long pentraxin PTX3 for the preparation of a medicament for the treatment of autoimmune diseases and of degenerative diseases of bone and cartilage.
Background of the invention
PTX3 is a glycoprotein capable of organising itself spontaneously in a homodecameric structure held together by disulphide bridges, which is expressed in various cell types (Bottazzi, et al., J. Biol. Chem., 1997; 272: 32817-32823), particularly in mononuclear phagocytes and endothelial cells after exposure to the inflammatory cytokines Interleukin lbeta (IL-lbeta) and Tumor Necrosis Factor alpha (TNF- alpha).
PTX3 consists of two structural domains, an N-terminal unrelated to any known molecule, and a C-terminal similar to the short pentraxins such as C-reactive protein (CRP). A substantial similarity has been found between human PTX3 (hPTX3) and animal PTX3s.
For an overview of the pentraxins, see H. Gewurz, et al, Current Opinion in Immunology, 1995, 7: 54-64.
Both recombinant PTX3 and PTX3 expressed by primary cells (e.g. fibroblasts, endothelial cells and innate immunity cells) are organised mainly in a decameric structure stabilised by disulphide bridges. The single monomer of PTX3 has a molecular weight of approximately 45 kDa which can be obtained from the decameric protein through reduction of disulphide bridges and subsequent alkylation of the reduced cysteines involved in the inter-monomer interaction or through site-specific mutagenesis of the same ( Bottazzi, et al., J. Biol. Chem., 1997; 272: 32817-32823). Recent studies of patients suffering from rheumatoid arthritis have shown a significant increase in expression levels of PTX3 in sinovial fluid. This increased PTX3 expression is associated with the inflammatory processes that characterise this disease (Lucchetti, et al, Clin. Exp. Immunol. 2000; 119: 196-202).
WO 03/086380 describes the use of an inhibitor of PTX3 gene expression for the treatment of autoimmune diseases, including rheumatoid arthritis.
WO 03/086380 differs from the present invention in that it envisages the use both of completely different compounds and of a completely different inhibition method compared to the compounds and inhibition method described in the present invention.
In fact, in the present patent application PTX3 antagonists are described that are capable of directly inhibiting the biological activity of the protein (PTX3).
The person skilled in the art is familiar with the fact that the regulation (in a selective manner) of gene expression by small molecules, such as not to modify the expression of other genes involved in the inflammation, as outlined in WO 03/086380, may be difficult. Furthermore, inhibiting, at gene level, the expression of a protein that plays a fundamental role in important biological functions might give rise to unwanted effects such as, for example, an increase in susceptibility to infections and reproductive sterility.
In the medical field, there therefore remains a strongly perceived need for the availability of additional inhibitors capable of functioning as PTX3 antagonists, which are useful for the treatment of diseases according to the present invention. Description of the invention
It has now been found that inhibitors or antagonists of PTX3 can be used to prevent and treat autoimmune diseases and degenerative diseases of bone and cartilage.
A non-limiting example, of PTX3 inhibitors according to the present invention are monoclonal or polyclonal anti-PXT3 antibodies, while a non-limiting example of PTX3 antagonists according to the present invention are monomeric PTX3 or its peptide or peptidomimetic derivatives.
The object of the present invention is therefore the use of inhibitors or antagonists of long pentraxin PTX3, which are capable of impeding the biological activity of long pentraxin PTX3, as agents useful for the preparation of a medicament for the treatment of autoimmune diseases selected from the group consisting of: systemic lupus erythematosus (SLE), multiple sclerosis (MS), arthritis, diabetes, thyroiditis, haemolytic anaemia, atrophic orchitis, Goodpasture's disease, autoimmune retinopathy, autoimmune thrombocytopenia, myasthenia gravis, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, dermatitis, chronic glomerulonephritis, Sjόgren's syndrome, Reiter's syndrome, myositis, systemic sclerosis and polyarthritis; and of degenerative bone and cartilage diseases selected from the group consisting of: osteoarthritis; osteoarthrosis; degenerative diseases of the joints; collagen deficiencies; cartilage or bone diseases characterised by endochondrial ossifications: primary arthritis, including, for example, rheumatoid arthritis, juvenile arthritis, undifferentiated chronic arthritis, and polyarthritis; secondary arthritis of autoimmune origin, including, for example, systemic lupus erythematosus arthritis, psoriasic arthritis, Crohn's disease arthritis; arthritis of dysmetabolic origin, including, for example, monosodium urate arthropathy, pyrophosphate arthropathy, calcium oxalate arthropathy; infectious arthritis, arthritis due to osteoporosis, aseptic osteonecrosis, benign and malignant bone tumours.
Detailed description of the invention
What is meant by "inhibitors of long pentraxin PTX3" is any monoclonal or polyclonal antibody, irrespective of its natural (human or animal), recombinant or synthetic origin, which is capable of binding PTX3 and impeding its biological activity. An example of the preparation of monoclonal antibodies according to the present invention is described by Godine, J.W., 1986, in Monoclonal Antibodies: Principle and Practice. Academic Press, San Diego, whereas an example of the preparation of polyclonal antibodies according to the present invention is described by Harlow E. and Lane D., in Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory, 1988; Cold Spring Harbor, NY.
What is meant by "monomeric pentraxin" is any monomeric pentraxin, irrespective of its natural (human or animal), recombinant or synthetic origin.
What is meant by "derivative of monomeric pentraxin" is either a functional analogue of said monomeric pentraxin bearing at least one mutation and conserving the functional capability of selectively inhibiting PTX3 activity, or a peptide or peptidomimetic analogue capable of simulating linear or conformational domains of PTX3 and conserving the functional capability of selectively inhibiting PTX3 activity.
The preferred type of monomeric pentraxin is human monomeric pentraxin, the sequence of which is described in WO99/32516.
The autoimmune diseases related to abnormal activation of PTX3 are comprised in the group consisting of: systemic lupus erythematosus (SLE), multiple sclerosis (MS), arthritis, diabetes, thyroiditis, haemolytic anaemia, atrophic orchitis, Goodpasture's disease, autoimmune retinopathy, autoimmune thrombocytopenia, myasthenia gravis, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, dermatitis, chronic glomerulonephritis, Sjδgren's syndrome, Reiter's syndrome, myositis, systemic sclerosis and polyarthritis.
The degenerative bone and cartilage diseases related to abnormal activation of PTX3 are comprised in the group consisting of: osteoarthritis; osteoarthrosis; degenerative diseases of the joints; collagen deficiencies; cartilage or bone diseases characterised by endochondrial ossifications: primary arthritis, including, for example, rheumatoid arthritis, juvenile arthritis, undifferentiated chronic arthritis, and polyarthritis; secondary arthritis of autoimmune origin, including, for example, systemic lupus erythematosus arthritis, psoriasic arthritis, Crohn's disease arthritis; arthritis of dysmetabolic origin, including, for example, monosodium urate arthropathy, pyrophosphate arthropathy, calcium oxalate arthropathy; infectious arthritis, arthritis due to osteoporosis, aseptic osteonecrosis, benign and malignant bone tumours.
The following example further illustrates the invention.
EXAMPLE 1
PTX3-deficient mice were used in a murine model of collagen-induced arthritis (CIA) (Campbell, et al, Eur. J. Immunol, 2000; 30: 1568-75). The aim of the experiment was to evaluate the susceptibility of PTX3-/- mice to the induction of an arthritic phenotype.
129 sv x C57 BL/6 PTX3-/- mice were treated with 100 μg of chicken type II collagen (SIGMA) in complete Freund's adjuvant added with 250 μg of heat-inactivated M. tuberculosis in a total volume of 100 μl by multiple intradermal injections in the region proximal to the tail.
The same treatment was repeated after 21 days. At the end of the administration period, the incidence and severity of arthritis were evaluated using an arbitrary scoring system that took account of the presence of inflamed joints and their size. The results obtained are presented in Table 1.
The greater incidence of the disease in the PTX3 +/+ mice, reported in Table 1, provides evidence that the PTX3 -/- mice are less susceptible to the development of collagen-induced arthritis. This finding is confirmed by the clinical score which shows a greater severity of arthritis in the PTX3+/+ mice than in the PTX3 -/- mice.
The results obtained indicate that the absence of PTX3 or its inhibition is useful for the prevention and treatment of inflammatory and/or degenerative diseases of bone and cartilage.
Table 1
Collagen-induced arthritis in PTX3+/+ and PTX3-/- mice
Animals Incidence* Clinicεtl score0 PTX3 +/+ 3/5 10 PTX3 -/- 3/7 3.6
incidence at the end of the experiment (60 days after the first immunisation).
° Mean clinical score of animals with arthritis at the end of the experiment.
Legend: After the second immunisation, the presence of clinical signs of arthritis of the limbs was evaluated twice a week. Each limb involved was scored from 1 to 4; each animal could therefore obtain a maximum score of 16.
As regards the aspects relating to industrial applicability, monomeric pentraxin PTX3 or its peptide or peptidomimetic derivatives or the anti-pentraxin PTX3 antibody will be in the form of a pharmaceutical composition in which the active ingredients are solubilised and/or vehicled by pharmaceutically acceptable excipents and/or diluents, such as sterile water, carboxymethyl-cellulose or other excipients known to the expert in the sector.
Examples of pharmaceutical compositions usable for the monomeric pentraxin are the same as those described for long pentraxin PTX3 in WO 99/32516.
The compounds according to the present invention can be administered by the enteral or parenteral routes, particularly preferred pharmaceutical forms being the slow-release implant or intr a- articular injection forms.
The daily dose will depend, according to the primary care physician's judgement, on the patient's weight, age and general condition.
It should be noted that the preparation of said pharmaceutical compositions, including the slow-release forms, can be done using routine techniques and instruments well known to pharmacists and to experts in pharmaceutical technology.

Claims

1. Use of inhibitors or antagonists of long pentraxin PTX3 for the preparation of a medicament for the prevention and treatment of degenerative diseases of bone and cartilage.
2. Use according to claim 1, in which what is meant by inhibitor of long pentraxin PTX3 is any monoclonal or polyclonal antibody capable of binding PTX3.
3. Use according to claim 2, in which the antibody is of natural (human or animal), recombinant or synthetic origin.
4. Use according to claim 1, in which the antagonist is monomeric PTX3, or one of its peptide or peptidomimetic derivatives that conserves the functional capability of selectively inhibiting PTX3 activity.
5. Use according to claim 4, in which the antagonist is of natural (human or animal), recombinant or synthetic origin.
6. Use according to claim 4, in which the monomeric pentraxin is of human origin.
7. Use according to claim 1, in which the autoimmune disease is selected from the group consisting of: systemic lupus erythematosus (SLE), multiple sclerosis (MS), arthritis, diabetes, thyroiditis, haemolytic anaemia, atrophic orchitis, Goodpasture's disease, autoimmune retinopathy, autoimmune thrombocytopenia, my asthenia gravis, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, dermatitis, chronic glomerulonephritis, Sjδgren's syndrome, Reiter's syndrome, myositis, systemic sclerosis and polyarthritis.
8. Use according to claim 1, in which said degenerative bone or cartilage disease is selected from the group consisting of: osteoarthritis; osteoarthrosis; degenerative diseases of the joints; collagen deficiencies; cartilage or bone diseases characterised by endochondrial ossifications: primary arthritis, including, for example, rheumatoid arthritis, juvenile arthritis, undifferentiated chronic arthritis, and polyarthritis; secondary arthritis of autoimmune origin, including, for example, systemic lupus erythematosus arthritis, psoriasic arthritis, Crohn's disease arthritis; arthritis of dysmetabolic origin, including, for example, monosodium urate arthropathy, pyrophosphate arthropathy, calcium oxalate arthropathy; infectious arthritis, arthritis due to osteoporosis, aseptic osteonecrosis, benign and malignant bone tumours.
PCT/IT2004/000714 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin ptx3 WO2005060997A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP04806879A EP1706144A2 (en) 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin ptx3
BRPI0418017-8A BRPI0418017A (en) 2003-12-23 2004-12-21 medicament comprising long ptx3 pentraxin inhibitors
US10/584,292 US20070098722A1 (en) 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin ptx3
CA002548452A CA2548452A1 (en) 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin ptx3
AU2004305341A AU2004305341A1 (en) 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin PTX3
JP2006546487A JP2007517021A (en) 2003-12-23 2004-12-21 Pharmaceutical containing an inhibitor of long pentraxin PTX3
MXPA06007080A MXPA06007080A (en) 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin ptx3.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000596A ITRM20030596A1 (en) 2003-12-23 2003-12-23 USE OF INHIBITORS OF LONG PTX3 PENTRAXINE, FOR THE PREPARATION OF A MEDICATION FOR THE PREVENTION AND TREATMENT OF PATHOLOGIES WHICH REPLY TO THE INHIBITION OF THE BIOLOGICAL ACTIVITY OF ITS PTX3.
ITRM2003A000596 2003-12-23

Publications (2)

Publication Number Publication Date
WO2005060997A2 true WO2005060997A2 (en) 2005-07-07
WO2005060997A3 WO2005060997A3 (en) 2005-09-09

Family

ID=34708534

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IT2004/000714 WO2005060997A2 (en) 2003-12-23 2004-12-21 Medicament comprising inhibitors of long pentraxin ptx3

Country Status (12)

Country Link
US (1) US20070098722A1 (en)
EP (1) EP1706144A2 (en)
JP (1) JP2007517021A (en)
CN (1) CN1893975A (en)
AR (1) AR047159A1 (en)
AU (1) AU2004305341A1 (en)
BR (1) BRPI0418017A (en)
CA (1) CA2548452A1 (en)
IT (1) ITRM20030596A1 (en)
MX (1) MXPA06007080A (en)
TW (1) TW200526246A (en)
WO (1) WO2005060997A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128647A1 (en) 2006-05-02 2007-11-15 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. USE OF THYMOSIN α1, ALONE OR IN COMBINATION WITH PTX3 OR GANCICLOVIR, FOR THE TREATMENT OF CYTOMEGALOVIRUS INFECTION

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1298487B1 (en) * 1997-12-19 2000-01-10 Sigma Tau Ind Farmaceuti PHARMACEUTICAL COMPOSITIONS INCLUDING PENTRAXIN LONG PTX3 FOR THE THERAPY OF INFECTIOUS, INFLAMMATORY OR CANCER TYPE DISEASES,
ITRM20020109A1 (en) * 2002-02-28 2003-08-28 Sigma Tau Ind Farmaceuti FUNCTIONAL DERIVATIVES OF PENTRAXIN LONG PTX3 TO PREPARE AN AUTOLOGOUS VACCINE FOR THE TREATMENT OF CANCERS.
EP1832295A1 (en) * 2006-03-10 2007-09-12 Tecnogen S.P.A. Use of PTX3 for the treatment of viral diseases
EP2245061A2 (en) * 2007-12-11 2010-11-03 Coda Therapeutics, Inc. Impaired wound healing compositions and treatments
CA2894696A1 (en) 2012-12-21 2014-06-26 Teikoku Pharma Usa, Inc. Compositions and methods for transdermal delivery of hormones and other medicinal agents
JP6959913B2 (en) * 2016-05-13 2021-11-05 国立大学法人 東京大学 A therapeutic agent for obesity-related diseases due to hepatic secretory metabolic regulator inhibitory action
CN106950366B (en) * 2017-02-15 2019-03-22 中国医学科学院北京协和医院 A kind of RA diagnosis marker of ACPA feminine gender and its application
TWI741216B (en) * 2017-09-19 2021-10-01 臻崴生物科技有限公司 Monoclonal antibody or antigen-binding fragment for specifically inhibiting or alleviate the binding of ptx3 and ptx3 receptor and use of the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032516A2 (en) * 1997-12-19 1999-07-01 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Pharmaceutical compositions containing the long pentraxin ptx3
WO2002036151A2 (en) * 2000-11-03 2002-05-10 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of the long pentraxin ptx3 for the preparation of medicament for the prevention and cure of autoimmune pathologies
WO2003086380A1 (en) * 2002-04-15 2003-10-23 Kowa Co., Ltd. Ptx3 gene expression suppressing method

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1317930B1 (en) * 2000-11-08 2003-07-15 Sigma Tau Ind Farmaceuti USE OF LONG PENTRAXIN PTX3 FOR THE PREPARATION OF A MEDICATION FOR THE TREATMENT OF PATALOGIES ASSOCIATED WITH AN ALTERED ACTIVATION

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032516A2 (en) * 1997-12-19 1999-07-01 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Pharmaceutical compositions containing the long pentraxin ptx3
WO2002036151A2 (en) * 2000-11-03 2002-05-10 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of the long pentraxin ptx3 for the preparation of medicament for the prevention and cure of autoimmune pathologies
WO2003086380A1 (en) * 2002-04-15 2003-10-23 Kowa Co., Ltd. Ptx3 gene expression suppressing method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
B. BOTTAZZI ET AL.: "Multimer formation and ligand recognition by the long pentraxin PTX3." THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 52, 26 December 1997 (1997-12-26), pages 32817-32823, XP002191385 Baltimore, MD, USA cited in the application *
M. LUCHETTI ET AL.: "Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA)." CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 119, no. 1, January 2000 (2000-01), pages 196-202, XP002191383 cited in the application *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128647A1 (en) 2006-05-02 2007-11-15 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. USE OF THYMOSIN α1, ALONE OR IN COMBINATION WITH PTX3 OR GANCICLOVIR, FOR THE TREATMENT OF CYTOMEGALOVIRUS INFECTION

Also Published As

Publication number Publication date
JP2007517021A (en) 2007-06-28
EP1706144A2 (en) 2006-10-04
US20070098722A1 (en) 2007-05-03
CA2548452A1 (en) 2005-07-07
BRPI0418017A (en) 2007-04-17
KR20070000415A (en) 2007-01-02
CN1893975A (en) 2007-01-10
AU2004305341A1 (en) 2005-07-07
TW200526246A (en) 2005-08-16
ITRM20030596A1 (en) 2005-06-24
MXPA06007080A (en) 2006-09-04
AR047159A1 (en) 2006-01-11
WO2005060997A3 (en) 2005-09-09

Similar Documents

Publication Publication Date Title
GIROIR Mediators of septic shock: new approaches for interrupting the endogenous inflammatory cascade
Ozgocmen et al. Anti-TNF agents in familial Mediterranean fever: report of three cases and review of the literature
KR101873773B1 (en) Composition for preventing or treating rheumatoid arthritis
JP5822822B2 (en) Peptides that target TNF family receptors and antagonize TNF action, compositions, methods and uses thereof
Chen et al. The effect of intra-articular injection of different concentrations of ozone on the level of TNF-α, TNF-R1, and TNF-R2 in rats with rheumatoid arthritis
US20010021380A1 (en) Soluble tumor necrosis factor receptor treatment of medical disorders
US20010053764A1 (en) Interleukin-1 inhibitors in the treatment of diseases
AU2002324625A1 (en) Interleukin-1 receptors in the treatment of diseases
WO2003014309A2 (en) Interleukin-1 receptors in the treatment of diseases
EA005583B1 (en) Use of il-18 inhibitors
US20110177065A1 (en) Methods of treating/preventing inflammation using combination of il-1 antagonist and il-18 binding protein
JP2021525234A (en) Compositions and methods for the treatment of diseases
US20070098722A1 (en) Medicament comprising inhibitors of long pentraxin ptx3
KR20050119149A (en) Use of clusterin for the treatment and/or prevention of peripheral neurological diseases
EP1740200B1 (en) Il-6 for therapy or prevention of chemotherapy-induced neuropathy
US20070191269A1 (en) Medicament comprising ptx3, alone or in combination with tsg-6, for treating degenerative diseases of cartilage and bone and treating female infertility
JP5346216B2 (en) Treatment
KR20060136385A (en) Medicament comprising inhibitors of long pentraxin ptx3
Joosten et al. IL-1 in chronic arthritis, lessons from animal models
WO2023033130A1 (en) Composition for treating or preventing bone diseases

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200480037194.7

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2004806879

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2004305341

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2548452

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2006/007080

Country of ref document: MX

Ref document number: 1020067012245

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2007098722

Country of ref document: US

Ref document number: 2006546487

Country of ref document: JP

Ref document number: 10584292

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

ENP Entry into the national phase

Ref document number: 2004305341

Country of ref document: AU

Date of ref document: 20041221

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004305341

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2057/KOLNP/2006

Country of ref document: IN

WWP Wipo information: published in national office

Ref document number: 2004806879

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0418017

Country of ref document: BR

WWP Wipo information: published in national office

Ref document number: 10584292

Country of ref document: US