EP0842274A1 - Nouvelle proteine humaine mp52 arg - Google Patents

Nouvelle proteine humaine mp52 arg

Info

Publication number
EP0842274A1
EP0842274A1 EP96928406A EP96928406A EP0842274A1 EP 0842274 A1 EP0842274 A1 EP 0842274A1 EP 96928406 A EP96928406 A EP 96928406A EP 96928406 A EP96928406 A EP 96928406A EP 0842274 A1 EP0842274 A1 EP 0842274A1
Authority
EP
European Patent Office
Prior art keywords
arg
leu
pro
ala
gly
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Withdrawn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
EP96928406A
Other languages
German (de)
English (en)
Inventor
Michio Kimura
Tomoaki Matsumoto
Mikiko Takahashi
Shinji Kawai
Yukio Fujino
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.)
Biopharm Gesellschaft zur Biotechnologischen Entwicklung von Pharmaka mbH
Original Assignee
Biopharm Gesellschaft zur Biotechnologischen Entwicklung von Pharmaka mbH
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 Biopharm Gesellschaft zur Biotechnologischen Entwicklung von Pharmaka mbH filed Critical Biopharm Gesellschaft zur Biotechnologischen Entwicklung von Pharmaka mbH
Publication of EP0842274A1 publication Critical patent/EP0842274A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • 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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/51—Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • 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
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P19/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/495—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to a new compound human MP52 Arg and a pharmaceutical medical composition inter alia for promoting cartilage and bone orphogenation comprising human MP52 Arg.
  • the medical composition is useful for treating bone diseases caused by abnormal bone metabolism such as osteoporosis, for treating bone fracture and for the purpose of orthopedic reconstruction, bone transplantation, cosmetic surgery and dental therapeutics. Further, it is useful for treating cartilage disorders.
  • compositions including vitamin D3, calcitonin, estrogen and bisphosphonate derivatives have been used in clinical practice for treating bone diseases. Their therapeutic results, however, are not entirely satisfactory, and a better pharmaceutical composition is highly desired.
  • TGF- ⁇ family of growth factors comprising BMP, TGF, and inhibin related proteins have been reported to be useful for wound healing and tissue repair.
  • the bone morphogenetic activity of some of those proteins has been also known.
  • PCT patent application WO 93/16099 and WO 25/04819 disclose DNA sequences encoding human TGF- ⁇ -like proteins, and as a preferred protein human MP52.
  • Mouse GDF5 has the same amino acid sequence of the predicted mature form as that of human MP52 except one amino acid. However, there is no suggestion in this publication to use those proteins for the treatment of bone diseases.
  • One embodiment of the present invention is therefore protein human MP52 Arg comprising amino acids 1 . to 121 of S ⁇ Q ID NO: 1.
  • human MP52 Arg induces formation of cartilage from undifferentiated esenchymal cell and stimulates the differentiation and maturation of osteoblasts. Therefore, human MP52 Arg is effective for preventing and/or treating bone diseases caused by abnormal bone metabolism such as osteoporosis. It also accelerates the healing process of bone fractures. Moreover, it is useful for orthopedic reconstructions, bone transplantations and dental therapeutics because of its bone morphogenetic activity. Furthermore, MP52 Arg is effective for preventing and/or treating cartilage disorders caused by abnormal cartilage metabolism.
  • a further object of the present invention is a process for the production of human MP52 Arg, wherein at least a part of a DNA sequence as shown in Sequence ID N0:1 is introduced into a suitable host cell under conditions favouring expression of the DNA sequence and protein formation, followed by isolation of said protein from other proteins produced by said host cell.
  • the DNA sequence depicted in SEQ ID NO:l may be used for producing human MP52 Arg, however also shorter portions thereof, provided they still encode human MP52 Arg and expression of the DNA sequence in a suitable vector/host cell system is possible.
  • Suitable expression systems are known to a person skilled in the art and it can easily be determined by routine experimentation what the minimum requirements for the length of the DNA sequence of SEQ ID NO:l are.
  • the proteins are recovered from the host cell by methods known per se and finally human MP52 Arg is isolated therefrom.
  • human MP52 and MP52 Arg which differ from one another only in respect of one amino acid, can be carried out using very precisely differentiating separation methods which are known to a person skilled in the art.
  • One example is the electrophoretic separation of MP52 Arg performed according to the method of Davis (Ann. NY Acad. Sci., 121, 404-427, 1964) with small modifications like addition of 0.1 % Nonidet P-40 and 6 M urea. After electrophoresis the separated MP52 Arg is electroeluted from the gel pieces in the same buffer.
  • a further object of the present invention is a pharmaceutical composition containing human MP52 Arg.
  • this composition may also include usual carrier substances, auxiliary substances, diluents and/or fillers.
  • the pharmaceutical composition according to the invention is useful for promoting bone morphogenation, treatment or prevention of damage to bone, cartilage, connective tissues, skin, mucous membranes, epithelium or teeth, for application in dental implants and for application in wound-healing and tissue regeneration processes.
  • human MP52 Arg is administered in systemic by injection such as intravenous injection, muscle injection and intraperitoneal injection, oral administration, non-oral administration such as suppository, and other any conventional methods.
  • matrix containing human MP52 Arg is preferably implanted in the area close to the fractured bone.
  • Suitable matrixes are natural polymers such as collagen and fibrin clot, and artificial polymers degradable in living body such as polylactated glycolic acid.
  • human MP52 Arg for example can be coated on the surface of bone and tooth to be implanted by means of collagen paste, fibrin glue and other adhering materials. It can also be applied to the tissue, the bone or alveolar bone around which the bone and tooth is transplanted. In case of bone transplantation it can be used for both natural and artificial bone.
  • As the material of artificial bone and tooth conventional materials such as metals, ceramics, glass and other natural or artificial inorganic substance are used. Hydroxyapatite is a preferred artificial substance.
  • Artificial bone can be constructed by dense material in the inner part and porous material in the other part. For example, dense steel covered porous steal can be cited. Porous hyroxyapatite is one of the materials to produce artificial bone. When such porous material is used, human MP52 Arg can be penetrated into it. The surface of artificial bone can also be roughened to keep human MP52 Arg on the surface.
  • the dose of human MP52 Arg to be obtained is decided depending upon the purpose and the method of application. In general, when it is administered in systemic, the dose is from 1 ⁇ g to 100 ⁇ g/kg. When it is used for implantation, the preferred dose is from 30 ⁇ g to 30 g per site.
  • This purified human MP52 Arg can be formulated in any conventional form such as injection liquid, pills, capsules and suppository.
  • human MP52 Arg can be included in a matrix such as collagen, fibrin glue and poly lactated glycolic acid.
  • a matrix such as collagen, fibrin glue and poly lactated glycolic acid.
  • the pSK52s plas id (WO 95/04819) was digested with Hind III and the DNA fragment containing the cDNA comprising the complete coding region for MP52 was isolated by extraction from 0.8 % low ⁇ melting agarose gels and ligated into the Hind III site of pABstop vector, which is supplied by Dr. Gerd Zettlmei ⁇ l of Behringwerke AG.
  • the structure of the resulting MP52 expression vector, pMSS99 (5.0 kb) was confirmed by the DNA sequencing and the restriction enzyme mapping.
  • the genetic elements of pMSS99 are schematically shown in Fig.l.
  • the MP52 sequence in pMSS99 comprises the nucleotides 576-2279 in SEQ ID NO:l of the Sequence Listing.
  • Dhfr-deficient CHO cells CHO-DUKX-B11 (Urlaub, G. and Chasin, L.A. (1980) Proc.Natl.Acad.Sci, USA, 77, pp.4216-4220) were cotransfected with the expression plasmid for MP52 (pMSS99) and pSVOAdhfr (Zettlmei ⁇ l, G. et al., (1987) Bio/Technology 5 , 720- 725) by calcium phosphate-mediated DNA transfer method. Then high producer clones of MP52 Arg were established by a gene amplification protocol using methotrexate (MTX) .
  • MTX methotrexate
  • the cells After a treatment with 10 % glycerol in MEMoJ containing 10 % FBS at room temperature for 3 in, the cells were cultured in MEM ⁇ 1* containing 10 % FBS for 2 days. Then the cells were placed in MEM ALPHA medium without ribo- and deoxyribo-nucleosides (MEM ⁇ T) containing 10 % dialyzed FBS to select the transformants. The transformant clones were isolated and assayed for the expression of MP52 Arg by Western blot analysis as described in the next section.
  • MEM ⁇ 1* containing 10 % FBS for 2 days.
  • MEM ⁇ T ribo- and deoxyribo-nucleosides
  • MP52 Arg high producer clones of MP52 Arg were established by a gene amplification protocol using methotrexate (MTX) .
  • the MP52 Arg producing clones were further selected stepwisely in increasing concentrations of methotrexate (MTX) to amplify the MP52 gene in accordance with the pSVOAdhfr gene.
  • MTX methotrexate
  • TTBS TBS
  • rabbit anti-chicken IgG-ALP conjugate Sigma A 9171
  • BIO-RAD Alkaline phosphatase Conjugate Substrate Kit
  • the CHO cell line with the highest productivity of MP52 Arg and MP52, MC-2 (deposited under No.FERM BP-5142 on June 21, 1995 with the National Institute of Bioscience and Human Technology, Japan) was grown with roller bottles containing MEM ⁇ * supplemented with 10 % FBS, 400 nM MTX, 100 U/ml Penicillin and 100 ⁇ g/ml Streptomycin.
  • MC-2 cells After the MC-2 cells had grown to confluency, they were washed with serum-free MEM ⁇ -n and then cultured in serum-free DME/F12 medium supplemented with 10 mM HEPES (pH 7.3) , 10 KIE/ml Aprotinin, 1 mM sodium butyrate, 6 ⁇ g/ml sodium selenate, 5 ⁇ g/ml transferrin, 18 ⁇ g/ml ethanol amine, 9 ⁇ g/ml insulin, 100 U/ml Penicillin and 100 ⁇ g/ml Streptomycin. The conditioned medium was collected every day for a week.
  • One liter of the culture supernatants were mixed with 0.1 volume of 0.2 M sodium phosphate buffer, pH 6.0, and applied to a POROS HS column (10 ml, PerSeptive Biosystems) .
  • the elution was performed by a linear gradient of NaCl from 0.3 to 2 M.
  • the eluate containing MP52 Arg was applied to reverse-phase column (RESOURCE RPC, Pharmacia) .
  • the elution was performed by linear gradient of acetonitrile, containing 0.05 % TFA and MP52 Arg was eluted at about 35 % acetonitrile.
  • the N-terminal amino acid sequence analysis for purified MP52 Arg was performed using a pulse liquid gas phase sequencer (Applied Biosystems model 476) . The result is shown in Table 1. It is indicated that MP52 Arg is processed proteolytically at Arg(380) -Arg(381) (amino acid positions -1 and +1 of Sequence ID NO:l) from its precursor. However, the precursor can also be processed at Arg(381) -Ala(382) (amino acid positions +1 and +2 of Sequence ID NO:l) .
  • Osteoprogenitor-like ROB-C26 cells (Calcif. Tissue Int. vol. 49, p. 221-225, 1991) were plated onto 48-well multi-well plates (Coaster) at a density of 1.5 x 10* cells/well and pre-incubated for 3 days in MEM ⁇ " containing 10% fetal bovine serum (FBS) . After the removal of culture medium, fresh MEM ⁇ " containing 10% FBS and serially diluted MP52 Arg in lOmM HCl (2 ⁇ l/ml) was added to the cultures and incubated for 6 days with changing the medium and the additives on day 3.
  • MEM ⁇ containing 10% fetal bovine serum
  • ATC TGC ACT GTG TTG GGT GCC CCT GAC TTG GGC CAG AGA CCC CAG GGG 750 lie Cy ⁇ Thr Val Leu Gly Ala Pro Asp Leu Gly Gin Arg Pro Gin Gly
  • GCC CGG AAC GTC TTC AGG CCA GGG GGT CAC AGC TAT GGT GGG GGG GCC 846 Ala Arg Asn Val Phe Arg Pro Gly Gly His Ser Tyr Gly Gly Gly Ala -325 -320 -315
  • GGT CCC GTG GTC AGG AAG CAG AGG TAC GTG TTT GAC ATT AGT GCC CTG 1326 Gly Pro Val Val Arg Lys Gin Arg Tyr Val Phe Asp He Ser Ala Leu -165 -160 -155
  • CTGTCCCTGG GACAGTTGAG AAGCTGACTG GGCAAGAGTG GGAGAGAAGA GGAGAGGGCT 2622

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • General Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Biotechnology (AREA)
  • Toxicology (AREA)
  • Wood Science & Technology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Cette invention se rapporte à une MP52 Arg humaine et à une composition médicale pharmaceutique contenant cette MP52 Arg humaine et permettant, entre autres, de favoriser la morphogenèse osseuse ou cartilagineuse. En particulier, ladite composition médicale s'avère utile pour traiter des maladies des os engendrées par un métabolisme osseux anormal telles que l'ostéoporose, pour traiter des fractures des os ainsi que pour la reconstruction orthopédique, les greffes osseuses, la chirurgie esthétique et la médecine dentaire. Ce nouveau composé s'avère en outre utile pour le traitement d'affections des cartilages.
EP96928406A 1995-08-03 1996-08-02 Nouvelle proteine humaine mp52 arg Withdrawn EP0842274A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP95112241 1995-08-03
EP95112241 1995-08-03
PCT/EP1996/003427 WO1997006254A1 (fr) 1995-08-03 1996-08-02 Nouvelle proteine humaine mp52 arg

Publications (1)

Publication Number Publication Date
EP0842274A1 true EP0842274A1 (fr) 1998-05-20

Family

ID=8219499

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96928406A Withdrawn EP0842274A1 (fr) 1995-08-03 1996-08-02 Nouvelle proteine humaine mp52 arg

Country Status (15)

Country Link
EP (1) EP0842274A1 (fr)
JP (1) JP2000511155A (fr)
KR (1) KR19990036081A (fr)
CN (1) CN1192237A (fr)
AR (1) AR003974A1 (fr)
AU (1) AU699708B2 (fr)
BR (1) BR9609983A (fr)
CA (1) CA2227204A1 (fr)
HU (1) HUP9900362A2 (fr)
IL (1) IL122817A0 (fr)
MX (1) MX9800801A (fr)
NO (1) NO980375D0 (fr)
PL (1) PL324822A1 (fr)
WO (1) WO1997006254A1 (fr)
ZA (1) ZA966489B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586388B2 (en) 1988-04-08 2003-07-01 Stryker Corporation Method of using recombinant osteogenic protein to repair bone or cartilage defects
GB9610281D0 (en) * 1996-05-16 1996-07-24 Ralston Stuart H Diagnostic method and apparatus
DE19906096A1 (de) 1999-02-13 2000-08-17 Walter Sebald Protein mit einem Heparin-bindenden Epitop
JP5837930B2 (ja) 2010-07-30 2015-12-24 ビオファーム・ゲゼルシャフト・ツァ・ビオテヒノロジッシェン・エントヴィックルング・フォン・ファルマカ・エムベーハー 創傷の治癒を加速する医薬送達装置及び増殖因子製剤
EP2537538A1 (fr) 2011-06-22 2012-12-26 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka mbH Pansement biorésorbable
EP2602264A1 (fr) 2011-12-05 2013-06-12 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka mbH Mutant de GDF-5 pour induire la formation de cartilage
KR101213355B1 (ko) * 2011-12-27 2012-12-18 오스템임플란트 주식회사 초기 안정성이 증진된 치과용 임플란트 및 그 제조 방법
EP4076502A1 (fr) 2019-12-18 2022-10-26 Merck Patent GmbH Utilisation du mutant du gdf-5 pour le traitement de la douleur et de la destruction du cartilage

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0625989T3 (da) * 1992-02-12 2000-06-26 Bioph Biotech Entw Pharm Gmbh DNA-sekvenser kodende for hidtil ukendte vækst-/differentieringsfaktorer
DE4420157B4 (de) * 1993-08-10 2013-04-25 Biopharm Gesellschaft Zur Biotechnologischen Entwicklung Von Pharmaka Mbh Neuer Wachstums/Differenzierungsfaktor der TGF-β-Familie
IL110589A0 (en) * 1993-08-10 1994-11-11 Bioph Biotech Entw Pharm Gmbh Growth/differentiation factor of the TGF- beta family
DE69434651T2 (de) * 1993-12-07 2007-03-08 Genetics Institute, Inc., Cambridge Bmp-12, bmp-13 und diese enthaltende sehne-induzierende zusammensetzungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9706254A1 *

Also Published As

Publication number Publication date
KR19990036081A (ko) 1999-05-25
JP2000511155A (ja) 2000-08-29
BR9609983A (pt) 1999-01-12
NO980375L (no) 1998-01-28
HUP9900362A2 (hu) 1999-05-28
AR003974A1 (es) 1998-09-30
AU699708B2 (en) 1998-12-10
CA2227204A1 (fr) 1997-02-20
MX9800801A (es) 1998-11-29
IL122817A0 (en) 1998-08-16
CN1192237A (zh) 1998-09-02
WO1997006254A1 (fr) 1997-02-20
ZA966489B (en) 1997-02-26
NO980375D0 (no) 1998-01-28
AU6789196A (en) 1997-03-05
PL324822A1 (en) 1998-06-22

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