DE4237502A1 - Medicaments contg. anti-idiotype-CD14 antibodies - having high endotoxin binding capacity, used for treating e.g. infections, burns, ARDS, septic shock or psoriasis - Google Patents

Medicaments contg. anti-idiotype-CD14 antibodies - having high endotoxin binding capacity, used for treating e.g. infections, burns, ARDS, septic shock or psoriasis

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Publication number
DE4237502A1
DE4237502A1 DE19924237502 DE4237502A DE4237502A1 DE 4237502 A1 DE4237502 A1 DE 4237502A1 DE 19924237502 DE19924237502 DE 19924237502 DE 4237502 A DE4237502 A DE 4237502A DE 4237502 A1 DE4237502 A1 DE 4237502A1
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antibodies
idiotype
therapy
medicament
prophylaxis
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Christine Prof Dr Schuett
Christian Dr Krueger
Sabine Dr Witt
Helmut Dr Dietz
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BIOMETEC GES fur BIO MEDIZINI
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BIOMETEC GES fur BIO MEDIZINI
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

Medicaments contain one or more monoclonal anti-idiotype antibodies (I) with CD14-imitating function. (I) are pref. humanised by genetic engineering or adapted for other species. Pref. (I) imitates sequences of glycosylated or non-glycosylated CD14. Also claimed are numerous uses of anti-idiotype-CD14 antibodies (I') (see "USE"). CD14, a monocyte differentiation antigen, is a glycosylated protein of human origin (CD = cluster of differentiation). USE/ADVANTAGE - (I) recognise and neutralise endotoxins (ET) (claimed). Claimed medicinal uses of (I') are for prophylaxis or therapy or diseases by reducing ET damage, prevention of sCD14-mediated cell activation and therapy of infections; the diseases involved are specifically burns (or sequellae), polytrauma (or sequellae), multi-organ failure, ARDS, septic shock, severe infections with AIDS, sequellae of therapy in immunosuppressed patients, liver diseases, immune defects, skin diseases (e.g. psoriasis), rejection crises, graft-versus-host disease and auto-immune disease. Other claimed uses of (I') are : for prodn. of ET-specific adsorbents, for removing ET from patients, animals, nutrient media, infusion solns., rinsing solns. and other sterile prods.; and for detection of ET, ET-binding substances, exotoxins and other specific binding substances. (I) are useful for therapy and prophylaxis of viral or bacterial infections, esp. those associated with sepsis or ET shock. They are also useful prophylactically, e.g. for excluding ET during operations or organ transplantation. (I) have high ET-binding capacity. Unlike conventional anti-ET antibodies (e.g. raised against ET, LPS or lipid A) (I) do are not gp.- or strain-specific, and do not bind differently to free ET and whole bacteria contg. cell-bonded ET.

Description

Gegenstand dieser Erfindung ist ein neues Arzneimittel enthaltend Antikörper mit CD14-imitierender Funktion. Gegenstand der vorliegenden Erfindung ist ein Arzneimittel enthaltend Anti-Idiotyp-Antikör­ per, welche aus Immunisierungen gegen idiotypische Abschnitte von Anti-CD14-Antikör­ pern gewonnen wurden und welche die Endotoxin-bindende Kapazität des Endotoxin- Rezeptors CD14 imitieren, sowie die Verwendung dieser Anti-Idiotyp-Antikörper zur Prophylaxe oder Therapie einer Sepsis.This invention relates to a new drug containing antibodies CD14 mimicking function. The present invention relates to a medicament containing anti-idiotype antibody per, which results from immunizations against idiotypic sections of anti-CD14 antibody and the endotoxin-binding capacity of the endotoxin Mimic receptor CD14, as well as the use of these anti-idiotype antibodies Prophylaxis or therapy for sepsis.

Darüber hinaus ist Gegenstand der Erfindung die Verwendung von Anti-Idiotyp-Antikörpern gegen Anti-CD14-Antikörper als Endotoxin-neutralisierendes Prinzip. Darüber hinaus ist Gegenstand der Erfindung die Verwendung von Anti-Idiotyp-Antikörpern gegen Anti-CD14-Antikörper zum Nachweis von Endotoxinen, endotoxinbindenden Substanzen.The invention also relates to the use of anti-idiotype antibodies against anti-CD14 antibodies as an endotoxin neutralizing principle. The invention also relates to the use of anti-idiotype antibodies against anti-CD14 antibodies for the detection of endotoxins, endotoxin binding Substances.

CD14 (Cluster of Differentiation) ist ein im Menschen vorkommendes, glykosyliertes Protein. Es ist ein membranständiges Differenzierungsantigen von Monozyten, das auch auf aktivierten neutrophilen Granulozyten und einigen Makrophagen exprimiert wird. Dieses Molekül kann mittels monoklonaler Antikörper nachgewiesen werden. Weiterhin ist bekannt, daß CD14 in löslicher Form im Serum und anderen Körperflüssigkeiten vorkommt (Bazil, V., Horejsi, V., Baudys, M., Kristofova, H., Strominger, J.L., Kostka, W. and Hilgert, I.: Biochemical characterization of a soluble form of the 53 kDa monocyte surface antigen. EUR. J. IMMUNOL. 16., 1583-1589 (1986)).CD14 (Cluster of Differentiation) is a glycosylated that occurs in humans Protein. It is a membrane-based monocyte differentiation antigen, too is expressed on activated neutrophil granulocytes and some macrophages. This molecule can be detected using monoclonal antibodies. Still is known that CD14 occurs in soluble form in serum and other body fluids (Bazil, V., Horejsi, V., Baudys, M., Kristofova, H., Strominger, J.L., Kostka, W. and Hilgert, I .: Biochemical characterization of a soluble form of the 53 kDa monocyte surface antigen. EUR. J. IMMUNOL. 16., 1583-1589 (1986)).

Aus Haziot, A. et al. (The monocyte differentiation antigen, CD14, is anchoraged to the cell membrane by a phosphatidylinositol linkage. J. IMMUNOL. 141, 547-552 (1988)) ist die CD14 Sequenz bekannt. Darüber hinaus wird in dieser Veröffentlichung festgestellt, daß CD14 über Phosphatidylinositol-Bindungen an die Zellmembran koppelt.From Haziot, A. et al. (The monocyte differentiation antigen, CD14, is anchoraged to the cell membrane by a phosphatidylinositol linkage. J. IMMUNOL. 141, 547-552 (1988)) the CD14 sequence is known. In addition, this publication states that CD14 couples to the cell membrane via phosphatidylinositol bonds.

Weiterhin ist aus Goyert, S.M. et al. (The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. SCIENCE 239, 439-500 (1988)) bekannt, daß CD 14 fünf N-Glykosylierungsstellen aufweist.Furthermore, from Goyert, S.M. et al. (The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. SCIENCE 239, 439-500 (1988)) known, that CD 14 has five N-glycosylation sites.

Membranständiges CD14 (mCD14) hat ein Molekulargewicht von ca. 53 kDa, lösliches CD14 (sCD14) ca. 48 kDa. CD14 ist als LPS-Rezeptor identifiziert worden. Die LPS-(Endotoxin)-Bindung wird über Serumproteine wie Septin oder LBP (LPS-bindendes Protein) vermittelt. (Wright, S.D. Ramos, R.A., Tobias, P.S., Ulevitch R.J., and Mathison, J.C . . CD14, a receptor for lipopolysaccharide (LPS) and LPS binding protein. SCIENCE 249 1431-1433 (1990), Wright, S.D. Ramos, R.A., Pate, M. and Miller, D.S.: Septin: a factor in plasma that opsonizes lipopolysaccharide bearing particles for recognition by CD14 on phagocytes. J. Exp. Med. 176, 719-727 (1992). CD14 ist eine Rezeptorstruktur, die die LPS-induzierbare TNF-Synthese der CD14-exprimierenden Zellen vermittelt (Wright, 1990 s. o.). CD14 ist eine Rezeptorstruktur, die außerdem die IL1 , IL6 und Sauerstoffradikal­ produktion vermittelt.Membrane-based CD14 (mCD14) has a molecular weight of approx. 53 kDa, soluble CD14 (sCD14) approx. 48 kDa. CD14 has been identified as an LPS receptor. The LPS (endotoxin) binding is via serum proteins such as septin or LBP (LPS-binding Protein) mediated. (Wright, S.D. Ramos, R.A., Tobias, P.S., Ulevitch R.J., and Mathison, J.C. . CD14, a receptor for lipopolysaccharide (LPS) and LPS binding protein. SCIENCE 249 1431-1433 (1990), Wright, S.D. Ramos, R.A., Pate, M. and Miller, D.S .: Septin: a factor in plasma that opsonizes lipopolysaccharide bearing particles for recognition by CD14 on phagocytes. J. Exp. Med. 176, 719-727 (1992). CD14 is a receptor structure that the LPS-inducible TNF synthesis of the CD14-expressing cells mediated (Wright, 1990 s. O.). CD14 is a receptor structure that also contains the IL1, IL6 and oxygen radical production mediates.

Diese Mediatoren sind maßgeblich beteiligt an der Entwicklung eines Multiorganversagens, Sepsis und Schock (Redl, H., Schlag, G . . Pathophysiology of multi organ failure (MOF) proposed mechanism. CLIN. INTENS. CARE 1, 66-71 (1990), Beutler, B. and Cermani, A.: Cachectin tumor necrosis factor: an endogenous mediator in shock and inflammation. IMMUNOL. RES. 5, 281-293 (1987), Joka, Th., Obertacke, U., Sturm, J., Jochum, M., Kirschfink, M., Schramm, W., Dwenger, A., und Bartels, H.: Startreaktionen des traumati­ schen Schocks. H. UNFALLHEILKUNDE 212, 45-53 (1990), Danner, R.L., Ein, R.J., Eilly, J.M., Hosseini, J.M., Schlesinger, T.L. and Parrillo, J.E. Endotoxinemia in human septic shock. CRIT. CARE MED. 16, 397 (1988); Beutler, B., Milsark, I.W. and Cerami, A.C.: Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. SCIENCE 229, 869-870 (1985); Michie, H.R. Manogue, K.R., Spriggs, D.R. et al.: Detection of circulating tumor necrosis factor after endotoxin administration. N. ENGL. J. MED. 318, 1481-1486 (1988).These mediators are instrumental in the development of multi-organ failure, Sepsis and shock (Redl, H., Schlag, G. Pathophysiology of multi organ failure (MOF) proposed mechanism. CLIN. INTENS. CARE 1, 66-71 (1990), Beutler, B. and Cermani, A .: Cachectin tumor necrosis factor: an endogenous mediator in shock and inflammation. IMMUNOL. RES. 5, 281-293 (1987), Joka, Th., Obertacke, U., Sturm, J., Jochum, M., Kirschfink, M., Schramm, W., Dwenger, A., and Bartels, H .: Start reactions of the traumati shocks. H. ACCIDENT HEALING 212, 45-53 (1990), Danner, R.L., Ein, R.J., Eilly, J.M., Hosseini, J.M., Schlesinger, T.L. and Parrillo, J.E. Endotoxinemia in human  septic shock. CRIT. CARE MED. 16, 397 (1988); Beutler, B., Milsark, I.W. and Cerami, A.C .: Passive immunization against cachectin / tumor necrosis factor protects mice from lethal effect of endotoxin. SCIENCE 229: 869-870 (1985); Michie, H.R. Manogue, K.R., Spriggs, D.R. et al .: Detection of circulating tumor necrosis factor after endotoxin administration. N. ENGL. J. MED. 318, 1481-1486 (1988).

Demzufolge ist die Verhinderung einer exzessiven Mediatorfreisetzung Ziel der therapeuti­ schen Konzepte.Accordingly, the prevention of excessive mediator release is the goal of therapeuti concepts.

CD14 in löslicher Form verhindert als löslicher Rezeptor die Aktivierung einer Zelle (Mono­ zyt oder Granulozyt) über das CD14-Molekül (Schütt, C. Schilling, T. and Krüger, C.: sCD14 prevents endotoxin inducible oxidative burst response of human monocytes ALLERGIE IMMUNOL. 37, 159-164 (1991); Schütt, C., Schilling, T., Grunwald, U., Schönfeld, W., Krüger, C.: Endotoxin-neutralizing capacity of soluble CD14. RES IMMUNOL. 143, 71-78 (1992)).CD14 in soluble form prevents the activation of a cell (mono cyt or granulocyte) via the CD14 molecule (Schütt, C. Schilling, T. and Krüger, C .: sCD14 prevents endotoxin inducible oxidative burst response of human monocytes ALLERGY IMMUNOL. 37: 159-164 (1991); Schütt, C., Schilling, T., Grunwald, U., Schönfeld, W., Krüger, C .: Endotoxin-neutralizing capacity of soluble CD14. RES IMMUNOL. 143: 71-78 (1992)).

Demzufolge können Antikörper mit gleicher/ähnlicher Struktur der hypervariablen Regionen mit gleichem Ziel eingesetzt werden.As a result, antibodies with the same / similar structure of the hypervariable regions can used with the same goal.

Es ist weiterhin bekannt, daß einige Anti-CD14-Antikörper Epitope am CD14 binden, die für die Endotoxin-Bindung wichtig sind (Schütt et al.: RES. IMMUNOL. s. o.). Werden gegen derartige Antikörper Antiidiotypische Antikörper hergestellt, können unter diesen Antikörper sein, die die CD14-Bindungsstelle in ihrer hypervariablen Region sozusagen als "internal image" imitieren, d. h. funktionell gleichartig wie CD14 binden.It is also known that some anti-CD14 antibodies bind epitopes to the CD14 that are important for endotoxin binding (Schütt et al .: RES. IMMUNOL. see above). Will Antiidiotypic antibodies against such antibodies can be produced among them Antibodies that act as the CD14 binding site in its hypervariable region imitate "internal image", d. H. bind functionally in the same way as CD14.

Im folgenden ist eine entsprechende Herstellung beispielhaft aufgeführt:A corresponding production is listed below as an example:

  • 1. Präparation von sCD14 aus menschlichem Urin.1. Preparation of sCD14 from human urine.
  • 2. Immunisierung von Mäusen mit Humanmonozyten (CD14-exprimierend) und anschließend mit sCD14.2. Immunization of mice with human monocytes (expressing CD14) and then with sCD14.
  • 3. Selektion von monoklonalen Anti-CD14-Antikörpern mit einer Epitopspezifität für LPS relevante CD14 Epitope, die eine funktionelle Hemmung der CD14-Endotoxin- Bindung verursachen, mittels FITC-markiertem LPS im FACS-Analysator an huma­ nen Monozyten (Grunwald et al., ClRCULATORY SHOCK 1992, in press) = Anti­ körper 1.3. Selection of monoclonal anti-CD14 antibodies with an epitope specificity for LPS-relevant CD14 epitopes that cause functional inhibition of CD14 endotoxin binding by means of FITC-labeled LPS in the FACS analyzer on human monocytes (Grunwald et al., ClRCULATORY SHOCK 1992, in press) = Anti body 1 .
  • 4. Immunisierung von Mäusen mit derartigem Antikörper 1 (Maus-Antikörpern).4. Immunization of mice with such antibody 1 (mouse antibodies).
  • 5. Selektion von Anti-Idiotyp-Antikörpern gegen Antikörper 1 = Antikörper 2 mittels ELISA und funktionelle Testung auf Hemmung der FITC-LPS-Bindung an humanen Monozyten.5. Selection of anti-idiotype antibodies against antibody 1 = antibody 2 by means of ELISA and functional testing for inhibition of FITC-LPS binding to human monocytes.
  • 6. Antibody engeneering (Humanisierung oder ähnliches) für geplante therapeutische Einsätze in verschiedenen Spezies bzw. Herstellung von Spaltprodukten dieser Antikörper.6. Antibody engineering (humanization or the like) for planned therapeutic Use in different species or production of fission products of these Antibody.

Die Aufgabe der vorliegenden Erfindung ist die Bereitstellung eines neuen Arzneimittels enthaltend Antikörper mit endotoxinneutralisierender Kapazität.The object of the present invention is to provide a new medicament containing antibodies with endotoxin neutralizing capacity.

Die EP-A-O 330 191 erwähnt die Verwendung gentechnologisch hergestellter CD-Moleküle als therapeutische und diagnostische Werkzeuge für verschiedene Zwecke. Dort wird beschrieben, daß aktive Fragmente der gentechnologisch hergestellten CD-Moleküle zu diesen Zwecken eingesetzt werden können. Betont wird dabei ausdrücklich die Verwen­ dung von rekombinanten CD-Molekülen und nicht etwa aus natürlichen Quellen isolierte CD-Moleküle. Die EP-A-O 330 191 umfaßt Arzneimittel enthaltend CD14. Hier wird die ausdrückliche Verwendung von natürlichem CD14 als Arzneimittel angezeigt. CD14 hat ein Molekulargewicht von 53 kDa. Die Anti-Idiotyp-Antikörper haben ein Molekulargewicht von ca. 150 kDa, besitzen 2 effektive Bindungsstellen, die die Rezeptorwirkung von CD14 erfüllen und haben ein Antikörper-typisches Fc-Fragment, daß wesentliche Funktionen bei der natürlichen Elimination der antikörpergebundenen Endotoxine erfüllt (z. B. Bindung an zelluläre Fc-Rezeptoren und nachfolgende Phagozytose etc.).EP-A-0 330 191 mentions the use of genetically engineered CD molecules as therapeutic and diagnostic tools for various purposes. There will described that active fragments of the genetically engineered CD molecules can be used for these purposes. The use is explicitly emphasized of recombinant CD molecules and not isolated from natural sources CD molecules. EP-A-0 330 191 comprises medicaments containing CD14. Here is the express use of natural CD14 indicated as a drug. CD14 has a molecular weight of 53 kDa. The anti-idiotype antibodies have a molecular weight of approx. 150 kDa, have 2 effective binding sites, which have the receptor effect of CD14 fulfill and have an antibody-typical Fc fragment that has essential functions the natural elimination of the antibody-bound endotoxins (e.g. binding to  cellular Fc receptors and subsequent phagocytosis etc.).

Aufgabe der vorliegenden Erfindung ist die Bereitstellung eines Arzneimittels zur Therapie und Prophylaxe von viralen oder bakteriellen Infektionen, insbesondere solchen, die im Zu­ sammenhang mit Sepsis und dem Endotoxin-Schock stehen. Das wirksame Prinzip des Arzneimittels sollte auch eine hohe Endotoxin-Bindungskapazität aufweisen und in eng sprechend aufbereiteter Form auch in präventiver Weise eingesetzt werden können, um beispielsweise iatrogene Einwirkungen in Form von Einschleppung von Endotoxinen während einer Operation oder einer Organverpflanzung zu verhindern.The object of the present invention is to provide a medicament for therapy and prophylaxis of viral or bacterial infections, especially those that are in the Zu related to sepsis and endotoxin shock. The effective principle of The drug should also have a high endotoxin binding capacity and be tight appropriately prepared form can also be used in a preventive manner for example iatrogenic effects in the form of the introduction of endotoxins during surgery or organ transplantation.

Diese Aufgabe wird überraschend gelöst durch ein Arzneimittel, enthaltend Antikörper mit analoger Wirkung wie ein löslicher LPS-Rezeptor, die als Mausantikörper, Spaltprodukte oder humanisierte Antikörper die CD14-Rezeptorbindung oder Endotoxin-Bindung imitieren. Diese Antikörper unterscheiden sich von Anti-Endotoxin-Antikörpern, die durch die Immunisierung mit Endotoxinen, LPS, Lipid A oder analogen Endotoxinbruchstücken verschiedener Gramnegativer Bakterien hergestellt werden.This object is surprisingly achieved by a medicament containing antibodies analogous effect as a soluble LPS receptor, which acts as a mouse antibody, cleavage products or humanized antibodies that mimic CD14 receptor binding or endotoxin binding. These antibodies differ from anti-endotoxin antibodies by which Immunization with endotoxins, LPS, Lipid A or analogous endotoxin fragments various Gram negative bacteria.

Diese binden entweder nicht Endotoxine beliebiger Erreger, d. h. sind gruppen- oder stammspezifisch oder binden nicht in gleicher Weise freie Endotoxine und ganze Bakterien mit membranverankertem Endotoxin.These either do not bind endotoxins from any pathogen, i. H. are group or strain-specific or do not bind free endotoxins and whole bacteria in the same way with membrane-anchored endotoxin.

Diese Aufgabe wird überraschend gelöst durch Anti-Idiotyp-Antikörper mit Endotoxin­ bindenden Kapazitäten, die der natürlichen Rezeptorbindung durch CD14 entspricht, d. h. sie besitzen absolute in vivo-Relevanz.This task is surprisingly achieved by anti-idiotype antibodies with endotoxin binding capacities corresponding to the natural receptor binding by CD14, d. H. they are absolutely relevant in vivo.

Diese Erfindung war überraschend. Im gesamten Stand der Tierkunde findet sich kein Hinweis auf eine entsprechende Wirkung, bzw. kein Hinweis auf Anti-Idiotyp-Antikörper mit endotoxin-neutralisierender Wirkung.This invention was surprising. There is none in the entire state of animal science Indication of a corresponding effect, or no indication of anti-idiotype antibodies with endotoxin neutralizing effect.

Überraschend war auch die hohe Bindungskapazität der Anti-Idiotyp-Antikörper.The high binding capacity of the anti-idiotype antibodies was also surprising.

Claims (22)

1. Arzneimittel enthaltend einen (mehrere) monoklonale Anti-Idiotyp-Antikörper mit CD14-imitierender Funktion.1. Medicament containing a (several) monoclonal anti-idiotype antibody CD14 mimicking function. 2. Arzneimittel gemäß Anspruch 1, dadurch gekennzeichnet, daß es durch antibody engeneering humanisiert, bzw. für andere Spezies angepaßt wird.2. Medicament according to claim 1, characterized in that it is by antibody Close humanization, or is adapted for other species. 3. Arzneimittel gemäß Anspruch 1 und 2, dadurch gekennzeichnet, daß es Sequenzen von glykosyliertem bzw. nicht-glykosyliertem CD14 imitiert. 4. Arzneimittel gemäß Anspruch 1 und 2, dadurch gekennzeichnet, daß es Endotoxine und Exotoxine erkennt und neutralisiert.3. Medicament according to claim 1 and 2, characterized in that there are sequences imitated by glycosylated or non-glycosylated CD14. 4. Medicament according to claim 1 and 2, characterized in that it is endotoxins and detects and neutralizes exotoxins. 5. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie von Krankheiten, bei denen Endotoxinschäden vermieden werden sollen.5. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the prophylaxis or therapy of diseases in which endotoxin damage should be avoided. 6. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Therapie von Verbrennungen und Prophylaxe von Folgeschäden.6. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the treatment of burns and prophylaxis of consequential damage. 7. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Therapie von Polytraumen und Prophylaxe von Folgeschäden.7. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the therapy of poly traumas and prophylaxis of consequential damage. 8. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie von Multiorganversagen.8. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the prophylaxis or therapy of multi-organ failure. 9. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie von ARDS.9. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the prophylaxis or therapy of ARDS. 10. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie von septischem Schock.10. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the prophylaxis or therapy of septic shock. 11. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie schwerer Infektionen bei AIDS.11. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the prophylaxis or therapy of severe infections in AIDS. 12. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe von Folgeschäden bei Therapie bei immunsupprimierten Patienten.12. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for the prevention of consequential damage during therapy in immunosuppressed patients. 13. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie bei Lebererkrankungen.13. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for prophylaxis or therapy for liver diseases. 14. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung eines Arzneimittels zur Prophylaxe oder Therapie bei Immundefekten.14. Use of anti-idiotype CD14 antibodies for the manufacture of a medicament for prophylaxis or therapy for immune deficiencies. 15. Verwendung dieses Arzneimittels in Human- und Veterinärmedizin (z. B. nach antibody engeneering zur Anpassung an entsprechende Spezies).15. Use of this medicinal product in human and veterinary medicine (e.g. after antibody engineering to adapt to corresponding species). 16. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Abwendung sCD14-vermittel­ ter Zellaktivierungen. 16. Use of anti-idiotype CD14 antibodies to avert sCD14 mediators cell activations.   17. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Therapie von Infektionen.17. Use of anti-idiotype CD14 antibodies to treat infections. 18. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Therapie von Hauterkrankun­ gen, z. B. Psoriasis.18. Use of anti-idiotype CD14 antibodies for the therapy of skin diseases gene, e.g. B. Psoriasis. 19. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Therapie von Rejektions­ krisen.19. Use of anti-idiotype CD14 antibodies for the therapy of rejection crises. 20. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Therapie von Graft versus- Host-Reaktionen.20. Use of anti-idiotype CD14 antibodies for the therapy of graft versus- Host reactions. 21. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Therapie von Autoimmuner­ krankungen.21. Use of anti-idiotype CD14 antibodies for the therapy of autoimmune diseases. 22. Verwendung von Anti-Idiotyp-CD14-Antikörpern zur Herstellung von endotoxin­ spezifischen Adsorbern zur Erreichung von Endotoxinfreiheit in Patienten, Tieren, Nährmedien, Infusionslösungen, Spüllösungen und anderen sterilen Produkten.22. Use of anti-idiotype CD14 antibodies for the production of endotoxin specific adsorbers to achieve freedom from endotoxins in patients, animals, Culture media, infusion solutions, irrigation solutions and other sterile products. 23. Verwendung von Anti-Idiotyp-CD14-Antikörpern zum Nachweis von Endotoxinen, endotoxinbindenden Substanzen, Exotoxinen und anderen spezifisch bindenden Substanzen.23. Use of anti-idiotype CD14 antibodies for the detection of endotoxins, endotoxin binding substances, exotoxins and other specific binding substances Substances.
DE19924237502 1992-11-06 1992-11-06 Medicaments contg. anti-idiotype-CD14 antibodies - having high endotoxin binding capacity, used for treating e.g. infections, burns, ARDS, septic shock or psoriasis Withdrawn DE4237502A1 (en)

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DE19924237502 DE4237502A1 (en) 1992-11-06 1992-11-06 Medicaments contg. anti-idiotype-CD14 antibodies - having high endotoxin binding capacity, used for treating e.g. infections, burns, ARDS, septic shock or psoriasis

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DE19924237502 DE4237502A1 (en) 1992-11-06 1992-11-06 Medicaments contg. anti-idiotype-CD14 antibodies - having high endotoxin binding capacity, used for treating e.g. infections, burns, ARDS, septic shock or psoriasis

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2279745A3 (en) * 2004-03-31 2011-02-16 Kazuhisa Maeda Adiponectin as endotoxin-neutralising agent

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2279745A3 (en) * 2004-03-31 2011-02-16 Kazuhisa Maeda Adiponectin as endotoxin-neutralising agent
US9341634B2 (en) 2004-03-31 2016-05-17 Kazuhisa Maeda Method for controlling post-operative sepsis infection by administering adiponectin

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