DE3444684A1 - Preparation of conjugated antigens and antibodies (immunoglobulins) directed against them for the purposes of tumour therapy and prophylaxis - Google Patents
Preparation of conjugated antigens and antibodies (immunoglobulins) directed against them for the purposes of tumour therapy and prophylaxisInfo
- Publication number
- DE3444684A1 DE3444684A1 DE19843444684 DE3444684A DE3444684A1 DE 3444684 A1 DE3444684 A1 DE 3444684A1 DE 19843444684 DE19843444684 DE 19843444684 DE 3444684 A DE3444684 A DE 3444684A DE 3444684 A1 DE3444684 A1 DE 3444684A1
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- Prior art keywords
- antigens
- antibodies
- tumor
- conjugated
- prophylaxis
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Links
- 102000036639 antigens Human genes 0.000 title claims abstract description 47
- 108091007433 antigens Proteins 0.000 title claims abstract description 47
- 239000000427 antigen Substances 0.000 title claims abstract description 46
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 30
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 4
- 238000011321 prophylaxis Methods 0.000 title claims abstract 3
- 108060003951 Immunoglobulin Proteins 0.000 title claims description 3
- 102000018358 immunoglobulin Human genes 0.000 title claims description 3
- 229940072221 immunoglobulins Drugs 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title description 7
- 208000003455 anaphylaxis Diseases 0.000 claims abstract description 5
- 206010002198 Anaphylactic reaction Diseases 0.000 claims abstract description 4
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- 238000000338 in vitro Methods 0.000 claims abstract description 4
- 230000000813 microbial effect Effects 0.000 claims abstract description 4
- 210000002826 placenta Anatomy 0.000 claims abstract description 4
- 210000002993 trophoblast Anatomy 0.000 claims abstract description 4
- 230000036783 anaphylactic response Effects 0.000 claims abstract description 3
- 238000001727 in vivo Methods 0.000 claims abstract 2
- 210000001519 tissue Anatomy 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 230000000699 topical effect Effects 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 5
- 230000006058 immune tolerance Effects 0.000 claims description 5
- 231100000614 poison Toxicity 0.000 claims description 3
- 239000002574 poison Substances 0.000 claims description 3
- 235000013311 vegetables Nutrition 0.000 claims description 3
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 19
- 208000000104 Arthus reaction Diseases 0.000 abstract description 8
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 206010070834 Sensitisation Diseases 0.000 abstract description 5
- 230000001605 fetal effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 230000000274 adsorptive effect Effects 0.000 abstract 1
- 231100000659 animal toxin Toxicity 0.000 abstract 1
- 210000001161 mammalian embryo Anatomy 0.000 abstract 1
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 230000001900 immune effect Effects 0.000 description 6
- 230000021615 conjugation Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000008313 sensitization Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- IORISFYTXJVNFE-UHFFFAOYSA-N 2,3-dinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O IORISFYTXJVNFE-UHFFFAOYSA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 210000003785 decidua Anatomy 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 231100000776 exotoxin Toxicity 0.000 description 1
- 239000002095 exotoxin Substances 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00118—Cancer antigens from embryonic or fetal origin
-
- 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
-
- 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
- A61K2039/6012—Haptens, e.g. di- or trinitrophenyl (DNP, TNP)
-
- 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
- A61K2039/6087—Polysaccharides; Lipopolysaccharides [LPS]
-
- 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
Herstellung von konjugierten Antigenen undProduction of conjugated antigens and
dagegen gerichteten Antikörpern(Immunglobulinen) ::z i.. therapeutischen iind prophylaktischen Zwecken bei Tumoren.antibodies directed against it (immunoglobulins) :: z i .. therapeutic iind prophylactic purposes in tumors.
Beschreibung: Das Verfahren der Patentanspruche dient zur Herstellung von Präparaten zur Immuntherapie von benignen und malignen Tumorendurch-Auslösung einer modifizierten Prausnitz-Küstner'schen Reaktion in Form einer aktiven oder passiven Arthus-Reaktion in oder am Tumorgewebe und Durchbrechung einer etwa bestehenden Immuntoleranz gegenüber körpereigenen Tumorantigenen. Dadurch wird nach Auslösung der Arthus-Reaktion die natürliche körpereigene Immunabwehr gegen den Tumor ermöglicht. Es werden dazu konjugierte Antigene aus tumorassoziierten Antigenen oder Haptenen und bzw. oder embryo-foetale Antigene, insbesondere aus Trophoblast und Chorion der Placenta spezifisch gegen diese gerichtete Antikörper bzw. Antikörperseren benötigt.Description: The process of the patent claims is used for production of preparations for the immunotherapy of benign and malignant tumors by triggering a modified Prausnitz-Küstner reaction in the form of an active or passive Arthus reaction in or on the tumor tissue and disruption of any existing Immune tolerance to the body's own tumor antigens. This will after triggering the Arthus reaction enables the body's own immune defense against the tumor. For this purpose, conjugated antigens from tumor-associated antigens or haptens are used and / or embryo-fetal antigens, in particular from trophoblast and chorion the placenta needs antibodies or antibody sera specifically directed against this.
Die Arthus-Reaktion ist eine entzündliche lokale, topische Reaktion, die durch die Reaktion präzipitierender Antikörper mit den lokal deponierten Antigenen hervorgerufen wird. Physiologisch beobachtet man außer Ödemen und Blutungen,vaskuläre Fibrinoidnekrose und eine massive Einwanderung der neutrophilen und eosinophilen Leukozyten. Die Reaktion aus pflanzlichen, mikrobiellen und bzw. oder chemischen Produktenjiconjugiert, d.h.an diese kovalent oder adsorptiv gebunden. Die Gewinnung von tumorassozijerten Antigenen wie auch embryo-foetalen Antigenen erfolgt nach bekannten Verfahren (vgl.The Arthus reaction is an inflammatory local, topical reaction, the antibodies precipitating through the reaction with the locally deposited antigens is caused. Physiologically, in addition to edema and bleeding, vascular ones are observed Fibrinoid necrosis and massive immigration of neutrophils and eosinophils Leukocytes. The reaction from vegetable, microbial and resp. or chemical products conjugated, i.e. bound to them covalently or adsorptively. The extraction of tumor-associated antigens as well as embryo-fetal antigens takes place according to known procedures (cf.
EPA 80106066.6) insbesondere durch Affinität chromatographische oder immunologische Absättigungsverfahren.EPA 80106066.6) in particular by affinity chromatographic or immunological satiety procedures.
Künstlich zusammengesetzte Antigene können nach verschiedenen Verfahren gewonnen werden: so zum Beispiel durch Kupplung an Eiweiß als Diazonium-Verbindung, die Behandlung mit Zyanaten, die umsetzung mit Carbobenzoxy Verbindungen, das Curtius'sche Azid-Verfahren, das Oxazolon-Verfahren, die Konjugation von Polysacchariden mit bakteriellen konjugierten Proteinen nach lV.J.T. Morgan, Verbindung von Aminosäuren mit Carbohydraten, Pyridin-Eiweißverbindungen und u.a. (vgl.Artificially assembled antigens can be produced by various methods obtained: for example, by coupling to protein as a diazonium compound, The treatment with cyanates, the conversion with carbobenzoxy compounds, Curtius' Azide process, the oxazolone process, the conjugation of polysaccharides with bacterial conjugated proteins according to IV.J.T. Morgan, compound of amino acids with carbohydrates, pyridine protein compounds and others (cf.
A. Schmidt: Fortschritte der Serologie, S. 67 u.f.: Verlag: Dietrich Steinkopf, Darmstadt, 1955; Helmut Friemel:Immunologische Arbeitsmethoden, S. 480 u.f.: Gustav Fischer-Verlag, 1984). Auch die Verwendung von Adjuvantien ist möglich.A. Schmidt: Advances in Serology, p. 67 u.f .: Publisher: Dietrich Steinkopf, Darmstadt, 1955; Helmut Friemel: Immunological working methods, p. 480 u.f .: Gustav Fischer-Verlag, 1984). The use of adjuvants is also possible.
Zur Auslösung des invers passiven Arthusphänomens werden zur i.v.-Injektion die dem Antigen entsprechenden spezifischen Antikörper bzw. Antikörperseren benötigt.IV injections are used to trigger the inverse passive Arthus phenomenon requires the specific antibodies or antibody sera corresponding to the antigen.
Diese können aus allogenen oder xenogenen immunisierten Individuen gewonnen werden. Bei gesunden Normalindividuen führt die Immunisierung mit konjugierten Tumorantigenen bzw. embryo-foetalen Antigenen zu keinen nachteiligen Nebenreaktionen, weil im Organismus keine Vorsensibilisierung gegen die entsprechenden Antigene besteht. Die Sensibilisierung bewirkt vielmehr einen pro-*) bzw. tierischen Giften phylaktischen Immunschutz gegen die Entstehung von Tumoren mit gleichen Antigenqualitäten und verhindert die Ausbildung von Immuntoleranz gegen solche Tumorzellen. Die Antikörper können aber auch in vitro aus Hybridom-Zellen, gegebenenfalls kloniert, erhalten werden. Zweckmäßig ist jedoch ein umfassendes Antikörperspektrum gegenüber den konjugierten Antigenen.These can be from allogeneic or xenogeneic immunized individuals be won. In healthy normal individuals, immunization with conjugated Tumor antigens or embryo-fetal antigens do not lead to any adverse side reactions, because there is no presensitization to the corresponding antigens in the organism. Rather, the sensitization causes a pro- *) or animal poison phylactic Immune protection against the development of tumors with the same antigen qualities and prevents the development of immune tolerance against such tumor cells. The antibodies but can also be obtained in vitro from hybridoma cells, optionally cloned will. However, it is useful to have a comprehensive range of antibodies against the conjugated Antigens.
Zur Auslösung der Prausnitz-Küstner'schen invers passiven Reaktion sind präzipitierende Antikörper erforderlich. Die zur i.v.-Injektion benötigten Antikörpermengen liegen je nach Art der Spezies und der Antigenqualität im mg-Bereich des AK-Stickstoffs / kg Körpergewicht (vgl. B. Steffen: Allgemeine und experimentelle Immunologie und Immunpathologie: Georg Thieme-Verlag, Stuttgart, 1968).To trigger the Prausnitz-Küstner inverse passive reaction precipitating antibodies are required. The ones needed for IV injection Antibody amounts are in the mg range, depending on the type of species and the quality of the antigen of AK nitrogen / kg body weight (see B. Steffen: Allgemeine und experimentalelle Immunology and immunopathology: Georg Thieme-Verlag, Stuttgart, 1968).
Um einen generalisierten anaphylaktischen Schock zu vermeiden, sollte der auslösenden topischen Antigen-Injektion an oder in den Tumor Adrenalin oder Epinephrin zugesetzt und auch zusätzlich systemisch verb.To avoid generalized anaphylactic shock, should the triggering topical antigen injection at or into the tumor adrenaline or Epinephrine added and also systemically verb.
reicht werden. Das Behandlungsprinzip ist die Auslösung einer topischen allergischen Reaktion gegen den Tumor.be enough. The principle of treatment is the triggering of a topical allergic reaction to the tumor.
Die Latenzzeit bei passiver Sensibilisierung zwischen der intravenösen Antikörperinjektion und der lokalen Auslösung durch Infiltration des Tumorgewebes oder des Tumorbettes mit dem konjugierten Antigen reicht bei der Verwendung von nicht-reaginen Antiköpern, die sich nicht im Gewebe fixieren, von Minuten bis wenigen Stunden. Die Auslösungsinjektion-kann deshalb unmittelbar vor oder nach der chirurgischen Entfernung des Tumors bei offenem Situs erfolgen. Auch ist die Injektion durch die Haut möglich. Ebenso ist eine topische Anwendung und Sensibilisierung und Auslösung möglich.The latency period in passive sensitization between the intravenous Antibody injection and local triggering by infiltration of the tumor tissue or the tumor bed with the conjugated antigen is sufficient when using non-reactive antibodies that do not fix themselves in the tissue, from minutes to a few Hours. The trigger injection can therefore be carried out immediately before or after the surgical one The tumor is removed with the site open. Also the injection is through the Skin possible. Likewise is a topical application and sensitization and elicitation possible.
Für die Durchbrechung einer Immuntoleranz gegen die Tumorantigene ist die primäre Antigen-Sensibilisierung vor der auslösenden Injektion mit Antikörpern zweckmäßig. Auch hier ist auf das relativ kurze Intervall zwischen Sensibilisierung und Auslösungsinjektion zu achten, weil auch die Antigene wegdiffundieren können.For breaking an immune tolerance to the tumor antigens is the primary antigen sensitization prior to the trigger injection with antibodies expedient. Again, this is due to the relatively short interval between awareness raising and trigger injection, because the antigens can also diffuse away.
Die Anwendung bivalenter präzipitierender Antikörper verursacht kein Tumor-Enhancement, wie dies bei aktiver Immunisierung mit den Tumorantigenen möglich ist. Während der Ausbildung des Arthusphånomens, insbesondere bei nekrotischer Entzündung, ist eine chemotherapeutische oder antibiotische Zusatztherapie gegen etwaige Infektionen einzuleiten und bei Operationen der Gefahr von Nachblutungen oder Perforationen zu begegnen.The use of bivalent precipitating antibodies does not cause any Tumor enhancement, as possible with active immunization with the tumor antigens is. During the development of the Arthus phenomenon, especially with necrotic inflammation, is an additional chemotherapeutic or antibiotic therapy against possible infections initiate and in operations there is a risk of bleeding or perforation to meet.
Beispiel 1: Es werden embryo-fetale Antigene aus Zellmembranen von isoliertem bovinen oder humanen Trophoblast oder Chorion der Plazenta nach bekannten biochemischen Verfahren, insbesondere durch fraktionierte Schwerkrafttrennung von chemisch aufgeschlossenen Homogenaten und unter Beseitigung von adulten Gewebefaktoren durch adsorptionschromatographische Absättigung an Säulen gebundenen Antikörpern gegen adultes Gewebe, wie z.B. der Dezidua, gewonnen. Die Zellfaktoren lassen sich auch aus in Massenkulturen gezüchteten Chorionzellen isolieren. Zur nachfolgenden Konjugation können Einzelfaktoren wie auch Gemische von embryo-fetalen Antigenen Verwendung finden. Diese werden an pflanzliche Polysaccharide, die mit einer begrenzten Anzahl von Fettsäureresten substituiert wurden, konjugiert. Diese adsorbieren sich ohne Bindeglied direkt an die Proteine (Hämmerling, U., O.Example 1: There are embryo-fetal antigens from cell membranes of isolated bovine or human trophoblast or chorion of the placenta according to known biochemical processes, in particular by fractional gravity separation of chemically digested homogenates and with the elimination of adult tissue factors Antibodies bound to columns by adsorption chromatographic saturation won against adult tissue such as the decidua. The cell factors can also isolate from chorionic cells grown in mass cultures. To the following Single factors as well as mixtures of embryo-fetal antigens can be conjugated Find use. These are bound to vegetable polysaccharides that come with a Number of fatty acid residues substituted were conjugated. These adsorb directly to the proteins without a link (Hämmerling, U., O.
Westphal: Europ. J. Biochem. 1, 46 (1967)). Bei Proteinantigenen kann auch die Tannin-Methode angewandt werden (Borduas, A., P. Grabar: Ann. Inst. Pasteur 84, 903 (t953); Stavitsky, A.: J. Immunol. 72, 360 (1954); Roitt, I. und Doniach, D.: WHO-Book of immunologic techniques S. 20: World Health Organisation, Genf (1966)).Westphal: Europ. J. Biochem. 1, 46 (1967)). In the case of protein antigens, the tannin method can also be used (Borduas, A., P. Grabar: Ann. Inst. Pasteur 84, 903 (t953); Stavitsky, A .: J. Immunol. 72, 360 (1954); Roitt, I. and Doniach, D .: WHO Book of immunologic techniques p. 20: World Health Organization, Geneva (1966)).
Auch die Benzidin-Methode ist dazu geeignet (Gordon, J., B. Roste, A. Sekon: J. exp. Med. 108, 37 (1958); Roberts, I., D. Doniach: WHO-Book of immunologic techniques S. 1: World Health Organisation, Genf (1966); Stavitsky, A., E. Arquilla: J.The benzidine method is also suitable for this (Gordon, J., B. Roste, A. Sekon: J. exp. Med. 108, 37 (1958); Roberts, I., D. Doniach: WHO-Book of immunologic techniques p. 1: World Health Organization, Geneva (1966); Stavitsky, A., E. Arquilla: J.
Immunol. 74, 306 (1955); Timpe, R., H. Furthmayr, I. Wolff: Int. Arch. Allergy 32, 318 (1967)).Immunol. 74, 306 (1955); Timpe, R., H. Furthmayr, I. Wolff: Int. Arch. Allergy 32, 318 (1967)).
Die konjugierten Antigene werden nun nach bekannten Verfahren zur Gewinnung von Antikörpern durch konventionelle Methoden der Immunisierung von xenogenen oder allogenen Antikörperbildnern oder aber in vitro zur Antikörperbildung in Lymphozyten oder Hybridomzellen verwendet (Herwart, Ambrosius: Antiserumgewinnung aus Tieren, S. 25; H. Fiebig: Herstellung monoklonaler Antikörper durch Zellfusion, S. 36 und S. Wichner: Antikörperbildung in der Zellkultur, S. 48 - in H. Friemel: Immunologische Arbeitsmethoden: Gustav Fischer Verlag, Stuttgart (1984)).The conjugated antigens are now according to known methods for Obtaining antibodies by conventional xenogenic immunization methods or allogeneic antibody formers or in vitro for antibody formation in lymphocytes or hybridoma cells are used (Herwart, Ambrosius: antiserum recovery from animals, P. 25; H. Fiebig: Production of Monoclonal Antibodies by Cell Fusion, p. 36 and S. Wichner: Antibody formation in cell culture, p. 48 - in H. Friemel: Immunologische Working methods: Gustav Fischer Verlag, Stuttgart (1984)).
Die konjugierten Antigene und die Antikörperpråparate werden zur Erzeugung eines passiven Arthus-Phänomens verwendet (C. Steffen: Allgemeine und experimentelle Immunologie und Immunpathologie, S. 530: Georg Thieme Verlag, Stuttgart). Eine aktive topisch-anaphylaktische Reaktion kann mit dem konjugierten Antigen nach Vorsensibilisierung mit diesem ausgelöst werden.The conjugated antigens and the antibody preparations are used to generate of a passive Arthus phenomenon (C. Steffen: Allgemeine und experimentalelle Immunology and immunopathology, P. 530: Georg Thieme Verlag, Stuttgart). An active topical anaphylactic reaction can follow with the conjugated antigen Presensitization can be triggered with this.
Beispiel 2: Es werden Antigene aus Einzelorganen oder Organmischungen von Tierfeten entsprechend Beispiel 1 gewonnen. Auch können die Ausgangsstoffe aus humanen fetalen Zellen oder Gewebekulturen entnommen werden. Die Konjugation erfolgt mit Dinitrobenzolsulfonat (vgl. J. Brock: Präparation von konjugierten Antigenen, S. 481 in H. Friemel: Immunol logische Arbeitsmethoden: Gustav Fischer Verlag, Stgt. (1984)). Nach Beendigung der Reaktion wird das DNP-Produkt durch Gelchromatographie an Sephadex gereinigt. Die Herstellung der entsprechenden Antikörper und die Anwendung der Präparationen erfolgt wie in Beispiel 1.Example 2: There are antigens from individual organs or mixtures of organs obtained from animal fetuses according to Example 1. The starting materials can also be made from taken from human fetal cells or tissue cultures. The conjugation takes place with dinitrobenzenesulfonate (see J. Brock: Preparation of conjugated antigens, S. 481 in H. Friemel: Immunol logical working methods: Gustav Fischer Verlag, Stgt. (1984)). After the reaction is complete, the DNP product is analyzed by gel chromatography cleaned on Sephadex. The production of the corresponding antibodies and the application the preparations are carried out as in Example 1.
Beispiel 3: Die Gewinnung von tumorassozierten Antigenen erfolgt aus Tumorgewebe, das vom lebenden Organismus gewonnen wird oder aus kulturgezüchteten Tumorzellen oder Tumorgeweben analog der Gewinnung von embryo-fetalen Antigenen nach den Methoden der Präparation von Gewebeextrakten (H. Werner: Präparation von Gewebsextrakten, S. 490, in H. Friemel: Immunologische Arbeitsmethoden: G. Fischer Verlag, Stgt. (1984)). Die Konjugation kann mit mikrobiellen oder viralen Antigenen, möglichst unter Ausschluß von Nukleinsäurebestandteilen durch enzymatischen Abbau derselben, mit den beschriebenen Konjugationsverfahren erfolgen. Es sind dazu insbesondere Endo- und Exotoxine, wie auch tierische Gifte geeignet (vgl. H. Schmidt: Fortschritte der Serologie: D. Steinkopf-Verlag, Darmstadt (1955)). Die Kupplung erfolgt als Diazoniumverbindung, die Gewinnung von Antikörpern oder Antikörperseren sowie auch die Anwendung nach Beispiel 1.Example 3: The extraction of tumor-associated antigens takes place from Tumor tissue obtained from the living organism or from culture grown Tumor cells or tumor tissues analogous to the production of embryo-fetal antigens according to the methods of the preparation of tissue extracts (H. Werner: Preparation of Tissue extracts, p. 490, in H. Friemel: Immunological working methods: G. Fischer Publishing house, Stgt. (1984)). The conjugation can be with microbial or viral antigens, if possible with the exclusion of nucleic acid components through enzymatic degradation the same, with the conjugation methods described. There are for this purpose in particular Endo- and exotoxins, such as animal poisons are also suitable (cf. H. Schmidt: Advances in serology: D. Steinkopf-Verlag, Darmstadt (1955)). the Coupling takes place as a diazonium compound, the production of antibodies or antibody sera as well as the application according to example 1.
Beispiel 4: Es wird ein Gemisch von embryo-fetalen Antigenen und Tumorantigenen gewonnen und weiterverarbeitet entsprechend den Beispielen 1 - 3.Example 4: A mixture of embryo-fetal antigens and tumor antigens is used obtained and further processed according to Examples 1 - 3.
Beispiel 5: Die Erzeugung bzw. Auslösung einer aktiven oder passiven topischen Anaphylaxie (Arthus-Reaktion) am Tumor erfolgt nach den allgemeinen immunologischen bzw. allergologischen Grundsätzen, desgleichen die Durchbrechung einer Immuntoleranz gegen Tumorantigene.Example 5: The generation or triggering of an active or passive topical anaphylaxis (Arthus reaction) on the tumor is carried out according to the general immunological or allergological principles, as well as breaking an immune tolerance against tumor antigens.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843444684 DE3444684A1 (en) | 1984-12-07 | 1984-12-07 | Preparation of conjugated antigens and antibodies (immunoglobulins) directed against them for the purposes of tumour therapy and prophylaxis |
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| Application Number | Priority Date | Filing Date | Title |
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| DE19843444684 DE3444684A1 (en) | 1984-12-07 | 1984-12-07 | Preparation of conjugated antigens and antibodies (immunoglobulins) directed against them for the purposes of tumour therapy and prophylaxis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000038710A2 (en) * | 1998-12-30 | 2000-07-06 | Thomas Jefferson University | Dual hapten modified tumor cells and tumor polypeptides and methods of treating cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA903671A (en) * | 1972-06-27 | J. Lewis Andrew | Soluble cancer antigens coupled to foreign proteins | |
| US4160018A (en) * | 1973-06-25 | 1979-07-03 | Bjorklund Knut B | Stabilized cancer associated polypeptide antigen and preparation thereof |
| CH627187A5 (en) * | 1975-09-03 | 1981-12-31 | Eisai Co Ltd |
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1984
- 1984-12-07 DE DE19843444684 patent/DE3444684A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA903671A (en) * | 1972-06-27 | J. Lewis Andrew | Soluble cancer antigens coupled to foreign proteins | |
| US4160018A (en) * | 1973-06-25 | 1979-07-03 | Bjorklund Knut B | Stabilized cancer associated polypeptide antigen and preparation thereof |
| CH627187A5 (en) * | 1975-09-03 | 1981-12-31 | Eisai Co Ltd |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000038710A2 (en) * | 1998-12-30 | 2000-07-06 | Thomas Jefferson University | Dual hapten modified tumor cells and tumor polypeptides and methods of treating cancer |
| WO2000038710A3 (en) * | 1998-12-30 | 2000-11-09 | Univ Jefferson | Dual hapten modified tumor cells and tumor polypeptides and methods of treating cancer |
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