DE3205847A1 - Daunorubicin-protein conjugates - Google Patents
Daunorubicin-protein conjugatesInfo
- Publication number
- DE3205847A1 DE3205847A1 DE19823205847 DE3205847A DE3205847A1 DE 3205847 A1 DE3205847 A1 DE 3205847A1 DE 19823205847 DE19823205847 DE 19823205847 DE 3205847 A DE3205847 A DE 3205847A DE 3205847 A1 DE3205847 A1 DE 3205847A1
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- daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- 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
- A61K47/62—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 a protein, peptide or polyamino acid
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
-
- 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
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
BESCHREIBUNG DESCRIPTION
Die Erfindung betrifft die Herstellung von Daunorubicinprotein-Ronjugaten, die als Antitumormittel nützlich sind.The invention relates to the production of daunorubicin protein ronjugates, which are useful as anti-tumor agents.
Es ist allgemein bekannt, daß die Hauptschwierigkeit bei der Krebschemotherapie die ist, daß den verfügbaren Arzneimitteln die Selektivität fehlt. Für die Erhöhung der selektiven Toxizität der Antikrebsmittel für Tumorzellen und dementsprechend für ihre therapeutische Wirksamkeit ist die Verbindung oder Assoziierung dieser Arzneimittel mit Trägermakromolekülen vorgeschlagen worden (A. Trouet, Europ. J. Cancer 14:' 105-111, 1978; M. Szekerke und, J.S. Driscoll, ibid, 13: 529-537, 1977). Anthracyclinantibiotika wurden bei dem immunochemischen Versuch verwendet, um die Selektivität dieser cytotoxischen Mittel zu erhöhen, aber die Verwendung von Antikörpern als spezifische Träger wurde durch die Schwierigkeiten bei der Herstellung von Antitumorantikörpern begrenzt.It is well known that the main difficulty in cancer chemotherapy that is, the drugs available lack selectivity. For the increase the selective toxicity of the anti-cancer drugs to tumor cells and accordingly for their therapeutic effectiveness is the connection or association of these Drugs with carrier macromolecules have been proposed (A. Trouet, Europ. J. Cancer 14: 105-111, 1978; M. Szekerke and, J.S. Driscoll, ibid, 13: 529-537, 1977). Anthracycline antibiotics were used in the immunochemical trial to treat the To increase the selectivity of these cytotoxic agents, but the use of antibodies as a specific carrier has been identified by the difficulties in producing anti-tumor antibodies limited.
Weiterhin umfassen alle bekannten Verfahren für das kovalente Binden von Daunorubicin an Antikrebsantikörper oder an andere weniger spezifische proteine die Oxidation oder Modifizierung der primären Aminogruppe des Zuckermolekülteils des Antibiotikums. Da die Anwesenheit und Stereochemie der unsubstituierten Aminofunktion in dem Antibiotikummolekül eine kritsche Determinante sowohl für die DNA-Bindungs- als auch für die biologische Aktivität ist, ergeben die bekannten Verfahren im allgemeinen weniger wirksame Arzneimittel als Folge des Verlusts des basischen Charakters und der elektrostatischen Bindungskomponente in dem Arzneimittel.Furthermore, include all known methods for covalent bonding from daunorubicin to anti-cancer antibodies or to other less specific proteins the oxidation or modification of the primary amino group of the sugar moiety of the antibiotic. Because the presence and stereochemistry of the unsubstituted amino function in the antibiotic molecule a critical determinant for both the DNA binding as well as biological activity, the known methods generally give less effective drugs as a result of the loss of basic character and the electrostatic binding component in the drug.
Zur Beseitigung dieser Nachteile hat die Anmelderin ein alternatives Verfahren für die Herstellung von Daunorubicinprotein-Konjugaten gefunden und entwickelt, bei den das 14-Bromderivat von DaunoruSicin zum Binden des Arzneimittels über seine Acetylseitenkette an unterschiedliche Proteine verwendet wurde (Arcamone et al., BE-PS 731 398 (13. Okt.To eliminate these disadvantages, the applicant has an alternative Process for the production of daunorubicin protein conjugates found and developed, in the case of the 14-bromo derivative of DaunoruSicin to bind the drug above its acetyl side chain was used on different proteins (Arcamone et al., BE-PS 731 398 (Oct. 13.
1969)).1969)).
Gegenstand der vorliegenden Erfindung ist ein Verfahren für die Herstellung eines Daunorubicinprotein-Ronjugats. Das Verfahren ist dadurch gekennzeichnet, daß man 14-Bromdaunorubicin in wäßrig-methanolischer Lösung bei Zimmertemperatur und während einer Zeit von 120 bis 140 Minuten mit einem überschuß eines Proteins umsetzt, während die Lösung durch Zugabe von verdünntem Natriumhydroxid neutral gehalten wird Anschließend wird irgendein vorhandener Niederschlag durch Zentrifugieren abgetrennt. Die überstehende Lösung wird entweder durch Vorbeileiten an einem Ionenaustauschharz, wenn negativ geladene Proteine verwendet werden, oder durch Vorbeileiten an einem Adsorptionsharz, wenn positiv geladene Proteine verwendet werden, gereinigt. Man erhält dabei die reinen Lösungen der gewünschten Daunorubicinprotein-Konjugate.The present invention relates to a method for production a daunorubicin protein ronjugate. The method is characterized in that one 14-Bromdaunorubicin in aqueous-methanolic solution at room temperature and reacts with an excess of a protein for a period of 120 to 140 minutes, while the solution was kept neutral by adding dilute sodium hydroxide Any precipitate present is then removed by centrifugation. The supernatant solution is either passed by an ion exchange resin, when negatively charged proteins are used, or by bypassing one Adsorption resin, if positively charged proteins are used, cleaned. Man receives the pure solutions of the desired daunorubicin protein conjugates.
Die erhaltenen Dannorubicinprotein-Konjugate, bei denen die primäre Aminogruppe des Antibiotikurtis, das für die cytotoxische Aktivität wesentlich ist, noch erhalten ist, zeigen eine cytotoxische Selektivität entweder in vitro durch Inhibierung der koloniebildenden Fähigkeit von HeLa-Zellen oder in vivo gegen Ehrlich -Ascites-tumor.The dannorubicin protein conjugates obtained, in which the primary Amino group of the antibiotic urticaria, which is essential for the cytotoxic activity, is still preserved, show a cytotoxic selectivity by either in vitro Inhibition of the colony-forming ability of HeLa cells or in vivo against Ehrlich -Ascites tumor.
Da man annimmt, daß das 14-Bromderivat des Daunorubicins mit den freien Aminogruppen oder mit den carboxylischen Gruppen der betreffenden Proteine reagiert, wird ein molarer überschuß an Protein (bezogen auf die Aminosäurereste) für die Herstellung der neuen Daunorubicinprotein-Ronjugate verwendet, wie es aus dem folgenden Beispiel folgt, das zur Erläuterung der Erfindung dient.Since it is assumed that the 14-bromo derivative of daunorubicin with the free Amino groups or reacts with the carboxylic groups of the proteins concerned, a molar excess of protein (based on the amino acid residues) for the Manufacture of the new Daunorubicin Protein Ronjugate uses as it is from the following The following example serves to explain the invention.
BEISPIEL 20 mg Protein werden in 2 ml Wasser gelöst. Der pH-Wert der Lösung wird durch Zugabe einer verdünnten wäßrigen Lösung von Natriumhydroxid auf 8,5 eingestellt. 2 mg 14-Bromdaunorubicin (frisch aufgelöst in 0,1 ml Methanol) werden dazugegeben, und das Gemisch wird unter Rühren bei Zimmertemperatur während 120 bis 240 Minuten stehengelassen, während man gleichzeitig den pH-Wert der Lösung auf einen neutralen Wert einstellt, indem man vorsichtig verdünnte wäßrige Natriumhydroxidlösung zugibt, um die während der Reaktion ge.-bildete Bromwasserstoffsäure zu neutralisieren. Nachdem die Reaktion beendigt ist (pH = 7), wird das Gemisch bei 5000 upm während 15 Minuten zentrifugiert. Die klare überstehende Lösung wird im Falle von negativ geladenen Proteinen durch eine Ionenaustauschsäule geleitet, die mit Dowex-50W-X2-Harz (Warenzeichen) gefüllt ist. Dabei wird freies Antibiotikum entfernt. Werden positiv geladene Proteine verwendet, so wird das möglicherweise vorhandene freie Arzneimittel durch Adsorptionschromatographie an Ainberlite-XAD-2-Harz (Warenzeichen) entfernt, um zu vermeiden, daß das Protein an das Ionenaustauschharz gebunden wird. Die entstehenden reinen Lösungen von Daunorubicinprotein-Konjugaten (durch HPLC läßt sich kein freies Arzneimittel nachweisen) werden als solche für die Bewertung ihrer biologischen Aktivität verwendet. EXAMPLE 20 mg of protein are dissolved in 2 ml of water. The pH the solution is made by adding a dilute aqueous solution of sodium hydroxide set to 8.5. 2 mg 14-bromo daunorubicin (freshly dissolved in 0.1 ml methanol) are added and the mixture is stirred while at room temperature Let stand for 120 to 240 minutes while simultaneously adjusting the pH of the solution adjusts to a neutral value by carefully diluting aqueous sodium hydroxide solution added in order to neutralize the hydrobromic acid formed during the reaction. After the reaction is over (pH = 7), the mixture is kept at 5000 rpm during Centrifuged for 15 minutes. The clear supernatant solution becomes negative in the case of charged proteins passed through an ion exchange column made with Dowex-50W-X2 resin (Trademark) is filled. Free antibiotic is removed in the process. Be positive If charged proteins are used, any free drug that may be present will be used removed by adsorption chromatography on Ainberlite XAD-2 resin (trademark), to avoid binding the protein to the ion exchange resin. The emerging pure solutions of daunorubicin protein conjugates (no free Medicinal products are used as such for the evaluation of their biological Activity used.
Biologische Aktivität Die Inhibierung der koloniebildenden Fähigkeit von HeLa-Zellen wurde verwendet, um die Aktivität des Arzneimittels, welches an verschiedene Proteine gebunden ist, quantitativ zu bestimmen. Im allgemeinen ist die Aktivität der Konjugat niedriger als die des reinen Daunorubicins, da typischerweise vierfach höhere Konzentrationen (oder noch mehr) der Konjugate (ausgedrückt als Daunorubicingehalt), verglichen mit dem Gehalt an freiem Antibiotikum, erforderlich sind, um eine 50%ige Inhibierung zu ergeben. Diese Verringerung war zu erwarten, da die begrenzte zellulare Aufnahme der Proteinmakromoleküle die intrazellulare Arzneimittelakkumulierung verringert Jedoch ist die Wirkung der verschiedenen Trägerproteine auf die cytotoxische Aktivität.von Daunomycin unterschiedlich.Biological activity The inhibition of colony-forming ability of HeLa cells was used to measure the activity of the drug which is attached to different proteins is bound to be quantified. In general is the activity of the conjugate is lower than that of pure daunorubicin, as typically four times higher concentrations (or even more) of the conjugates (expressed as Daunorubicin content) compared to the free antibiotic content are to a To give 50% inhibition. This reduction was to be expected because of the limited cellular uptake of the protein macromolecules Intracellular drug accumulation decreases However, the effect is different Carrier proteins on cytotoxic activity. Different from daunomycin.
Obgleich der tatsächliche Mechanismus der Antitumoraktivität des makromolekularen Derivats des cytotoxischen Arzneimittels noch festgelegt werden muß, ist es eindeutig, daß die Verwendung von einigen Proteinen in den meisten Fällen einen wesentlichen Vorteil ergibt. Bei Daunorubicinprotein-Konjugaten legt, wenn die Cytotoxizität zu dem Arzneimittelgehalt in Korrelation steht, die beachtliche Variation in der Inhibitorpotenz der Konjugate (Tabelle I) bestimmte proteinspezifische Effekte nahe.Although the actual mechanism of antitumor activity of the macromolecular Derivative of the cytotoxic drug has yet to be determined, it is clear that the use of some proteins is essential in most cases Advantage. In the case of daunorubicin protein conjugates, if the cytotoxicity specifies is correlated to the drug content, the considerable variation in the Inhibitory potency of the conjugates (Table I) suggests certain protein-specific effects.
Daunorubicin, welches an Kasein, Rionuclease A, Asialofeteuin, Immunoglobulin und Concanavalin A gebunden ist, ist wesentlich aktiver als das Arzneimittel, das an Rinderserumalbumin, Fetuin, Lysozym oder Histone.gebunden ist. Die cytotoxische Wirkung kann nicht der Proteinkomponente der Konjugate zugeordnet werden, da nichtmodifizierte Proteine, wenn sie in Abwesenheit von Daunorubicin getestet werden, keine cytotoxische Wirkung bei ähnlichen oder höheren Konzentrationen (bis zu 20 gjml) zeigen.Daunorubicin, which is linked to casein, rionuclease A, asialofeteuin, immunoglobulin and Concanavalin A is bound, is much more active than the drug that bound to bovine serum albumin, fetuin, lysozyme or histones. The cytotoxic The effect cannot be assigned to the protein component of the conjugates, as they are not modified Proteins, when tested in the absence of daunorubicin, are not cytotoxic Show effect at similar or higher concentrations (up to 20 gjml).
Daunorubicin, das an Immunoglobulin gebunden ist, behält seine relevante Aktivität bei.Daunorubicin, which is bound to immunoglobulin, retains its relevant Activity at.
Tabelle I Biologische Aktivität der Daunorubicinprotein-Konjugate
Tn-vivo-Antitumoruntersuchungen CD1-Mäise (22-28 g) werden intraperitoneal mit Ehrlich-Ascites-Tumorzellen (5 * 106 Zellen pro Tier) 24 Stunden vor der Behandlung mit einer Einzeldosis inokuliert. Bei diesen Bedingungen sind die umorzellen bei 100% der nichtbehandelten Mäuse in 16 bis 18 Tagen tödlich Jede Versuchsgruppe enthält mindestens zehn Mäuse. Vorversuche, die man mit Daunorubicin-Immunoglobulin (Rind, nicht spezifisch)-Konjugat erhält, zeigen an, saß das an das'Protein gebundene Arzneimittel mindestens teilweise seine Aktivität bei höheren Dosismengen beibehält. Jedoch ist eine Verringerung der Potenz mit einer beachtlichen Verringerung' der Toxizität assoziiert (Tabelle II). Daunorubicin, das an ein synthetisches Polypeptid, Poly-l-iys,in gebunden ist, zeigt eine Verringerung der Antitumorpotenz wie im Falle des Daunorubicin-Immunoglobulin-Konjugats. Jedoch ist das Daunorubicin-Poly-l-lysin-Konjugat so aktiv (oder aktiver) wie das freie Arzneimittel bei der geprüften Maximaldosis (16 mg/kg). Wieder ist das an das Protein gebundene Arzneimittel weniger toxisch als das freie Arzneimittel. Die Antitumoraktivität kann nicht auf die Proteinkomponente in dem Konjugat zurückzuführen sein, da das nichtmodifizierte Protein bei der gleichen Dosismenge völlig inaktiv ist.Tn Vivo Antitumor Studies CD1 mice (22-28 g) are administered intraperitoneally with Ehrlich ascites tumor cells (5 * 106 cells per animal) 24 hours before treatment inoculated with a single dose. In these conditions the tumor cells are at 100% of the untreated mice are fatal in 16 to 18 days. Each experimental group contains at least ten mice. Preliminary tests carried out with daunorubicin immunoglobulin (beef, non-specific) conjugate, indicate that the drug bound to the protein was present at least partially retains its activity at higher dose levels. However is a decrease in potency with a considerable decrease in toxicity associated (Table II). Daunorubicin linked to a synthetic polypeptide, poly-l-iys, in bound shows a decrease in antitumor potency as in the case of the daunorubicin-immunoglobulin conjugate. However, the daunorubicin-poly-l-lysine conjugate is as active (or more active) as that free drugs at the tested maximum dose (16 mg / kg). Again this is on the protein-bound drug is less toxic than the free drug. the Antitumor activity cannot be attributed to the protein component in the conjugate because the unmodified protein is completely inactive at the same dose level is.
Tabelle II Aktivität von Daunorubicinprotein-Konjugaten auf Ehrlich-Ascites-Tumorzellen
Claims (2)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB8114167 | 1981-05-08 |
Publications (1)
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DE3205847A1 true DE3205847A1 (en) | 1982-12-16 |
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ID=10521675
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DE19823205847 Withdrawn DE3205847A1 (en) | 1981-05-08 | 1982-02-18 | Daunorubicin-protein conjugates |
Country Status (3)
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JP (1) | JPS57197295A (en) |
BE (1) | BE893109A (en) |
DE (1) | DE3205847A1 (en) |
Families Citing this family (2)
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JPH05239961A (en) * | 1991-08-09 | 1993-09-17 | Fujitsu Ten Ltd | Electronic lock device for car door |
JPH05239963A (en) * | 1991-08-09 | 1993-09-17 | Fujitsu Ten Ltd | Electronic lock device for car door |
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JPS51126281A (en) * | 1975-02-04 | 1976-11-04 | Searle & Co | Cytootoxic substance |
IL47372A (en) * | 1975-05-27 | 1979-10-31 | Yeda Res & Dev | Fab'dimers bound to daunomycin or adriamycin,their preparation and pharmaceutical compositions containing same |
-
1982
- 1982-02-18 DE DE19823205847 patent/DE3205847A1/en not_active Withdrawn
- 1982-05-06 JP JP57074640A patent/JPS57197295A/en active Pending
- 1982-05-07 BE BE0/208030A patent/BE893109A/en not_active IP Right Cessation
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Publication number | Publication date |
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BE893109A (en) | 1982-08-30 |
JPS57197295A (en) | 1982-12-03 |
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