HRP20010154A2 - Bifunctional antibodies and their use in targeting anti-tumour agents - Google Patents
Bifunctional antibodies and their use in targeting anti-tumour agents Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- C—CHEMISTRY; METALLURGY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
Description
Područje izuma Field of invention
Ovaj izum se odnosi na bifunkcionalna antitijela i na njihovu upotrebu u ciljanju anti-tumorskih sredstava in vivo. This invention relates to bifunctional antibodies and their use in targeting anti-tumor agents in vivo.
Pozadina izuma Background of the invention
Usmjeravanje terapijskih sredstava na određena mjesta in vivo, je dobro poznato. Naročito, vrlo je poželjno usmjeriti anti-tumorska sredstva na mjesto tumora, da se poveća koncentracija sredstva na mjestu i tako poboljša njegova djelotvornost u neutraliziranju tumora. Primjeri sredstava koja ciljaju tumore su dobro poznati, mnoga od njih se oslanjaju na specifičnost monoklonalnih antitijela za dostavljanje dijagnostičkog ili terapijskog sredstva na ciljno mjesto. Jedan pristup je upotreba konjugata radionuklid-antitijelo, koji se lokalizira u ciljnom tkivu, gdje radionuklid može vršiti svoj citotoksični učinak. The targeting of therapeutic agents to specific sites in vivo is well known. In particular, it is highly desirable to direct the anti-tumor agents to the site of the tumor, to increase the concentration of the agent at the site and thus improve its effectiveness in neutralizing the tumor. Examples of tumor targeting agents are well known, many of them relying on the specificity of monoclonal antibodies to deliver a diagnostic or therapeutic agent to the target site. One approach is the use of a radionuclide-antibody conjugate, which localizes in the target tissue, where the radionuclide can exert its cytotoxic effect.
Međutim, pokazalo se da postoje problemi s korisnošću konjugata radionuklid-antitijelo, na primjer slaba penetracija konjugata na ciljno mjesto zahvaljujući velikoj molekulskoj masi konjugata. Dodatno, da bi konjugat bio terapijski djelotvoran, mora mu se dati vremena da lokalizira tumor. Zbog toga je radionuklid prisutan u organizmu u produženom periodu, i to rezultira neželjenom toksičnošću na ne-ciljnim mjestima. However, it has been shown that there are problems with the utility of radionuclide-antibody conjugates, for example poor penetration of the conjugate into the target site due to the high molecular weight of the conjugate. Additionally, for the conjugate to be therapeutically effective, it must be given time to localize to the tumor. Because of this, the radionuclide is present in the body for an extended period, and this results in unwanted toxicity at non-target sites.
Zbog toga je poželjno primijeniti antitijela nezavisno od citotoksičnog radiooznačenog sredstva, omogućujući antitijelu da se lokalizira na ciljnom mjestu prije primjene citotoksičnog radiooznačenog sredstva. Therefore, it is desirable to administer the antibody independently of the cytotoxic radiolabeled agent, allowing the antibody to localize to the target site prior to administration of the cytotoxic radiolabeled agent.
US-A-5630996 opisuje jedan pristup, koji upotrebljava konjugate antitijelo-streptavidin za usmjeravanje radionuklid-označenog biotina. Streptavidin ima visok afinitet za biotin i može lokalizirati radionuklid na ciljnom mjestu pomoću interakcije biotin-streptavidin. Međutim, streptavidin je protein koji je imunogen kod ljudi i posljedično, može biti neprikladan za ponavljanu dugoročnu upotrebu. US-A-5630996 describes one approach, which uses antibody-streptavidin conjugates to target radionuclide-labelled biotin. Streptavidin has a high affinity for biotin and can localize the radionuclide to the target site using the biotin-streptavidin interaction. However, streptavidin is a protein that is immunogenic in humans and, consequently, may not be suitable for repeated long-term use.
US-A-5591828 otkriva bispecifična antitijela koja imaju afinitet za metalne kelate i za određeni proteinski epitop. Međutim, kelati, EDTA-Y90 i DTPA-Y90 poželjno zahtijevaju kovalentno vezanje fos-peptida koji međusobno djeluje sa jun-peptidom na antitijelu, za lokaliziranje dovoljno Y90 na ciljnom mjestu. Dodatno, može doći do disocijacije između kelirajućeg sredstva (EDTA) i radionuklida (Y90). Zbog toga, lokalizacija na tumorskom mjestu ne mora biti učinkovita, i postupak proizvodnje fos-peptid-metal kelatnog konjugata je dugačak i neprikladan za proizvodnju u velikom mjerilu. US-A-5591828 discloses bispecific antibodies having affinity for metal chelates and for a specific protein epitope. However, the chelates, EDTA-Y90 and DTPA-Y90 preferably require the covalent attachment of a fos-peptide that interacts with the jun-peptide on the antibody, to localize sufficient Y90 to the target site. Additionally, dissociation between the chelating agent (EDTA) and the radionuclide (Y90) may occur. Therefore, the localization at the tumor site may not be efficient, and the production process of the phos-peptide-metal chelate conjugate is long and unsuitable for large-scale production.
Kratak opis izuma Brief description of the invention
Sadašnji izum se odnosi na bifunkcionalna antitijela koja imaju afinitet i za antigen prisutan na tumorskom mjestu, i za terapijsko ili dijagnostičko sredstvo, pritom sredstvo je organska molekula koja je radiooznačena ili kovalentno vezana za citotoksično sredstvo. U drugom ostvarenju, organska molekula je vezana za enzim koji je sposoban za prevođenje prolijeka u citotoksični oblik. The present invention relates to bifunctional antibodies that have an affinity both for an antigen present at the tumor site and for a therapeutic or diagnostic agent, the agent being an organic molecule that is radiolabeled or covalently bound to a cytotoxic agent. In another embodiment, the organic molecule is attached to an enzyme capable of converting the prodrug into a cytotoxic form.
Izum prema tome pruža sredstvo za povećavanje lokalizacije terapijskog sredstva na ciljnom mjestu kod sisavca, uzastopnom primjenom bifunkcionalnog antitijela i organske molekule. Izum može imati upotrebu u terapijskim ili dijagnostičkim primjenama. The invention therefore provides a means of increasing the localization of a therapeutic agent at a target site in a mammal, by sequential application of a bifunctional antibody and an organic molecule. The invention may have use in therapeutic or diagnostic applications.
Tipično, organska molekula je biotin ili organska molekula koja pokazuje dobru penetraciju na ciljno mjesto i inače neutralnu biodistribuciju in vivo. Typically, the organic molecule is biotin or an organic molecule that exhibits good target site penetration and otherwise neutral biodistribution in vivo.
Jedna od prednosti sadašnjeg izuma je to, da je moguće primijeniti citotoksično sredstvo koje će se lokalizirati na željenom cilju zbog interakcije s antitijelom, ali koje će imati smanjenu toksičnost u ne-ciljnim tkivima, jer će se nevezano sredstvo djelotvorno ukloniti iz organizma. One of the advantages of the present invention is that it is possible to apply a cytotoxic agent that will be localized on the desired target due to interaction with the antibody, but which will have reduced toxicity in non-target tissues, because the unbound agent will be effectively removed from the organism.
U jednom ostvarenju, citotoksično sredstvo je radionuklid, i kovalentno je vezan za organsku molekulu, ili je sam po sebi dio organske molekule. Radionuklid može biti odabran tako da pruži terapijski učinak, npr. kao anti-tumorsko sredstvo, ili se može primijeniti u dijagnostičke svrhe, npr. oslikavanje tumora. In one embodiment, the cytotoxic agent is a radionuclide, and is covalently attached to an organic molecule, or is itself part of an organic molecule. The radionuclide may be selected to provide a therapeutic effect, eg as an anti-tumor agent, or may be used for diagnostic purposes, eg tumor imaging.
U drugom ostvarenju, organska molekula je vezana za enzim koji može biti upotrijebljen za prevođenje prikladnog prolijeka u aktivni citotoksični oblik. In another embodiment, the organic molecule is attached to an enzyme that can be used to convert a suitable prodrug into an active cytotoxic form.
Opis izuma Description of the invention
Antitijela iz sadašnjeg izuma se mogu proizvesti upotrebom konvencionalnih tehnika, na primjer, sinteze hibridoma, tehnikama rekombinantne DNA ili izlaganjem faga. Antitijela mogu biti dobivena iz bilo koje vrste, uključujući glodavce, iako je poželjno da antitijela budu dobivena od sisavaca osim glodavaca, npr. ovaca, koza ili krava, da se razviju visokoafinitetna antitijela. Antibodies of the present invention can be produced using conventional techniques, for example, hybridoma synthesis, recombinant DNA techniques, or phage display. Antibodies can be obtained from any species, including rodents, although it is preferred that the antibodies are obtained from mammals other than rodents, eg, sheep, goats or cows, to develop high-affinity antibodies.
Tipično, antitijela će imati afinitet do najmanje 1010 l/mol, poželjno 1011 l/mol, poželjnije 1012 l/mol i najpoželjnije 1013 l/mol za pojedine ligande. Typically, antibodies will have an affinity of at least 1010 l/mol, preferably 1011 l/mol, more preferably 1012 l/mol and most preferably 1013 l/mol for individual ligands.
Bifunkcionalno antitijelo prema izumu može biti potpuno antitijelo ili može biti njegov fragment, npr. f(ab)2. U daljnjem ostvarenju, antitijelo može sadržavati dva jednolančana fv fragmenta. Priprava bifunkcionalnih sFv je dobro poznata. Na primjer, Carter i sur., Current Opinion in Biotechnology 1997, 8: 449-454, otkriva proizvodnju bifunkcionalnih sFv pomoću biblioteka izloženih faga. The bifunctional antibody according to the invention may be a complete antibody or may be a fragment thereof, eg f(ab)2. In a further embodiment, the antibody may contain two single-chain fv fragments. The preparation of bifunctional sFv is well known. For example, Carter et al., Current Opinion in Biotechnology 1997, 8: 449-454, discloses the production of bifunctional sFv using phage display libraries.
Dodatno, antitijela se mogu modificirati tehnikama rekombinantne DNA za “humaniziranje” antitijela, što ih čini manje imunogenima kad se primjenjuju pacijentu. Humanizirana antitijela bi trebala sadržavati barem hipervarijabilnu regiju i iz monoklonalnog antitijela koje ima afinitet za ciljni antigen, i monoklonalnog antitijela koje ima afinitet za organsku molekulu. Ostatak varijabilne regije antitijela može biti iz ljudskog imunoglobulina. Veći udio ljudskog imunoglobulina može biti prisutan u cijelom antitijelu ili fragmentu, npr. F(ab’)2. Kad se upotrebljava jednolančani Fv fragment, fragment može sadržavati hipervarijabilne regije kako je opisano iznad i, po potrebi, varijabilni okvir iz ljudskog imunoglobulina. Additionally, antibodies can be modified by recombinant DNA techniques to “humanize” the antibodies, making them less immunogenic when administered to a patient. Humanized antibodies should contain at least a hypervariable region from both a monoclonal antibody having affinity for the target antigen and a monoclonal antibody having affinity for the organic molecule. The remainder of the variable region of the antibody may be from human immunoglobulin. A greater proportion of human immunoglobulin may be present in the whole antibody or a fragment, eg F(ab')2. When a single-chain Fv fragment is used, the fragment may contain hypervariable regions as described above and, if necessary, a variable frame from a human immunoglobulin.
Antitijelo će imati afinitet za određeno ciljno mjesto. Tipično, ciljno mjesto će biti tumor, i antitijelo će imati afinitet za antigen povezan s tumorom. Primjer antigena povezanog s tumorom je karcinoembrionski antigen (CEA), koji se nalazi na kolorektalnim tumorima i drugim adeno-karcinomima. An antibody will have an affinity for a specific target site. Typically, the target site will be a tumor, and the antibody will have an affinity for a tumor-associated antigen. An example of a tumor-associated antigen is carcinoembryonic antigen (CEA), which is found on colorectal tumors and other adenocarcinomas.
U poželjnom ostvarenju, antitijelo ima ligandni afinitet za organsku molekulu koja je radiooznačena. Izum obuhvaća i zasebno kovalentno pričvršćivanje radionuklida za organsku molekulu, i dodatno jednostavno radiooznačavanje prikladnog atoma na samoj organskoj molekuli. Na primjer, organska molekula može sadržavati atom fosfora ili joda, koji je radiooznačen, da se dobije citotoksična organska molekula. Primjena molekule će lokalizirati radionuklid na mjestu tumora vezanjem za antitijelo, da vrši citotoksični učinak na tumor. Radionuklidi koji imaju citotoksični učinak na tumor su dobro poznati. Poželjni radionuklid koji se može upotrijebiti u izumu je radioizotop joda, npr. I123, I124 i I125, koji se mogu upotrijebiti u dijagnostičke svrhe i I131 koji se može upotrijebiti za terapiju. Idući poželjni radionuklid, koji se može upotrijebiti u izumu, je P32. In a preferred embodiment, the antibody has ligand affinity for an organic molecule that is radiolabeled. The invention includes separate covalent attachment of the radionuclide to the organic molecule, and additionally simple radiolabeling of a suitable atom on the organic molecule itself. For example, an organic molecule may contain a phosphorus or iodine atom, which is radiolabelled, to produce a cytotoxic organic molecule. Application of the molecule will localize the radionuclide at the tumor site by binding to the antibody, to exert a cytotoxic effect on the tumor. Radionuclides that have a cytotoxic effect on the tumor are well known. A preferred radionuclide that can be used in the invention is a radioisotope of iodine, eg I123, I124 and I125, which can be used for diagnostic purposes and I131 which can be used for therapy. A further preferred radionuclide which can be used in the invention is P32.
Citotoksično sredstvo može također biti citotoksični lijek, npr. ricin ili kaliheamicin. The cytotoxic agent may also be a cytotoxic drug, eg, ricin or calicheamicin.
U alternativnom ostvarenju, organska molekula je vezana (konjugirana) za enzim. Enzim je sposoban za prevođenje odgovarajućeg prolijeka u aktivni citotoksični oblik. Termin “prolijek” je ovdje upotrijebljen da definira neaktivni oblik lijeka, koji se može cijepati enzimskim djelovanjem da se otpusti terapijski aktivni oblik. Prikladni sustavi enzim-prolijek su poznati stručnjacima i uključuju karboksipeptidaze i modificirane derivate gorušičinog ulja. In an alternative embodiment, the organic molecule is attached (conjugated) to the enzyme. The enzyme is capable of converting the appropriate prodrug into an active cytotoxic form. The term “prodrug” is used herein to define an inactive form of a drug, which can be cleaved by enzymatic action to release the therapeutically active form. Suitable enzyme-prodrug systems are known to those skilled in the art and include carboxypeptidases and modified mustard oil derivatives.
Organske molekule koje su korisne u sadašnjem izumu moraju biti sposobne za specifičnu interakciju s antitijelom. Molekule moraju zbog toga biti dovoljno velike da bi izazvale imuni odgovor za proizvodnju antitijela kad su konjugirane s proteinskim nosačem, ili biti dovoljno velike da bi olakšale stvaranje antitijela iz biblioteka antitijela, npr. izloženih na filamentoznom fagu. Poželjno, organske molekule vezane na citotoksično sredstvo ili enzim su sposobne za prolazak kroz stijenku žila, da bi dosegle ciljno mjesto. Molekulska masa organskih molekula je poželjno manja od 1500, poželjnije manja od 1000. Organske molekule poželjno nisu toksične kad nisu radiooznačene. Dodatno, označene organske molekule bi trebale imati neutralnu biodistribuciju kad se primijene pacijentu u odsutnosti bispecifičnog antitijela, i poželjno je da se odaberu molekule koje se ne akumuliraju u štitnjači i brzo se izlučuju preko bubrega. Također je korisno ako se molekule lako dobivaju iz ne-označene početne molekule i ako je derivirana, označena molekula stabilna nakon primjene. Konjugat bi trebao poželjno biti topljiv u vodi, da se olakša priprava u odgovarajućim ekscipijentima. Prikladne organske molekule uključuju ne-toksične spojeve, iako se molekule mogu načiniti citotoksičnima radiooznačavanjem. Organic molecules useful in the present invention must be capable of specific interaction with an antibody. The molecules must therefore be large enough to elicit an immune response to produce antibodies when conjugated to a protein carrier, or be large enough to facilitate antibody generation from antibody libraries, eg displayed on filamentous phage. Preferably, the organic molecules bound to the cytotoxic agent or enzyme are capable of passing through the vessel wall to reach the target site. The molecular weight of organic molecules is preferably less than 1500, more preferably less than 1000. Organic molecules are preferably non-toxic when they are not radiolabeled. Additionally, labeled organic molecules should have neutral biodistribution when administered to a patient in the absence of bispecific antibody, and it is desirable to select molecules that do not accumulate in the thyroid gland and are rapidly excreted via the kidney. It is also useful if the molecules are easily obtained from the unlabeled starting molecule and if the derivatized, labeled molecule is stable after administration. The conjugate should preferably be soluble in water, to facilitate preparation in suitable excipients. Suitable organic molecules include non-toxic compounds, although the molecules can be made cytotoxic by radiolabelling.
U poželjnom ostvarenju, radiooznačena organska molekula je radiooznačeni biotin. U daljnjem poželjnom ostvarenju, molekula ima formulu I In a preferred embodiment, the radiolabeled organic molecule is radiolabeled biotin. In a further preferred embodiment, the molecule has formula I
[image] [image]
tj. 4,4-bis(4-hidroksi-3,5-dijodfenil)pentan kiselina. ie 4,4-bis(4-hydroxy-3,5-diiodophenyl)pentanoic acid.
U daljnjem poželjnom ostvarenju, molekula ima formulu II In a further preferred embodiment, the molecule has formula II
[image] [image]
gdje R1 i R2 su, svaki nezavisno, radiooznačena skupina, npr. radiooznačeni jod, metil skupina ili fenil skupina, i X1 i X2 su, svaki nezavisno, H ili OH. wherein R 1 and R 2 are each independently a radiolabeled group, eg, radiolabeled iodine, a methyl group or a phenyl group, and X 1 and X 2 are each independently H or OH.
Poželjne radiooznačene molekule su N-(4-hidroksi-3,5-dijodbenzoil)-1,6-heksandiamin i N-(2-hidroksi-3,5-dijodbenzoil)-1,6-heksandiamin, gdje bilo koji ili svaki od atoma joda može biti bilo koji od radioizotopa I123, I125, I124 i I131. Preferred radiolabeled molecules are N-(4-hydroxy-3,5-diiodobenzoyl)-1,6-hexanediamine and N-(2-hydroxy-3,5-diiodobenzoyl)-1,6-hexanediamine, where any or each of iodine atom can be any of the radioisotopes I123, I125, I124 and I131.
Za upotrebu u izumu, bispecifično antitijelo i citotoksično sredstvo se mogu formulirati u kompletu, npr. koji sadrži dvije komponente zasebno pakirane ili u zasebnim spremnicima. Svaka komponenta može biti formulirana s prikladnim nosačem ili ekscipijentom, primjeri kojih su dobro poznati, ovisno o putu primjene, npr. oralno ili intravenski. For use in the invention, the bispecific antibody and the cytotoxic agent may be formulated in a kit, eg, containing the two components separately packaged or in separate containers. Each component may be formulated with a suitable carrier or excipient, examples of which are well known, depending on the route of administration, eg oral or intravenous.
Dvije komponente će se obično primjenjivati uzastopno. Stručnjak može lako odrediti djelotvornu količinu svake, i ovisit će o tipičnim faktorima kao što je lokacija, ozbiljnost i raširenost tumora, stanje subjekta itd. Naravno, značajka ovog izuma je to, da će količina citotoksičnog sredstva koja je potrebna biti manja nego u odsutnosti antitijela. The two components will usually be applied sequentially. The effective amount of each can be readily determined by the skilled artisan, and will depend on typical factors such as the location, severity and spread of the tumor, condition of the subject, etc. Of course, it is a feature of the present invention that the amount of cytotoxic agent required will be less than in the absence of antibody. .
Claims (20)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9819411.1A GB9819411D0 (en) | 1998-09-04 | 1998-09-04 | Antibodies |
| PCT/GB1999/002938 WO2000014119A2 (en) | 1998-09-04 | 1999-09-06 | Bifunctional antibodies and their use in targeting anti-tumour agents |
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| Publication Number | Publication Date |
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| HRP20010154A2 true HRP20010154A2 (en) | 2002-02-28 |
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| HR20010154A HRP20010154A2 (en) | 1998-09-04 | 2001-03-02 | Bifunctional antibodies and their use in targeting anti-tumour agents |
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| EP (1) | EP1107995A2 (en) |
| JP (1) | JP2002524470A (en) |
| KR (1) | KR20010072988A (en) |
| CN (1) | CN1315967A (en) |
| AU (1) | AU5641299A (en) |
| BG (1) | BG105293A (en) |
| BR (1) | BR9913429A (en) |
| CA (1) | CA2341753A1 (en) |
| EA (1) | EA200100311A1 (en) |
| GB (1) | GB9819411D0 (en) |
| HR (1) | HRP20010154A2 (en) |
| HU (1) | HUP0104091A2 (en) |
| ID (1) | ID28873A (en) |
| IL (1) | IL141524A0 (en) |
| MX (1) | MXPA01002349A (en) |
| NO (1) | NO20011102L (en) |
| PL (1) | PL346861A1 (en) |
| TR (2) | TR200103405T2 (en) |
| WO (1) | WO2000014119A2 (en) |
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| WO2020019232A1 (en) * | 2018-07-26 | 2020-01-30 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and methods for imaging |
| CN110811820B (en) * | 2019-12-11 | 2022-07-12 | 江西华晨医疗设备有限公司 | Straight rod type flushing and suction electrocoagulation cutter |
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| US4474893A (en) * | 1981-07-01 | 1984-10-02 | The University of Texas System Cancer Center | Recombinant monoclonal antibodies |
| IL89491A0 (en) * | 1988-11-17 | 1989-09-10 | Hybritech Inc | Bifunctional chimeric antibodies |
| US5217713A (en) * | 1988-12-27 | 1993-06-08 | Takeda Chemical Industries, Ltd. | Cytotoxic bispecific monoclonal antibody, its production and use |
| WO1991009134A1 (en) * | 1989-12-15 | 1991-06-27 | Takeda Chemical Industries, Ltd. | Biospecific antibody to cancer cell and enzyme with prodrug-activating characteristics |
| JPH05184383A (en) * | 1990-06-19 | 1993-07-27 | Dainabotsuto Kk | Bispecific antibody |
| EP0981748A4 (en) * | 1997-02-26 | 2002-09-18 | Ban-An Khaw | Signal enhancement of bispecific antibody-polymer probe for immunoassay use |
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1998
- 1998-09-04 GB GBGB9819411.1A patent/GB9819411D0/en not_active Ceased
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1999
- 1999-09-06 KR KR1020017002437A patent/KR20010072988A/en not_active Application Discontinuation
- 1999-09-06 EP EP99943138A patent/EP1107995A2/en not_active Withdrawn
- 1999-09-06 TR TR2001/03405T patent/TR200103405T2/en unknown
- 1999-09-06 BR BR9913429-2A patent/BR9913429A/en not_active IP Right Cessation
- 1999-09-06 HU HU0104091A patent/HUP0104091A2/en unknown
- 1999-09-06 MX MXPA01002349A patent/MXPA01002349A/en not_active Application Discontinuation
- 1999-09-06 ID IDW20010752A patent/ID28873A/en unknown
- 1999-09-06 AU AU56412/99A patent/AU5641299A/en not_active Abandoned
- 1999-09-06 JP JP2000568876A patent/JP2002524470A/en active Pending
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- 1999-09-06 CA CA002341753A patent/CA2341753A1/en not_active Abandoned
- 1999-09-06 PL PL99346861A patent/PL346861A1/en not_active Application Discontinuation
- 1999-09-06 CN CN99810368A patent/CN1315967A/en active Pending
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| JP2002524470A (en) | 2002-08-06 |
| WO2000014119A2 (en) | 2000-03-16 |
| BG105293A (en) | 2001-12-29 |
| PL346861A1 (en) | 2002-03-11 |
| NO20011102L (en) | 2001-03-05 |
| KR20010072988A (en) | 2001-07-31 |
| CN1315967A (en) | 2001-10-03 |
| AU5641299A (en) | 2000-03-27 |
| NO20011102D0 (en) | 2001-03-02 |
| MXPA01002349A (en) | 2003-10-15 |
| CA2341753A1 (en) | 2000-03-16 |
| ZA200101574B (en) | 2002-02-26 |
| BR9913429A (en) | 2001-09-25 |
| TR200103405T2 (en) | 2002-06-21 |
| HUP0104091A2 (en) | 2002-03-28 |
| TR200100651T2 (en) | 2001-07-23 |
| IL141524A0 (en) | 2002-03-10 |
| GB9819411D0 (en) | 1998-10-28 |
| EP1107995A2 (en) | 2001-06-20 |
| WO2000014119A3 (en) | 2000-11-30 |
| ID28873A (en) | 2001-07-12 |
| EA200100311A1 (en) | 2001-08-27 |
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