EP1007547A1 - Peptides contenant un epitope de lymphocyte t specifique au collagene ii - Google Patents

Peptides contenant un epitope de lymphocyte t specifique au collagene ii

Info

Publication number
EP1007547A1
EP1007547A1 EP98902337A EP98902337A EP1007547A1 EP 1007547 A1 EP1007547 A1 EP 1007547A1 EP 98902337 A EP98902337 A EP 98902337A EP 98902337 A EP98902337 A EP 98902337A EP 1007547 A1 EP1007547 A1 EP 1007547A1
Authority
EP
European Patent Office
Prior art keywords
apg
amino acid
ppg
peptide
sequence
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.)
Withdrawn
Application number
EP98902337A
Other languages
German (de)
English (en)
Inventor
Sinasi Bayrak
Rikard Holmdahl
Avrion Mitchison
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.)
Holmdahl Rikard
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1007547A1 publication Critical patent/EP1007547A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention provides new peptides derived from collagen CII, methods for their preparation and their use in medical therapy, particularly in the treatment of rheumatoid arthritis and related autoimmune conditions
  • Collagen molecules are some of the main structural proteins of connective tissue. They consist of three polypeptide chains forming an extended triple helical structure with a unique X-Y-Gly repetitive amino acid sequence.
  • the extracellular matrix of cartilage is unique in containing collagens mainly of type II, but also of types IX and XI.
  • CII has recently been cloned from the mouse and its entire sequence of 1419 amino acids determined (Metsarantam et al., 1991, J Biol Chem, 266: 16862-9).
  • Type Il-collagen is thought to be "hidden" from cells of the immune system as it is only found in avascular tissues, such as the cartilage, and the vitreous body of the eye.
  • the immune system is therefore not completely tolerant of its own type II collagen
  • CII has the ability, when injected in Freund's complete adjuvant, to induce tissue-specific autoimmune disease.
  • the disease that it induces is termed collagen induced arthritis (CIA).
  • CIA collagen induced arthritis
  • CIA is normally induced by injection of foreign CII, which provokes the production of T cells and antibodies able to recognise the corresponding self- protein.
  • CII is an autoantigen in rheumatoid arthritis(RA).
  • Miyahara, H. et al ( Immunology 199586 110-115) describe the use of a fragment of type II collagen in the suppression of arthritis in mice.
  • the fragment used (CII 607-621) does however not contain a binding motif to any of the HLA-DR molecules associated with RA in man and would therefore not be effective for use as a toleragen in human RA therapy.
  • WO 96/20950 purports to describe type II collagen peptides capable of binding to the human HLA DRB 1 MHC protein which it is suggested would be of use in RA therapy.
  • these peptides which are present in the 273-404 region of collagen CII protein show only weak activity in relevant assays for putative toleragens for RA .
  • the peptides of the present invention are of a significantly greater therapeutic efficacy.
  • the present invention provides peptides which have been found to be particularly effective in inducing immune tolerance to collagen CII derived T-cell epitopes. These peptides may be used in the treatment of autoimmune conditions such as rheumatoid arthritis.
  • a ⁇ represents an amino acid residue with an aromatic or aliphatic side chain
  • A4 represents an asparagine or arginine residue or an amino acid residue with an aromatic or aliphatic side chain
  • A5 represents any naturally occurring amino acid
  • A7 represents an amino acid with a negatively charged residue
  • Xaa represents any amino acid residue
  • Gly represents a glycine residue.
  • Peptide of the present invention are preferably 9, 10 , 11, 12, 13, 14 or 15 amino acid peptides; and are more preferably 9 amino acid peptides.
  • -Ai is F, I, L, A or P and is most preferably F -A4 is F, I, L, A, R, N or P and is most preferably F -A5 is K or R -A7 is E , D, Q, P or N and is most preferably Q.
  • Preferred peptides according to the present invention include those comprising, or having, one of the following sequences:
  • ESG SPG ENG PPG ADG QPG, ARG NDG QPG, QPG AKG DQG, APG AKG EAG, PTG VTG PKG, AQG SRG EPG, RVG PPG ANG, PAG ASG NPG, ANG NPG PAG, TDG IPG AKG, DPG LQG PAG, SAG APG IAG, APG EKG EPG, IAG APG FPG, PQG LAG QRG, FPG PRG PPG, PKG ANG DPG, APG ASG DRG, LPG ARG LTG, DAG PQG KVG, ALG APG APG, PAG ANG EKG, KQG DRG EAG, or ARG APG EPG (SEQ IDs Nos 1 to 25 respectively); and more preferably either RVG PPG ANG (SEQ ID No 8) or ANG NPG PAG (SEQ ID No 10).
  • Preferred examples of peptides according to the invention also include those comprising, or having, one of the following amino acid sequences:
  • the peptide according to the invention comprises a 9 to 15 amino acid sequence present uninterrupted in the 701 -721 region of collagen IL
  • the invention also relates to a peptide comprising a T-cell epitope specific to collagen II which peptide comprises at least nine amino acids having the same sequence as and selected consecutively from the 110-239, 338-379 and 587-895 portions of the sequence of collagen II wherein each amino acid is optionally replaced by a functionally equivalent amino acid and wherein the peptide is of formula I as defined above.
  • compositions comprising a peptide according to the invention in association with a pharmaceutically acceptable carrier or diluent.
  • the compositions are preferably for use in providing tolerance against an autoimmune condition such as rheumatoid arthritis and relapsing polychondritis.
  • the invention further provides the use of a peptide according to the invention or of a composition according to the invention in the manufacture of a medicament for use in the treatment of an autoimmune condition.
  • a method of treating a human or animal suffering from an autoimmune condition such as rheumatoid arthritis and relapsing polychondritis, which method comprises supplying the human or animal with a therapeutically effective amount of the peptide or of the composition.
  • the peptides according to the invention may be prepared using methods known to the skilled man. For example by using the standard solid phase sequential coupling technique utilising an automatic peptide synthesiser (see for example: Jones, J. The Chemical Synthesis of Peptides, pp 132-156, first edition, Oxford University Press, 1991 and R. Epton (ed) Innovation and Perspectives in Solid Phase Peptide Synthesis, SPCC (UK), Ltd, 1990).
  • the preparation starts from the C-terminal amino acid which can be obtained grafted to a methylbenzhydrylamine, benzhydrylamine or chloromethylated resin or a suitable solid support.
  • the other amino acids are grafted step by step, after having protected the side chains thereof.
  • the alpha-amino groups of the amino acids are protected with F-moc or t-Boc methodology.
  • Protective groups for the side chains of amino acids are well known in the art.
  • the whole protected peptide is released from the chloromethylated resin by ammoniolysis to obtain the protected amide, or from the methylbenzhydrylamine or benzhydrylamine resins by acidolysis.
  • Peptides according to the invention may also be prepared using solution methods, by either stepwise or fragment condensations (see for example: Jones, J. The Chemical Synthesis of Peptides, pp 1 15-131, first edition, Oxford University Press, 1991).
  • An appropriately alpha aminoprotected amino acid is coupled to an appropriately alpha carboxyl protected amino acid (such protection may not be required depending on the coupling method chosen) using diimides, symmetrical or unsymmetrical anhydrides, or other coupling reagents or techniques known to those skilled in the art. These techniques may be either chemical or enzymatic.
  • the alpha amino acid an/or alpha carboxyl protecting groups are removed and the next suitably protected amino acid or block of amino acids are coupled to extend the growing peptide.
  • the peptides according to the invention are defined as comprising a T-cell epitope. In other words they are capable of activating T-cells.
  • There are several known techniques for determining binding strength Preferably a peptide according to invention can activate the T-cells with a binding strength of at least 2 in an IFN- ⁇ release assay and/or with a stimulation index of at least 3.
  • the IFN- ⁇ release assay can be carried out using methods known in the art or by using the methodology described in the Examples herein.
  • the stimulation index can be determined using known proliferation assays, for example those described in "Analysis of type II collagen reactive T cells in the mouse” Andersson and Holmdahl, Eur J Immunol 20:1061-1066, 1990, preferably the assay is carried out using the methodology used in the Examples herein.
  • the peptides of the invention are of use in therapy without modification but alternatively the peptides may be modified, for example they may be conjugated, e.g. bound covalently, to delivery systems, for example to mucosal binding structures which include the cholera ⁇ toxin which assists absorption in the intestine.
  • the peptides of the present invention may be used in the treatment, prophlaxis or diagnosis of autoimmune conditions and the terms 'therapy' and 'treatment' as used herein should be taken also to include prophylaxis and diagnosis.
  • a peptide of the present invention is to be taken to be an isolated peptide in the sense that peptides of the present invention do not include peptides present in an organism.
  • Peptides of the present invention may be either isolated from a naturally or recombinantly produced peptide or protein or may be chemically synthesised as herein described.
  • the compounds may be administered at a dosage from about 10 ⁇ g to 10 mg per day either as a single dose or in divided doses 2 to 4 times per day.
  • unit doses comprise from 2.5 ⁇ g to 10 mg of a compound according to the invention.
  • the compounds may be administered intranasally in the form of solutions, suspensions, HFA aerosols and dry
  • ® powder formulations e.g. Turbuhaler formulations
  • systemically e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, or by rectal administration in the form of suppositories.
  • the compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier.
  • a pharmaceutically acceptable diluent, adjuvant or carrier particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (e.g. oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C8-C20 fatty acid or salt thereof, (e.g. oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyols.
  • Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • the pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral solutions or suspensions for parenteral administration or suppositories for rectal administration.
  • the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • the compound may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol , mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • Example 1 The invention is now illustrated by the following Examples which should not be interpreted as limiting the present invention.
  • Example 1 The invention is now illustrated by the following Examples which should not be interpreted as limiting the present invention.
  • the CII peptide chains listed in Table 1 each consisting of 15 amino acids were synthesised using an SMPS 350 automated synthesiser (Zinsser, Frankfurt/Main, Germany) using known Fmoc chemistry (see Atherton and Sheppard, Solid Phase Peptide Synthesis - A Practical Approach. IRL Press, Oxford). Each peptide was then acetylated at the N- terminus and amidated at the C- terminus. The quality of the peptides was assessed by HPLC and mass spectroscopy of a sample of the peptides confirmed the expected molecular weight.
  • Mouse CII was extracted from xiphisterna by pepsin digestion using known techniques and then further purified by salt precipitation. Rat CII was purified from the Swarm chondrosarcoma again using known techniques. The collagens were dissolved in 0.1 M acetic acid. Collagen for use in restimulating primed lymph node cells was denatured by incubating at 56°C for 30 minutes.
  • mice Male (B10.Q X DBA/1) FI mice, 7-10 weeks of age, were immunised in each hind foot pad with 50 ⁇ g mouse CII or synthetic peptide emulsified in CFA (containing H37Ra, Difco,
  • mice were boosted with 50 ⁇ g of CII emulsified in a 1 : 1 ratio by weight with IFA (DIFCO, Detroit, MI). Lymph node cells drained from severely arthritic joints from these mice were then removed and pooled to test reactivity to the panel of mouse CII peptides prepared in Examples 1 in a proliferation assay in the following way.
  • IFA DIFCO, Detroit, MI
  • Cytokine release was assayed from 50 ⁇ l supematants of primary cultures of mouse CII primed lymph node cells were restimulated in vitro with the panel of CII peptides prepared according to Example 1 using IFN- ⁇ and E -4 minikits (Endogen, Cambridge, MA).
  • Lymph node cells from mice primed with mouse CII were depleted of either T cells or B cells by passage through a magnetically activated cell sorter (MACS) using super- paramagnetic microbeads conjugated with monoclonal rat anti-mouse L3T4 (CD4) antibodies or rat anti-mouse B220 (CD45R) (both from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) as recommended by the manufacturer except that PBS containing 2% FCS, 5 mM EDTA, 50 ⁇ M 2-ME and 10 mM HEPES was substituted for PBS/BSA buffer.
  • MCS magnetically activated cell sorter
  • the fractions were analysed on a FACScan flow cytometer (Becton Dickinson) using FITC-conjugated anti-mouse-CD3- ⁇ for staining T-cells and FIT C-conjugated anti-mouse- K-light-chain for B cells (Pharmigen, San Diego, CA).
  • the cells were washed three times with DMEM medium without serum after separation and then put into proliferation assays using the method described in Example 3.
  • Enriched CD4+ T cells were mixed together with spleen cells from spleens from syngeneic mice as antigen presenting cells in a ratio of 1 :2 by weight.
  • AP cells are used in the form of a single cell suspension from spleens treated with 0.84% NH4CI at pH 7.4 to lyse red blood cells.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Transplantation (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un peptide isolé comprenant une séquence d'acides aminés de la formule (I): A1-Xaa-Gly-A4-A5-Gly-A7-Xaa-Gly, où A1 représente un reste d'acide aminé ayant une chaîne latérale aromatique ou aliphatique; A4 représente un reste d'asparagine ou d'arginine ou un reste d'acide aminé ayant une chaîne latérale aromatique ou aliphatique; A5 représente un acide aminé quelconque naturel; A7 représente un acide aminé avec un reste chargé négativement; Xaa représente un reste d'acide aminé quelconque et Gly représente un reste de glycine. L'invention concerne également l'utilisation de tels peptides dans le traitement médical, en particulier dans le traitement d'états autoimmuns tels que la polyarthrite rhumatoïde.
EP98902337A 1997-01-31 1998-01-29 Peptides contenant un epitope de lymphocyte t specifique au collagene ii Withdrawn EP1007547A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9700301A SE9700301D0 (sv) 1997-01-31 1997-01-31 New compound
SE9700301 1997-01-31
PCT/SE1998/000128 WO1998033811A1 (fr) 1997-01-31 1998-01-29 Peptides contenant un epitope de lymphocyte t specifique au collagene ii

Publications (1)

Publication Number Publication Date
EP1007547A1 true EP1007547A1 (fr) 2000-06-14

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Application Number Title Priority Date Filing Date
EP98902337A Withdrawn EP1007547A1 (fr) 1997-01-31 1998-01-29 Peptides contenant un epitope de lymphocyte t specifique au collagene ii

Country Status (19)

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EP (1) EP1007547A1 (fr)
JP (1) JP2001511143A (fr)
KR (1) KR20000070542A (fr)
CN (1) CN1246125A (fr)
AU (1) AU744907B2 (fr)
BR (1) BR9811250A (fr)
CA (1) CA2278638A1 (fr)
EE (1) EE9900334A (fr)
HU (1) HUP0000836A3 (fr)
ID (1) ID22802A (fr)
IL (1) IL131045A0 (fr)
IS (1) IS5138A (fr)
NO (1) NO993684L (fr)
NZ (1) NZ336745A (fr)
PL (1) PL334877A1 (fr)
SE (1) SE9700301D0 (fr)
SK (1) SK102199A3 (fr)
TR (1) TR199901831T2 (fr)
WO (1) WO1998033811A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPO571297A0 (en) * 1997-03-19 1997-04-10 Montech Medical Developments Pty Ltd Method for the diagnosis of rheumatoid arthritis
CA2452593C (fr) * 2001-07-12 2015-02-03 Arexis Ab Complexes triple de polypeptides
CN100346823C (zh) * 2001-09-14 2007-11-07 比奥拉比奥埃克斯公司 用于调节免疫反应的釉质基质蛋白组合物
CN1169829C (zh) 2002-06-27 2004-10-06 北京大学人民医院 非t细胞结合肽及其用途
WO2008130217A1 (fr) * 2006-08-08 2008-10-30 Applied Nanosystems B.V. Analogues d'angiotensines cycliques
KR20170002734U (ko) 2016-01-21 2017-07-31 김인수 자동 목재절단 장치

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08151396A (ja) * 1994-11-28 1996-06-11 Teijin Ltd Ｈｌａ結合性オリゴペプチド及びそれを含有する免疫調節剤
AU4695296A (en) * 1995-01-06 1996-07-24 Immulogic Pharmaceutical Corporation Compositions and methods for treating rheumatoid arthritis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9833811A1 *

Also Published As

Publication number Publication date
KR20000070542A (ko) 2000-11-25
NO993684L (no) 1999-09-02
AU744907B2 (en) 2002-03-07
ID22802A (id) 1999-12-09
HUP0000836A3 (en) 2001-04-28
NZ336745A (en) 2001-09-28
CN1246125A (zh) 2000-03-01
SK102199A3 (en) 2000-08-14
BR9811250A (pt) 2000-09-26
NO993684D0 (no) 1999-07-29
TR199901831T2 (xx) 1999-10-21
IL131045A0 (en) 2001-01-28
CA2278638A1 (fr) 1998-08-06
SE9700301D0 (sv) 1997-01-31
JP2001511143A (ja) 2001-08-07
WO1998033811A1 (fr) 1998-08-06
HUP0000836A2 (hu) 2000-11-28
IS5138A (is) 1999-07-28
EE9900334A (et) 2000-02-15
AU5889298A (en) 1998-08-25
PL334877A1 (en) 2000-03-27

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