JPH05508856A - 抗体接合体 - Google Patents
抗体接合体Info
- Publication number
- JPH05508856A JPH05508856A JP91512871A JP51287191A JPH05508856A JP H05508856 A JPH05508856 A JP H05508856A JP 91512871 A JP91512871 A JP 91512871A JP 51287191 A JP51287191 A JP 51287191A JP H05508856 A JPH05508856 A JP H05508856A
- Authority
- JP
- Japan
- Prior art keywords
- antibody
- conjugate
- cells
- group
- superantigen
- 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.)
- Granted
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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- 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
- A61K39/385—Haptens or antigens, bound to carriers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6829—Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- 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
- 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
-
- 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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
-
- 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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6068—Other bacterial proteins, e.g. OMP
-
- 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
- A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
- A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims (22)
- 1.抗体および超抗原からなる可溶性抗体接合体。
- 2.(i)抗体は疾患に関連する標的細胞の細胞表面構造に特異的であり、 (ii)超抗原はT細胞によって認識され、細胞障害性T細胞(CTL)を活性 化可能で、好ましくはT細胞受容体複合体の部分たとえばT細胞受容体Vβ鎖と 相互作用可能である請求項1記載の可溶性抗体接合体。
- 3.標的細胞は、癌、自己免疫、寄生体感染および微生物感染、たとえばウイル ス感染、かび感染および細菌感染からなる群より選ばれる疾患に関連し、抗体は その標的細胞上に存在する抗原決定基に対して特異的である請求項1および2記 載の接合体。
- 4.疾患は癌であり、抗体は腫瘍細飽たとえば結腸癌関連細胞上に存在する抗原 決定基(エピトープ)に対する抗体である請求項2および3記載の接合体。
- 5.抗体はC242エピトープに特異的である請求項4記載の接合体。
- 6.抗体はGA−733ファミリーに属する蛋白質上のエピトープ、とくにC2 15エピトープに特異的である請求項4記載の接合体。
- 7.抗体残基あたり、超抗原残基が少なくとも1〜5、好ましくは1〜3存在す る請求項1〜6のいずれかに記載の接合体。
- 8.抗体はモノクローナル抗体である請求項1〜7のいずれかに記載の接合体。
- 9.超抗原は細菌起源のものであり、とくにブドウ球菌エンテロトキシンからな る群より選ばれる請求項1〜8のいずれかに記載の接合体。
- 10.超抗原はSEAである請求項1〜9のいずれかに記載の接合体。
- 11.超抗原および抗体は共有結合有機連鎖構造−B−を介して保持され、連鎖 構造は少なくとも1個のアミド構造からなり、好ましくは、連鎖は少なくとも6 原子長であることを条件に親水性である請求項1〜10のいずれかに記載の接合 体。
- 12.連鎖−B−は、構造 −SrRCONHCH2CH2(OCH2CH2)nO(CH2)mCOY− (I)(式中、rは整数1または2であり、Rは1〜4個の炭素原子を有するア ルキレン基であり、nは整数1〜20であり、mは1または2であり、Yは−N H−、−NHNH−または−NHN=CH−である)からなる請求項11記載の 接合体。
- 13.接合体の抗体残基がそれに対して向けられている細胞表面構造をもつ標的 細胞の溶解のために使用される請求項1〜11のいずれかに記載の接合体。
- 14.超抗原に連結された抗体からなり、抗体は標的細胞に特異的で、超抗原は T細胞によって認識され細胞障害性T細胞(CTL)を活性化できる可溶性抗体 接合体の標的細胞溶解有効量を標的細胞と接触させる、標的細胞の溶解方法。
- 15.超抗原、抗体、および抗体を超抗原に連結させる連鎖構造は請求項1〜1 3のいずれかで定義された通りである請求項14記載の溶解方法。
- 16.(i)超抗原を抗体に、(a)炭水化物構造、ならびに(b)官能基すな わちチオール基、ジスルフィド基、カルボキシ基およびアミノ基から選ばれる少 なくとも1つの構造を介して、それ自体知られた方法によってカップリングさせ て抗体および/または超抗原から接合体を合成し、(ii)接合体をそれがその 中で製造された媒体から回収する工程からなる接合体の製造方法。
- 17.カップリングは超抗原および/または抗体中のアミノ基で行わせる請求項 16記載の接合体の製造方法。
- 18.カップリングは、(i)抗体または超抗原を、チオール反応性基およびア ミノ反応性基を含有する有機試薬と反応させて、チオール基をもつ抗体または超 抗原を形成させ、 (ii)超抗原および抗体の残基部を、チオール基または保護チオール基および アミノ反応性基を含有する有機試薬と反応させて、チオール基または保護チオー ル基をもつ超抗原または抗体を形成させ、ついで(iii)工程(i)および( ii)からそれぞれ得られた生成物を互いに反応させ、超抗原がジスルフィドま たはチオエーテルを介して抗体に連結した接合体を形成させる各工程からなる請 求項17記載の接合体の製造方法。
- 19.チオール反応性基を含有するアミノ反応性基はα−ハロアセチルハライド であり、チオール基または保護チオール基を含有する化合物は式II −Z1RCONHCH2CH2(OCH2CH2)nO(CH2)mZ1′ ( II)〔式中、mは整数1または2であり、nは整数1〜20であり、Z1はH S−反応性求電子基、チオール(−SH)または保護チオール(たとえばAcS −)であり、ただしチオール基およびヒドロキシ基はR中の一つの同一炭素原子 に結合していてはならない。Z1′は活性化カルボキシである〕で表される二官 能性カップリング試薬である請求項18記載の接合体の製造方法。
- 20.超抗原および抗体は請求項2〜10のいずれかで定義された通りである請 求項16〜19のいずれかに記載の接合体の製造方法。
- 21.癌、自己免疫、ウイルス、細菌またはかびによる感染、および寄生体によ る感染からなる群より選ばれる疾患に罹患したヒト個体を含めた哺乳動物の処置 方法において、その動物に請求項1〜12のいずれかに記載の接合体の標的細胞 溶解有効量を投与し、この場合、標的細胞は処置する疾患に関連する方法。
- 22.癌、自己免疫、ウイルス、細菌もしくはかびによる感染、または寄生体に よる感染の処置を意図した医薬組成物の製造における請求項1〜12のいずれか に記載の接合体の使用。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9002479A SE9002479D0 (sv) | 1990-07-20 | 1990-07-20 | Antibody conjugates |
SE9002484-5 | 1990-07-20 | ||
SE9002484A SE9002484L (sv) | 1990-07-20 | 1990-07-20 | Nya substituerade polyetrar |
SE9002479-5 | 1990-07-20 | ||
PCT/SE1991/000496 WO1992001470A1 (en) | 1990-07-20 | 1991-07-16 | Target specific antibody-superantigen conjugates and their preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH05508856A true JPH05508856A (ja) | 1993-12-09 |
JP3334130B2 JP3334130B2 (ja) | 2002-10-15 |
Family
ID=26660818
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51287191A Expired - Lifetime JP3334130B2 (ja) | 1990-07-20 | 1991-07-16 | 抗体接合体 |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0610179B1 (ja) |
JP (1) | JP3334130B2 (ja) |
KR (1) | KR100189024B1 (ja) |
AT (1) | ATE144145T1 (ja) |
AU (1) | AU656906B2 (ja) |
CA (1) | CA2087164C (ja) |
DE (1) | DE69122777T2 (ja) |
DK (1) | DK0610179T3 (ja) |
ES (1) | ES2094231T3 (ja) |
GR (1) | GR3022202T3 (ja) |
HK (1) | HK1007955A1 (ja) |
HU (1) | HU218603B (ja) |
LV (1) | LV10201B (ja) |
NO (1) | NO312816B1 (ja) |
RU (1) | RU2125889C1 (ja) |
WO (1) | WO1992001470A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996035451A1 (fr) * | 1995-05-10 | 1996-11-14 | Kyowa Hakko Kogyo Co., Ltd. | Nouveau complexe de toxines |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6042837A (en) * | 1989-09-20 | 2000-03-28 | Kalland; Terje | Methods of staphylococcal enterotoxin directed cell-mediated cytotoxicity (SDCC) |
US6126945A (en) | 1989-10-03 | 2000-10-03 | Pharmacia Ab | Tumor killing effects of enterotoxins, superantigens, and related compounds |
US5728388A (en) | 1989-10-03 | 1998-03-17 | Terman; David S. | Method of cancer treatment |
US6197299B1 (en) | 1990-07-20 | 2001-03-06 | Pharmacia & Upjohn Ab | Antibody conjugates |
GB9114399D0 (en) * | 1991-07-03 | 1991-08-21 | Ici Plc | Conjugates |
SE9102074D0 (sv) * | 1991-07-03 | 1991-07-03 | Kabi Pharmacia Ab | Tomour antigen specific antibody |
US5965132A (en) | 1992-03-05 | 1999-10-12 | Board Of Regents, The University Of Texas System | Methods and compositions for targeting the vasculature of solid tumors |
PT627940E (pt) * | 1992-03-05 | 2003-07-31 | Univ Texas | Utilizacao de imunoconjugados para o diagnostico e/ou terapia de tumores vascularizados |
US6749853B1 (en) | 1992-03-05 | 2004-06-15 | Board Of Regents, The University Of Texas System | Combined methods and compositions for coagulation and tumor treatment |
EP0659438A1 (en) * | 1993-12-23 | 1995-06-28 | Boehringer Mannheim Gmbh | Conjugates consisting of peptidic T cell antigens and cell binding groups, and their use for therapy |
GB9326574D0 (en) * | 1993-12-31 | 1994-03-02 | King S College London | Dry power inhalers |
SE9402430L (sv) * | 1994-07-11 | 1996-01-12 | Pharmacia Ab | Konjugat mellan modifierat superantigen och en målsökande förening samt användning av konjugaten |
SE9601245D0 (sv) | 1996-03-29 | 1996-03-29 | Pharmacia Ab | Chimeric superantigens and their use |
TW517061B (en) | 1996-03-29 | 2003-01-11 | Pharmacia & Amp Upjohn Ab | Modified/chimeric superantigens and their use |
US6818213B1 (en) | 1998-07-13 | 2004-11-16 | Board Of Regents, The University Of Texas System | Cancer treatment compositions comprising therapeutic conjugates that bind to aminophospholipids |
IL140700A0 (en) | 1998-07-13 | 2002-02-10 | Univ Texas | Cancer treatment methods using therapeutic conjugates that bind to aminophospholipids |
US8029803B2 (en) | 2002-06-20 | 2011-10-04 | Paladin Labs, Inc. | Chimeric antigens for eliciting an immune response |
US8025873B2 (en) | 2002-06-20 | 2011-09-27 | Paladin Labs, Inc. | Chimeric antigens for eliciting an immune response |
US8007805B2 (en) | 2003-08-08 | 2011-08-30 | Paladin Labs, Inc. | Chimeric antigens for breaking host tolerance to foreign antigens |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4545985A (en) * | 1984-01-26 | 1985-10-08 | The United States Of America As Represented By The Secretary, Dept. Of Health And Human Services | Pseudomonas exotoxin conjugate immunotoxins |
US4797491A (en) * | 1986-03-17 | 1989-01-10 | Cetus Corporation | Compound 1-(3-(2-pyridyldithio)propionamido)-12-(5-hydrazidoglutaramido)-4,9-dioxadodecane |
US4806494A (en) * | 1986-07-24 | 1989-02-21 | The United States Of America As Represented By The Department Of Health & Human Services | Monoclonal antibody against ovarian cancer cells (OVB-3) |
GB8626413D0 (en) * | 1986-11-05 | 1986-12-03 | Gilliland L K | Antibodies |
US4981979A (en) * | 1987-09-10 | 1991-01-01 | Neorx Corporation | Immunoconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
US5004692A (en) * | 1987-12-15 | 1991-04-02 | Protein Design Labs, Inc. | Cloning and expression of phosopholipase C genes |
IL89504A0 (en) * | 1988-03-08 | 1989-09-10 | Univ Wyoming | Diphtheria toxin derivative,process for the preparation thereof and pharmaceutical composition containing the same |
EP0334300A1 (en) * | 1988-03-21 | 1989-09-27 | Neorx Corporation | The use of monoclonal antibodies and conjugates thereof as signals to direct sensitized effector cells to tumor sites |
JPH02196799A (ja) * | 1988-04-08 | 1990-08-03 | Agency Of Ind Science & Technol | 抗ヒト癌蛋白複合体 |
-
1991
- 1991-07-16 ES ES91914023T patent/ES2094231T3/es not_active Expired - Lifetime
- 1991-07-16 JP JP51287191A patent/JP3334130B2/ja not_active Expired - Lifetime
- 1991-07-16 AU AU82941/91A patent/AU656906B2/en not_active Ceased
- 1991-07-16 DE DE69122777T patent/DE69122777T2/de not_active Expired - Lifetime
- 1991-07-16 RU RU93004918A patent/RU2125889C1/ru not_active IP Right Cessation
- 1991-07-16 EP EP91914023A patent/EP0610179B1/en not_active Expired - Lifetime
- 1991-07-16 DK DK91914023.6T patent/DK0610179T3/da active
- 1991-07-16 AT AT91914023T patent/ATE144145T1/de not_active IP Right Cessation
- 1991-07-16 WO PCT/SE1991/000496 patent/WO1992001470A1/en active IP Right Grant
- 1991-07-16 CA CA002087164A patent/CA2087164C/en not_active Expired - Lifetime
- 1991-07-16 HU HU9300148A patent/HU218603B/hu not_active IP Right Cessation
- 1991-07-16 KR KR1019930700181A patent/KR100189024B1/ko not_active IP Right Cessation
-
1993
- 1993-01-19 NO NO19930174A patent/NO312816B1/no unknown
- 1993-12-22 LV LVP-93-1362A patent/LV10201B/en unknown
-
1996
- 1996-12-31 GR GR960403689T patent/GR3022202T3/el unknown
-
1998
- 1998-06-26 HK HK98107094A patent/HK1007955A1/xx not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996035451A1 (fr) * | 1995-05-10 | 1996-11-14 | Kyowa Hakko Kogyo Co., Ltd. | Nouveau complexe de toxines |
Also Published As
Publication number | Publication date |
---|---|
CA2087164C (en) | 2002-11-26 |
HK1007955A1 (en) | 1999-04-30 |
DK0610179T3 (da) | 1997-03-24 |
ATE144145T1 (de) | 1996-11-15 |
WO1992001470A1 (en) | 1992-02-06 |
DE69122777T2 (de) | 1997-04-10 |
EP0610179A1 (en) | 1994-08-17 |
GR3022202T3 (en) | 1997-03-31 |
LV10201B (en) | 1995-08-20 |
ES2094231T3 (es) | 1997-01-16 |
EP0610179B1 (en) | 1996-10-16 |
HU9300148D0 (en) | 1993-04-28 |
HUT67502A (en) | 1995-04-28 |
HU218603B (hu) | 2000-10-28 |
NO930174D0 (no) | 1993-01-19 |
AU656906B2 (en) | 1995-02-23 |
NO312816B1 (no) | 2002-07-08 |
NO930174L (no) | 1993-01-19 |
RU2125889C1 (ru) | 1999-02-10 |
KR100189024B1 (ko) | 1999-06-01 |
CA2087164A1 (en) | 1992-01-21 |
LV10201A (lv) | 1994-10-20 |
AU8294191A (en) | 1992-02-18 |
JP3334130B2 (ja) | 2002-10-15 |
DE69122777D1 (de) | 1996-11-21 |
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