DK167936B1 - MONOCLONAL ANTIBODIES AGAINST ANTIGENS OF HUMAN CARCINOMA CELLS, THEIR PREPARATION AND USE, AND ANTIGENS OF CARCINOMA CELLS FROM HUMAN EPITHEL - Google Patents
MONOCLONAL ANTIBODIES AGAINST ANTIGENS OF HUMAN CARCINOMA CELLS, THEIR PREPARATION AND USE, AND ANTIGENS OF CARCINOMA CELLS FROM HUMAN EPITHEL Download PDFInfo
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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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- 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
- A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
DK 167936 B1DK 167936 B1
Den foreliggende opfindelse angår monoklonale antistoffer mod antigener fra humane carcinomaceller, en fremgangsmåde til fremstilling deraf, anvendelse af de monoklonale antistoffer samt membranassocierede antigener fra 5 carcinomaceller fra humant epitel.The present invention relates to monoclonal antibodies to human carcinoma cell antigens, to a method for their preparation, to the use of the monoclonal antibodies, and to membrane associated antigens from human carcinoma cells from human epithelium.
Teknikken til immunisering med definerede, isolerede antigener og produktionen af antistoffer imod sådanne antigener er kendt. Det er også kendt at immunisere med urenset antigenmateriale og selektere de antistoffer, der erkender 10 en bestemt komponent i en sådan antigenblanding.The technique of immunizing with defined isolated antigens and the production of antibodies against such antigens is known. It is also known to immunize with crude antigenic material and select those antibodies that recognize a particular component of such an antigenic composition.
Ved et forsøg på at inducere sådanne antistoffer er det lykkedes at selektere monoklonale antistoffer, der under ikke-reducerende betingelser reagerer med følgende proteinantigener: antigen 1: Molekylvægt (MW) 33 kD ± 3, antigen 2: 15 MW 134 kD ± 3, antigen 3: MW 80 kD ± 3, antigen 4: 55 kD ± 3, antigen 5: 60 kD ± 3, antigen 6: 54 kD ± 3, antigen 7:In an attempt to induce such antibodies, we have succeeded in selecting monoclonal antibodies that react under non-reducing conditions with the following protein antigens: antigen 1: molecular weight (MW) 33 kD ± 3, antigen 2: 15 MW 134 kD ± 3, antigen 3: MW 80 kD ± 3, antigen 4: 55 kD ± 3, antigen 5: 60 kD ± 3, antigen 6: 54 kD ± 3, antigen 7:
260 kD ± 3, antigen 8: ikke bestemmelig, antigen 9: ikke bestemmelig, antigen 10: MW 143 kD ± 3, 119 kD ± 3, antigen 11: MW 178 ± 3, antigen 12: MW ikke bestemmelig, antigen 20 13: MW 34 kD ± 3, antigen 14: MW 195 kD ± 3, antigen 15: MW260 kD ± 3, antigen 8: undetectable, antigen 9: undetectable, antigen 10: MW 143 kD ± 3, 119 kD ± 3, antigen 11: MW 178 ± 3, antigen 12: MW undetermined, antigen 20 13: MW 34 kD ± 3, antigen 14: MW 195 kD ± 3, antigen 15: MW
44 kD ± 7, antigen 16: MW 43 kD ± 3, antigen 17: MW 130 kD ± 3.44 kD ± 7, antigen 16: MW 43 kD ± 3, antigen 17: MW 130 kD ± 3.
De på antigenerne 1-17 af antistofferne 1-17 erkendte epitoper er følsomme på forskellig måde overfor en behandling 25 med dithiothreitol (50 mmol/liter, 2 timer, 37°C). Epito-perne på Agl, 2 og 15 forandres ved ovennævnte behandling, epitoperne på Ag4, 10 og 14 forbliver uændret.The epitopes recognized on antigens 1-17 of antibodies 1-17 are sensitive to different treatment with dithiothreitol treatment (50 mmol / liter, 2 hours, 37 ° C). The epitopes on Ag1, 2 and 15 are altered by the above treatment, the epitopes on Ag4, 10 and 14 remain unchanged.
In vitro specificiteterne af antistofferne 1-17 er anført i tabel I.The in vitro specificities of antibodies 1-17 are listed in Table I.
30 De monoklonale antistoffer ifølge opfindelsen er ejen dommelige ved, at de bindes til et membranassocieret antigen fra carcinomaceller fra humant epitel, hvor antigenerne er valgt blandt et antigen (Agl) med en molekylvægt på tilnærmelsesvis 33 ± 3 kD, et antigen (Ag2) med en molekylvægt på 35 tilnærmelsesvis 134 ± 3 kD, et antigen (Ag3) med en molekylvægt på tilnærmelsesvis 80 ± 3 kD, et antigen (Ag4) med en DK 167936 B1 2 molekylvægt på tilnærmelsesvis 55 ± 3 kD, et antigen (Ag5) med en molekylvægt på tilnærmelsesvis 60 ± 3 kD, et antigen (Ag6) med en molekylvægt på tilnærmelsesvis 54 ± 3 kD, et antigen (Ag7) med en molekylvægt på tilnærmelsesvis 260 ± 3 5 kD, et antigen (Ag8) med en ikke bestemmelig molekylvægt, et antigen (Ag9) med en ikke bestemmelig molekylvægt, et antigen (AglO) med en molekylvægt på tilnærmelsesvis 143 ± 3 kD og 119 ± 3 kD, et antigen (Agil) med en molekylvægt på tilnærmelsesvis 178 ± 3 kD, et antigen (Agl2) med en ikke 10 bestemmelig molekylvægt, et antigen (Agl3) med en molekylvægt på tilnærmelsesvis 34 ± 3kD, et antigen (Agl4) med en molekylvægt på tilnærmelsesvis 195 ± 3 kD, et antigen (Agl5) med en molekylvægt på tilnærmelsesvis 44 ± 7 kD, et antigen (Agl6) med en molekylvægt på tilnærmelsesvis 43 ± 3kD eller 15 et antigen (Agl7) med en molekylvægt på 130 ± 3 kD, hvilke antistoffer med de i tabel I angivne cellelinier udviser de specifikke reaktionsmønstre og er fremstillet ved immunisering af pattedyr med humane, in vitro dyrkede cellelinier, celleekstrakter eller ekstrakter fra humane væv.The monoclonal antibodies of the invention are highly judgmental in that they bind to a membrane-associated antigen of human epithelial carcinoma cells, wherein the antigens are selected from an antigen (Ag1) having a molecular weight of approximately 33 ± 3 kD, an antigen (Ag2) with a molecular weight of approximately 134 ± 3 kD, an antigen (Ag3) having a molecular weight of approximately 80 ± 3 kD, an antigen (Ag4) having a molecular weight of approximately 55 ± 3 kD, an antigen (Ag5) having a molecular weight of approximately 60 ± 3 kD, an antigen (Ag6) having a molecular weight of approximately 54 ± 3 kD, an antigen (Ag7) having a molecular weight of approximately 260 ± 35 kD, an antigen (Ag8) of an undetermined molecular weight , an antigen (Ag9) having an undetermined molecular weight, an antigen (Ag10) having a molecular weight of approximately 143 ± 3 kD and 119 ± 3 kD, an antigen (Agil) having a molecular weight of approximately 178 ± 3 kD, an antigen ( Agl2) with one non e 10 determinable molecular weight, an antigen (Agl3) having a molecular weight of approximately 34 ± 3kD, an antigen (Agl4) having a molecular weight of approximately 195 ± 3kD, an antigen (Agl5) having a molecular weight of approximately 44 ± 7kD, a antigen (Agl6) having a molecular weight of approximately 43 ± 3kD or an antigen (Agl7) having a molecular weight of 130 ± 3kD which exhibits the specific reaction patterns in the cell lines and produced by immunization of human mammals , in vitro cultured cell lines, cell extracts or extracts from human tissues.
20 Antigenet ifølge opfindelsen er ejendommeligt ved, åt det er et membranassocieret antigen fra carcinomaceller fra humant epitel, og at det har en molekylvægt på 33 ± 3 kD (Agl) eller 134 + 3 kD (Ag2), en molekylvægt på tilnærmelsesvis 80 ± 3 kD (Ag3) , en molekylvægt på tilnærmelsesvis 25 55 + 3 kD (Ag4), en molekylvægt på tilnærmelsesvis 60 ± 3 (Ag5), en molekylvægt på tilnærmelsesvis 54 ± 3 kD (Ag6), en molekylvægt på tilnærmelsesvis 260 ± 3 kD (Ag7), en ikke bestemmelig molekylvægt (Ag8), en ikke bestemmelig molekylvægt (Ag9), en molekylvægt på tilnærmelsesvis 143 ± 3 kD og 30 119 ± 3 kD (AglO), en molekylvægt på tilnærmelsesvis 178 ± 3 kD (Agil), en ikke bestemmelig molekylvægt (Agl2), en molekylvægt på tilnærmelsesvis 34 ± 3 kD (Agl3) , en molekylvægt på tilnærmelsesvis 195 ± 3 kD (Agl4) , en molekylvægt på tilnærmelsesvis 44 ± 7 kD (Agl5), en molekylvægt på til-35 nærmelsesvis 43 ± 3 kD (Agl6) eller en molekylvægt på 130 ± 3 kD (Agl7) og med specificitet for de monoklonale antistof- DK 167936 B1 3 fer ifølge opfindelsen.The antigen of the invention is peculiar in that it is a membrane-associated antigen of human epithelial carcinoma cells and has a molecular weight of 33 ± 3 kD (Agl) or 134 + 3 kD (Ag2), a molecular weight of approximately 80 ± 3. kD (Ag3), a molecular weight of approximately 55 ± 3 kD (Ag4), a molecular weight of approximately 60 ± 3 (Ag5), a molecular weight of approximately 54 ± 3 kD (Ag6), a molecular weight of approximately 260 ± 3 kD ( Ag7), an undetermined molecular weight (Ag8), an undetermined molecular weight (Ag9), a molecular weight of approximately 143 ± 3 kD and 119 ± 3 kD (Ag10), a molecular weight of approximately 178 ± 3 kD (Agil), a undetermined molecular weight (Agl2), a molecular weight of approximately 34 ± 3 kD (Agl3), a molecular weight of approximately 195 ± 3 kD (Agl4), a molecular weight of approximately 44 ± 7 kD (Agl5), a molecular weight of approximately 35 43 ± 3 kD (Agl6) or a molecular weight of 130 ± 3 kD (Agl7) and with specificity for the monoclonal antibody according to the invention.
Antigenerne 4, 8, 9 og 10 er Mycoplasma-antigener, der er til stede på de cellelinier, der er beskrevet i tabellen.Antigens 4, 8, 9 and 10 are Mycoplasma antigens present on the cell lines described in the table.
5 Som immunogen til induktion af antistoffer ifølge opfindelsen tjener humane in vitro-kultiverede cellelinier, celleekstrakter eller ekstrakter af humanvæv. Der foretrækkes permanente human-cellelinier, især CaLu-1-, Chago-, Oat 75-, PaTuII- og Bewo-cellelinien. Der kan også anvendes 10 Agl-Agl7 til fremstilling af antistof 1 - antistof 17.As immunogen for the induction of antibodies of the invention, human in vitro cultured cell lines, cell extracts or extracts of human tissue serve. Permanent human cell lines, especially the CaLu-1, Chago, Oat 75, PaTuII and Bewo cell lines, are preferred. 10 Agl-Agl7 can also be used to prepare antibody 1 - antibody 17.
Pattedyr, fortrinsvis mus, immuniseres intraperito-nealt med 1 x 106-108 celler, fortrinsvis 107 celler, fra en sådan cellelinie (dag 0-120, fortrinsvis på dag 0 og 7), og efter 1-150 dage, fortrinsvis på dag 11, fusioneres (Na-15 ture 256, 495-497, 1975) miltcellerne fra sådanne dyr med cellelinien X63 Ag 8653 (The Journal of Immunology 173, 4, 1548-1550, 1979).Mammals, preferably mice, are immunized intraperitoneally with 1 x 10 6-108 cells, preferably 107 cells, from such a cell line (days 0-120, preferably days 0 and 7), and after 1-150 days, preferably day 11 , the spleen cells of such animals are merged with the cell line X63 Ag 8653 (The Journal of Immunology 173, 4, 1548-1550, 1979) (Na-15 Tours 256, 495-497, 1975).
De efter 3 uger opståede hybridomer testes for indhold af antistoffer med den ønskede specificitet. I dette tilfælde 20 testes en palette med 30 in vitro-kultiverede cellelinier, humane perifere blodceller og human-knoglemarv ved hjælp af indirekte immunfluorescens (Behring Inst. Mitt. 59, 64-70, 1976) og cellesorteringsanalyse (Acta Cytol. 19, 374-377, 1975) (Proc. Natl. Acad. Sci. , USA 77/8, 4914-4917, 1980) 25 for reaktivitet med antistofferne.The hybridomas that occur after 3 weeks are tested for antibody content of the desired specificity. In this case 20, a palette of 30 in vitro cultured cell lines, human peripheral blood cells and human bone marrow is tested by indirect immunofluorescence (Behring Inst. Mitt. 59, 64-70, 1976) and cell sorting analysis (Acta Cytol. 19, 374 -377, 1975) (Proc. Natl. Acad. Sci., USA 77/8, 4914-4917, 1980) for reactivity with the antibodies.
Overraskende nok befinder der sig blandt de testede, ovenstående hybridomvæsker nogle, der indeholder antistoffer med ovennævnte interessante specificitet. De hybridomer, der secernerer disse antistoffer, klones ved hjælp 30 af mikromanipulator, og de monoklonale antistoffer, der udvindes fra disse hybridomakloner, benyttes til at karakterisere det antigen, de erkender, immunkemisk. Hertil so-lubiliseres celle-"geister" (Hybridoma 1, 4, 413-421 (1982)), der udvindes fra vævskulturceller, ved hjælp af detergent 35 og ultracentrifugeres, og den således opnåede antigenblanding opdeles elektrophoretisk under ikke reducerende betingelser DK 167936 B1 4 i SDS-polyacrylamidgel (10 g/100 ml acylamid/O,026 g/100 ml bisacrylamid) (Nature, 127, 680-685 (1970)). Derefter overføres alle således opdelte antigener ved hjælp af elektro-"blotting" fra SDS-gelen til et nitrocellulosefilter (Proc.Surprisingly, among the above hybridoma fluids, there are some containing antibodies with the above interesting specificity. The hybridomas that secrete these antibodies are cloned by micromanipulator and the monoclonal antibodies recovered from these hybridoma clones are used to characterize the antigen they recognize as immunochemical. For this, cell "geists" (Hybridoma 1, 4, 413-421 (1982)) extracted from tissue culture cells are solubilized by means of detergent 35 and ultracentrifuged, and the antigen mixture thus obtained is electrophoretically subdivided under non-reducing conditions DK 167936 B1 4 in SDS-polyacrylamide gel (10 g / 100 ml acylamide / 0.126 g / 100 ml bisacrylamide) (Nature, 127, 680-685 (1970)). Then, all thus divided antigens are transferred by electro-blotting from the SDS gel to a nitrocellulose filter (Proc.
5 Natl. Acad. Sci., USA, 76, 4350-4354 (1979)). Derefter sker reaktionen af de antigener, der er immobiliseret på nitrocellulosefilteret, med det specifikke antistof (Hoppe-Seylers Z. Physiol. Chem. 363, 1133-1140 (1982)). Påvisningen af bindingen af dette antistof sker ved reaktion med 125J-pro-10 tein A og autoradiografi af filteret. Molekylvægten bestemmes ved sammenligning med kommercielt tilgængelige markeringsstoffer.5 Natl. Acad. Sci., USA, 76, 4350-4354 (1979)). Then, the antigens immobilized on the nitrocellulose filter are reacted with the specific antibody (Hoppe-Seyler Z. Physiol. Chem. 363, 1133-1140 (1982)). The binding of this antibody is detected by reaction with 125 J protein A and autoradiography of the filter. The molecular weight is determined by comparison with commercially available markers.
En præparativ rensning af de tilsvarende antigener sker affinitetschromatografisk.A preparative purification of the corresponding antigens is effected by affinity chromatography.
15 Nitrocellulosepapir (15 x 15 cm) (Hoppe-Seylers S.15 Nitrocellulose Paper (15 x 15 cm) (Hoppe-Seylers S.
Physiol. Chem. 363, 1133-1140 (1982) inkuberes efter befugt-ning med en phosphatpufferet kogsaltopløsning (PBS pH-værdi 7,2) med renset monoklonalt antistof-protein (1 time, 4eC, 30 ml, 1-100 /xg protein/ml) . Derefter fjernes det ubundne i 20 protein ved vask i 500 ml PBS. Efter inkubation af filteret i 1 time ved 40°C i 3 g/100 ml BSA (okseserumalbumin), 0,05 g/100 ml "Tween 20"® i PBS pH-værdi 7,2 (blokering) inkuberes filteret i 1 time ved 4°C efter tre gange vask med PBS med urensede celleekstrakter, der er opløst i 0,5% na-25 triumdeoxycholater, 20 mM phenylmethylsulfonylfluorid i PBS.Physiol. Chem. 363, 1133-1140 (1982) after incubation with a phosphate buffered saline (PBS pH 7.2) incubated with purified monoclonal antibody protein (1 hour, 4 ° C, 30 ml, 1-100 µg protein / ml) . Then, the unbound in 20 protein is removed by washing in 500 ml of PBS. After incubating the filter for 1 hour at 40 ° C in 3 g / 100 ml BSA (bovine serum albumin), 0.05 g / 100 ml "Tween 20" ® in PBS pH 7.2 (blocking), the filter is incubated for 1 hour at 4 ° C after three times washing with PBS with crude cell extracts dissolved in 0.5% sodium deoxycholates, 20 mM phenylmethylsulfonyl fluoride in PBS.
Derefter fjernes det ikke-bundne materiale ved hjælp af tre gange vask med PBS. Det specifikt bundne antigen løsnes ved inkubation af filteret i 1-9 M NH4SCN, fortrinsvis 6 M NH4SCN, i PBS i 5-30 minutter, fortrinsvis 15 minutter, 30 ved 4°C. Det således rensede antigen kan efter fjernelse af NH4SCN (gelchromatografisk, dialyse) finde anvendelse som immunogen eller til andre formål.Then, the unbonded material is removed by three times washing with PBS. The specifically bound antigen is released by incubating the filter in 1-9 M NH 4 SCN, preferably 6 M NH 4 SCN, in PBS for 5-30 minutes, preferably 15 minutes, 30 at 4 ° C. The antigen thus purified may, after removal of NH 4 SCN (gel chromatographic, dialysis) find use as immunogen or for other purposes.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at pattedyr immuniseres med celler fra en human cel-35 lelinie dyrket in vitro, en celleekstrakt fra en sådan cellelinie eller en ekstrakt fra et humant væv, miltceller DK 167936 B1 5 udtages fra et sådant immuniseret dyr, fusioneres med cellelinie X 63 Ag 8653, hybridomen selektioneres, og det mono-klonale antistof udvindes.The method of the invention is characterized in that mammals are immunized with cells from a human cell line grown in vitro, a cell extract from such a cell line or an extract from a human tissue, spleen cells DK 167936 B1 taken from such an immunized animal, fused with cell line X 63 Ag 8653, the hybridoma is selected and the monoclonal antibody is recovered.
Opfindelsen angår også anvendelsen af de monoklonale 5 antistoffer ifølge opfindelsen som in vitro-diagnostiske stoffer og som bærestoffer for farmaceutisk aktive forbindelser.The invention also relates to the use of the monoclonal antibodies of the invention as in vitro diagnostic agents and as carriers for pharmaceutically active compounds.
De på grund af deres reaktivitet med Agl og Ag2 karakteriserede monoklonale antistoffer kan anvendes som in 10 vitro-diagnostisk middel til at skelne mellem celler, der stammer fra fast humant væv, og animalske celler. Endvidere kan de finde anvendelse som positiv-kontrol for humant væv i immunhistologien og til at skelne mellem animalske væv.The monoclonal antibodies characterized by their reactivity with Ag1 and Ag2 can be used as an in vitro diagnostic agent to distinguish cells derived from solid human tissue from animal cells. Furthermore, they may find use as a positive control for human tissue in immunohistology and for distinguishing between animal tissues.
Forbundet med aktive stoffer kan AK1 til AK17 endvi-15 dere anvendes til at finde målrettet til virkningsstedet, f.eks. ved autolog knoglemarvstransplantation. Anvendelsen af disse antistoffer til påvisning af det tilsvarende antigen i legemsvæsker udgør en diagnostisk anvendelsesmulighed af dette antistof. Antistofferne kan anvendes i koncentrationer 20 på 0,01 μς til 1 mg/ml.Furthermore, associated with active substances, AK1 to AK17 can also be used to find the targeted site, e.g. by autologous bone marrow transplant. The use of these antibodies to detect the corresponding antigen in body fluids constitutes a diagnostic utility of this antibody. The antibodies can be used at concentrations 20 of 0.01 μς to 1 mg / ml.
DK 167936 B1 6DK 167936 B1 6
OISLAND
Reaktivitet af antistoffer 1-17 på in vi tro-cellerReactivity of antibodies 1-17 to in vitro cells
Afprøvede celler 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Lungetumorcelle-5 linierTested Cells 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Lung Tumor Cell-5 Lines
CaLu-1 + + + + + + + + + E-14 +--+ + + + + + + + - - - - - + B 109/4 + + -+ --- -- A 549 + + + +---- 10 Oat 75 + + - + -+ + + -+--- + + - + S HP—77 + + -+ + + + - +CaLu-1 + + + + + + + + + E-14 + - + + + + + + + + - - - - - + B 109/4 ++ + - + --- - A 549 +++ + ---- 10 Oat 75 ++ - + - + + + - + --- + + - + S HP — 77 + + - + + + + - +
Chago + -- + + -- + +- -- -- - +Chago + - + + - + + - - - - +
Bro-Ca-Hoff_+ + - - + - - + - -_-Bro-Ca-Hoff_ + + - - + - - + - -_-
Pankreastumor-15 cellelinierPancreatic tumor cell lines
Pa Tu II + 4-----+---- + - - - + ±Pa Tu II + 4 ----- + ---- + - - - + ±
Pa Tu III +-+--+ -+ +- -- MIA-Pa-Ca 2 + +---+----- - - - - -Pa Tu III + - + - + - + + - - MIA-Pa-Ca 2 ++ --- + ----- - - - - -
Panc-1_+ + -.4.-4. + - - - - - - - - ΛΛPanc-1_ + + -.4.-4. + - - - - - - - - ΛΛ
Gynækologiske tumorcellelinierGynecological tumor cell lines
Bewo +- + + + + + — —- + + - +Bewo + - + + + + + - —- + + - +
HeLa ++ +- + +---___ + + _ +HeLa ++ + - + + ---___ + + _ +
Pa-1_-4- + + + - + -- + - - -_- - - + 25Pa-1_-4- + + + - + - + - - -_- - - + 25
Melanomcelle- linierMelanoma cell lines
Mel-ULF + + - + - + + -± - + - + - + +Mel-ULF + + - + - + + - ± - + - + - + +
Mel-RPMI + + - + - + + -+ --- + - +Mel-RPMI + + - + - + + - + --- + - +
Mel-51-2 + + - +----± + 30Mel-51-2 ++ - + ---- ± + 30
Mel-21-C-48_+ + - + + - + -+ + - + + - + +Mel-21-C-48_ + + - + + - + - + + - + + - + +
Ikke beslægtede tumorcellelinier ZR-75-1 + + -- + + - - + - - MCF-7 + + - +---- ' - 35Unrelated tumor cell lines ZR-75-1 + + - + + - - + - - MCF-7 + + - + ---- '- 35
Mamma-Ca-12 + - - + + + -Mum-Ca-12 + - - + + + -
Colon-Ca-Ax + - - -Colon-Ca-Ax + - - -
"V"V
DK 167936 B1 7 oDK 167936 B1 7 o
Afprøvede celler l 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Tested cells l 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Colon-Wi + + -- ..-- - - ___ _ HT-1080 + +Colon-Wi ++ - ..-- - - ___ _ HT-1080 ++
Leiomyosaroom + + 5 Hypernephrom TUW - I MR 32 +------- ____Leiomyosaroma + + 5 Hypernephroma TUW - I MR 32 + ------- ____
Raji + - - - - - -Raji + - - - - - - -
Daudi +_____ - 10 1788 + --- 6666/1 + ---- - - - - -Daudi + _____ - 10 1788 + --- 6666/1 + ---- - - - - -
Immunocytom_-t- - - + -_- -_Immunocytoma_-t- - - + -_- -_
Normale lymphoide 15 cellerNormal lymphoid 15 cells
Lymphocyten + + -_--_--- i - - - i -Lymphocytes + + -_ - _--- i - - - i -
Monocyten ++-------- -- - - + -Monocytes ++ -------- - - - + -
Granulocyten ++__+_____ __ _ _ _ ±The granulocytes ++ __ + _____ __ _ _ _ ±
Erythrocyten --------- - - - - - - pnThe erythrocytes --------- - - - - - - pn
Knoglemarv_ + + __ + -- _- __- - - - +Bone marrow_ + + __ + - _- __- - - - +
Normale humane fibroblaster LL-29 ++-- --- -- ___ 25Normal human fibroblasts LL-29 ++ - --- - ___ 25
Hu-Fi-Br 32 + + +------- --____Hu-Fi-Br 32 +++ ------- --____
Hu-Fi-Br 43 + + ---- -- --Hu-Fi-Br 43 ++ ---- - -
Hu-Fi-Br 47 ++------ --Hu-Fi-Br 47 ++ ------ -
Hu-Fi-Br 16 + + +---------Hu-Fi-Br 16 +++ ---------
Hu-Fi-Mel-1 + + +------- -- - - 30Hu-Fi-Mel-1 +++ ------- - - - 30
Hu-Fi-Mag-13_++ -------_- - _- -Hu-Fi-Mag-13 _ ++ -------_- - _- -
Animalske cellerAnimal cells
Vero __ _ + _ 35 Greyhound __________ - - - - - BHK ------+--- --- - -Vero __ _ + _ 35 Greyhound __________ - - - - - BHK ------ + --- --- - -
Rottefibroblaster ---------- - - - - -Rat fibroblasts ---------- - - - - -
Musefibroblaster ----------_- - - - 8 DK 167936 B1Mouse fibroblasts ----------_- - - - 8 DK 167936 B1
OISLAND
+ = signifikant positiv reaktion i det indirekte immunfluorescens-forsøg, i radioimmunforsøg og i den cytofluormetriske analyse.+ = significant positive response in the indirect immunofluorescence test, in the radioimmunoassay and in the cytofluorometric assay.
5 + = svag positiv reaktion med en del af dén afprøvede population.5 + = weak positive reaction with part of the population tested.
- = ingen signifikant reaktion.- = no significant reaction.
10 15 20 25 30 3510 15 20 25 30 35
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833329184 DE3329184A1 (en) | 1983-08-12 | 1983-08-12 | MONOCLONAL ANTIBODIES WITH SPECIFICITY FOR MEMBRANE-ASSOCIATED ANTIGENS |
| DE3329184 | 1983-08-12 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK388384D0 DK388384D0 (en) | 1984-08-10 |
| DK388384A DK388384A (en) | 1985-02-13 |
| DK167936B1 true DK167936B1 (en) | 1994-01-03 |
Family
ID=6206422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK388384A DK167936B1 (en) | 1983-08-12 | 1984-08-10 | MONOCLONAL ANTIBODIES AGAINST ANTIGENS OF HUMAN CARCINOMA CELLS, THEIR PREPARATION AND USE, AND ANTIGENS OF CARCINOMA CELLS FROM HUMAN EPITHEL |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0141079B1 (en) |
| JP (1) | JPS6089500A (en) |
| AT (1) | ATE71411T1 (en) |
| CA (1) | CA1277612C (en) |
| DE (2) | DE3329184A1 (en) |
| DK (1) | DK167936B1 (en) |
| ZA (1) | ZA846214B (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3432714A1 (en) * | 1984-09-06 | 1986-04-24 | Behringwerke Ag, 3550 Marburg | TUMOR THERAPEUTICS AND METHOD FOR THE PRODUCTION THEREOF |
| DE3531301A1 (en) * | 1985-09-02 | 1987-03-05 | Behringwerke Ag | MONOCLONAL ANTIBODIES AGAINST TUMOR ASSOCIATED GLYCOPROTEINS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| US6294172B1 (en) * | 1983-08-12 | 2001-09-25 | Dade Behring Marburg Gmbh | Monoclonal antibodies with specificity for membrane-associated antigens |
| DE3629640A1 (en) * | 1986-08-30 | 1988-03-03 | Behringwerke Ag | USE OF MONOCLONAL ANTIBODIES FOR THE TREATMENT OF TUMORS |
| DE3416774A1 (en) * | 1984-05-07 | 1985-11-14 | Behringwerke Ag, 3550 Marburg | MONOCLONAL ANTIBODIES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| US4701408A (en) * | 1984-01-30 | 1987-10-20 | Smithkline Beckman Corporation | Monoclonal antibody to activated macrophages |
| JPS61104783A (en) * | 1985-09-10 | 1986-05-23 | Wakunaga Seiyaku Kk | Hybridoma producing anti-human carcinoma monoclonal antibody |
| JPS61103837A (en) * | 1984-10-26 | 1986-05-22 | Wakunaga Seiyaku Kk | Human anticancer monoclonal antibody |
| US4851332A (en) * | 1985-04-01 | 1989-07-25 | Sloan-Kettering Institute For Cancer Research | Choriocarcinoma monoclonal antibodies and antibody panels |
| ATE92081T1 (en) * | 1986-04-17 | 1993-08-15 | Hybritech Inc | TUMOR-ASSOCIATED ANTIGEN. |
| FR2606033B1 (en) * | 1986-10-31 | 1988-12-16 | Cird | CYTOPLASMIC PROTEIN OF THE SUBBASAL SKIN CELLS, ANTIBODIES CAPABLE OF RECOGNIZING THIS PROTEIN, AND HYBRID CELL LINES CAPABLE OF SECRETING SUCH ANTIBODIES |
| FR2606034B1 (en) * | 1986-10-31 | 1989-06-02 | Cird | NOVEL SURFACE PROTEIN OF BASAL CELLS OF THE EPIDERMIS, ANTIBODIES CAPABLE OF RECOGNIZING THIS PROTEIN, AND THEIR USE, AND HYBRID CELL LINES CAPABLE OF SECRETING SUCH ANTIBODIES |
| DE3854821T2 (en) * | 1987-02-19 | 1996-05-23 | Scripps Clinic Res | Cell surface marker for human pancreatic cancer cells |
| US5344919A (en) * | 1987-02-19 | 1994-09-06 | The Scripps Research Institute | Integrin from human epithelial cells |
| US5320942A (en) * | 1987-02-19 | 1994-06-14 | Vito Quaranta | Method of diagnosing the presence of abnormal epithelial tissue using monoclonal antibodies to the A6 B4 cell surface protein |
| DE3825615A1 (en) * | 1988-07-28 | 1990-02-01 | Behringwerke Ag | ANTIGENT CONSTRUCTS OF "MAJOR HISTOCOMPATIBILITY COMPLEX" CLASS I ANTIGENS WITH SPECIFIC CARRIER MOLECULES, THEIR PRODUCTION AND USE |
| DE3909799A1 (en) * | 1989-03-24 | 1990-09-27 | Behringwerke Ag | MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE |
| CA2015862A1 (en) * | 1989-05-04 | 1990-11-04 | Gajanan Nilaver | Cell surface antigen that binds with l6 monoclonal antibody |
| DE3920358A1 (en) * | 1989-06-22 | 1991-01-17 | Behringwerke Ag | BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE |
| DE3935016A1 (en) * | 1989-10-20 | 1991-04-25 | Behringwerke Ag | GLYCOSYL ETOPOSIDE PRODRUGS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN COMBINATION WITH FUNCTIONALIZED TUMOR-SPECIFIC ENZYME CONJUGATES |
| US6610299B1 (en) | 1989-10-19 | 2003-08-26 | Aventis Pharma Deutschland Gmbh | Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates |
| US7241595B2 (en) | 1989-10-20 | 2007-07-10 | Sanofi-Aventis Pharma Deutschland Gmbh | Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates |
| US6475486B1 (en) | 1990-10-18 | 2002-11-05 | Aventis Pharma Deutschland Gmbh | Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates |
| DE4133791A1 (en) * | 1991-10-11 | 1993-04-15 | Behringwerke Ag | MONOCLONAL ANTIBODIES AGAINST TUMOR ASSOCIATED ANTIGENS, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| US6030797A (en) * | 1992-10-08 | 2000-02-29 | Dade Behring Marburg Gmbh | Monoclonal antibodies against tumor-associated antigens, processes for the preparation thereof and the use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4349528A (en) * | 1979-11-21 | 1982-09-14 | The Wistar Institute | Monocolonal hybridoma antibody specific for high molecular weight carcinoembryonic antigen |
| US4579827A (en) * | 1983-03-11 | 1986-04-01 | Sloan-Kettering Institute For Cancer Research | Monoclonal antibodies to human gastrointestinal cancers and hybridoma method of production of the monoclonal antibodies |
| US4569788A (en) * | 1983-05-18 | 1986-02-11 | The United States Of America As Represented By The Department Of Health And Human Services | Monoclonal antibodies against non small cell lung cancer |
-
1983
- 1983-08-12 DE DE19833329184 patent/DE3329184A1/en not_active Withdrawn
-
1984
- 1984-08-08 EP EP84109406A patent/EP0141079B1/en not_active Expired - Lifetime
- 1984-08-08 DE DE8484109406T patent/DE3485432D1/en not_active Expired - Lifetime
- 1984-08-08 AT AT84109406T patent/ATE71411T1/en not_active IP Right Cessation
- 1984-08-10 ZA ZA846214A patent/ZA846214B/en unknown
- 1984-08-10 DK DK388384A patent/DK167936B1/en not_active IP Right Cessation
- 1984-08-10 CA CA000460725A patent/CA1277612C/en not_active Expired - Lifetime
- 1984-08-10 JP JP59166646A patent/JPS6089500A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| EP0141079A3 (en) | 1987-09-23 |
| ATE71411T1 (en) | 1992-01-15 |
| JPS6089500A (en) | 1985-05-20 |
| EP0141079A2 (en) | 1985-05-15 |
| EP0141079B1 (en) | 1992-01-08 |
| CA1277612C (en) | 1990-12-11 |
| DK388384D0 (en) | 1984-08-10 |
| DE3485432D1 (en) | 1992-02-20 |
| DK388384A (en) | 1985-02-13 |
| DE3329184A1 (en) | 1985-02-21 |
| ZA846214B (en) | 1985-03-27 |
| JPH0542267B2 (en) | 1993-06-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |