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EP1024831A2 - Application of tnf antagonists as medicaments for treating septic diseases - Google Patents

Application of tnf antagonists as medicaments for treating septic diseases

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Publication number
EP1024831A2
EP1024831A2 EP98955459A EP98955459A EP1024831A2 EP 1024831 A2 EP1024831 A2 EP 1024831A2 EP 98955459 A EP98955459 A EP 98955459A EP 98955459 A EP98955459 A EP 98955459A EP 1024831 A2 EP1024831 A2 EP 1024831A2
Authority
EP
European Patent Office
Prior art keywords
tnf
treatment
serum level
interleukin
antagonists
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98955459A
Other languages
German (de)
French (fr)
Inventor
Hartmut Kupper
Martin Kaul
Jürgen Eiselstein
Lothar Daum
Joachim Kempeni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP1024831A2 publication Critical patent/EP1024831A2/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • TNF antagonists as a medicine for the treatment of septic diseases
  • the present invention relates to the use of TNF antagonists in the treatment of septic diseases.
  • tumor necrosis factor encompasses two cytotoxic factors (TNF- ⁇ and TNF- ⁇ ), which are largely formed by activated ymphocytes and monocytes.
  • anti-TNF antibodies are described which are used in diseases which are associated with an increase in TNF in the blood, such as septic shock, graft rejection, allergies, autoimmune diseases, shock lungs, blood coagulation disorders or inflammatory bone diseases Inactivation of TNF should be usable.
  • septic diseases are defined as a collective clinical term for conditions in which - starting from a focus - inflammatory pathogens, e.g. Bacteria enter the bloodstream, which triggers a wide range of subjective and objective symptoms. Furthermore, it is found that depending on the type of pathogen, the reaction situation of the organism, the primary focus and the changing organ involvement, the clinical picture can vary very much (Sturm et al. "Basic terms of internal medicine", 13th edition, page 570, Gustav Fischer Verlag , Stuttgart, 1984).
  • TNF cytokines
  • IL-6 cytokine interleukin-6
  • Waage describes that the concentrations of the cytokines IL-6 and IL-8 correlate with the severity of the shock; that they do not, either alone or in combination with TNF, influence the development of a shock syndrome with regard to lethality (Libra in "Tumor Necrosis Factors", ed. B. Beutler, Raven Press, New York, 1992, pages 275-283).
  • IL-6 Some scientists attribute IL-6 to a favorable role in septic shock, since IL-6 inhibits LPS-induced TNF production in the form of a negative feedback control (Libert et al. In “Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance ", ed. W. Fiers, Karger, Basel, 1993, pages 126-131).
  • WO 95/00291 teaches TNF antagonists as medicaments for the treatment of sepsis in those patients in whom interleukin-6 serum values of 500 pg / ml and more occur.
  • the task was therefore to reliably and quickly identify those who can be successfully treated with TNF-antagonists within the patients suffering from sepsis.
  • the interleukin-6 serum level is increasing, ie within a measurement interval that is at least thirty minutes, the value measured later is higher than the value measured first.
  • the treatment is preferably carried out in those patients in whom the interleukin-6 serum level in the measurement interval is at least 500 pg / ml. However, it can also be significantly above this value and can be up to the order of a few mg / ml.
  • the second, later measured value should be collected within a period of 30 minutes to 48 hours after the first IL-6 measured value (measuring interval).
  • the measurement interval is preferably 2 to 24 hours, in particular 4 to 10 hours.
  • the patients to be treated are usually under intensive medical treatment, which sometimes does not allow compliance with strict measurement interval limits.
  • the extent of the IL-6 serum level increase between the two measurements is not so critical for the use according to the invention.
  • the serum concentrations of IL-6 can be determined using standard detection methods such as RIA or ELISA.
  • a well-suited detection system is, for example, the "IL-6-EASIA" from Medgenix.
  • the concentration of IL-6 can also be determined using an activity test in which, for example, C-reactive protein is tested. Since different measurement methods or test systems sometimes produce different results for the same measurement, it is recommended either to use the same measurement method or test system to determine the IL-6 values or - if different systems are used - to calibrate them against each other.
  • Suitable TNF antagonists are anti-TNF antibodies, TNF receptors and soluble fragments thereof, TNF binding proteins or TNF derivatives which still have TNF receptor binding but no longer have TNF activity. Such TNF antagonists are characterized in that they capture already formed TNF and do not allow them to reach the TNF receptor or that they compete with TNF for the receptor.
  • TNF antagonists which prevent the formation or release of TNF are also suitable for the use according to the invention. Such substances inhibit, for example, the gene expression of TNF or the release of TNF from precursor forms. Suitable TNF antagonists are, for example, inhibitors of TNF convertase.
  • TNF-antagonistic activities include xanthine derivatives, glucocorticoids, prostaglandin E 2, thalidomide, interleukin-4, interleukin-10, granulocyte stimulating factor
  • G-CSF G-CSF
  • cyclosporin cyclosporin
  • ⁇ -antitrypsin Such compounds are therefore also suitable as TNF antagonists.
  • TNF antagonists suitable for the use according to the invention are described, for example, by Mariott et al. DDT, Vol. 2, No. 7, July 1997 and described in the literature cited there.
  • Anti-TNF antibodies and their fragments are particularly preferred for the use according to the invention.
  • anti-TNF antibodies suitable for use according to the invention are known (EP 260 610, EP 351 789, EP 218 868). Both polyclonal and monoclonal antibodies can be used. TNF-binding antibody fragments such as Fab or F (ab ') 2 fragments or single-chain Fv fragments are also suitable.
  • humanized or human anti-TNF antibodies or their TNF-binding fragments are also well suited, since these molecules should not cause anti-mouse antigenicity in human patients.
  • Mixtures of various anti-TNF antibodies or of anti-TNF antibodies and TNF receptor fragments can also be used as the active ingredient.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the anti-TNF antibodies and processes for the preparation of these preparations.
  • the anti-TNF antibodies are formulated in a manner customary for biotechnologically produced active ingredients, generally as a liquid formulation or lyophilisate (see, for example, Hagers Handbuch der Pharmaceuticaltechnik, Vol. 2, 5th Edition, 1991, p. 720, ISBN 3- 540-52459-2).
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient or excipients.
  • the active ingredient (s) suitable for the use according to the invention in total amounts of about 0.1 to about 100, preferably 0.1 to 10 mg / kg of body weight per 24 hours, optionally in the form of several individual doses or to be administered as a continuous infusion and possibly over a therapy period of several days to achieve the desired results.
  • the application can be carried out as an intravenous short infusion of the individual doses or as a continuous long-term infusion of the daily dose over 24 hours.
  • a single dose contains the active ingredient (s) preferably in amounts of about 0.1 to about 10 mg / kg body weight.
  • MAK 195F Treatment of sepsis patients with a murine anti-TNF antibody fragment (F (ab ') 2 ) called MAK 195F (INN: AFELIMOMAB).
  • a multi-center clinical study analyzed a total of 251 patients with severe sepsis who were treated either with an anti-TNF antibody fragment (afelimomab) or as control patients. Of the 251 patients, 47 had an increasing IL-6 serum level, 178 a decreasing one.
  • the figure shows that in the group with increasing IL-6 value a reduction in mortality can be achieved by treatment (55.6% mortality compared to 69% in control).
  • the treatment group received the investigational drug afelimomab over a period of 3 days as a total of nine short infusions over 15 minutes at eight-hour intervals in a single dose of 1 mg / kg body weight.
  • the control group also received a pharmacologically ineffective sham preparation (placebo) in the same application scheme.

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Abstract

The invention relates to the application of TNF antagonists in order to produce medicaments for treating septic diseases characterized by an increasing coarse of the interleukin-6 serum level during a measurement interval of at least thirty minutes.

Description

Verwendung von TNF-Antagonisten als Arzneimittel zur Behandlung von septischen ErkrankungenUse of TNF antagonists as a medicine for the treatment of septic diseases
Beschreibungdescription
Die vorliegende Erfindung betrifft die Verwendung von TNF-Antagonisten bei der Behandlung von septischen Erkrankungen.The present invention relates to the use of TNF antagonists in the treatment of septic diseases.
Es ist bekannt, daß der Begriff Tumor Nekrose Faktor (TNF) zwei zytotoxische Faktoren (TNF-α und TNF-ß) umfaßt, die größtenteils von aktivierten ymphozyten und Monozyten gebildet werden.It is known that the term tumor necrosis factor (TNF) encompasses two cytotoxic factors (TNF-α and TNF-β), which are largely formed by activated ymphocytes and monocytes.
In der EP 260 610 werden beispielsweise anti-TNF-Antikörper be- schrieben, die bei Krankheiten, die mit einer Erhöhung von TNF im Blut verbunden sind, wie septischer Schock, Transplantatab- stoßung, Allergien, Autoimmunkrankheiten, Schocklunge, Blutgerinnungsstörungen oder entzündlichen Knochenerkrankungen zur Inaktivierung von TNF einsetzbar sein sollen.In EP 260 610, for example, anti-TNF antibodies are described which are used in diseases which are associated with an increase in TNF in the blood, such as septic shock, graft rejection, allergies, autoimmune diseases, shock lungs, blood coagulation disorders or inflammatory bone diseases Inactivation of TNF should be usable.
In medizinischen Lehrbüchern werden septische Erkrankungen als klinischer Sammelbegriff für Zustände definiert, bei denen - ausgehend von einem Herd - Entzündungserreger, z.B. Bakterien in die Blutbahn gelangen, wodurch ein großes Spektrum subjektiver und objektiver Krankheitserscheinungen ausgelöst wird. Weiterhin wird festgestellt, daß in Abhängigkeit vom Erregertyp, der Reaktionslage des Organismus, dem Primärherd und den wechselnden Organbeteiligungen das Krankheitsbild sehr variieren kann (Sturm et al . "Grundbegriffe der Inneren Medizin", 13. Auflage, Seite 570, Gu- stav Fischer Verlag, Stuttgart, 1984) .In medical textbooks, septic diseases are defined as a collective clinical term for conditions in which - starting from a focus - inflammatory pathogens, e.g. Bacteria enter the bloodstream, which triggers a wide range of subjective and objective symptoms. Furthermore, it is found that depending on the type of pathogen, the reaction situation of the organism, the primary focus and the changing organ involvement, the clinical picture can vary very much (Sturm et al. "Basic terms of internal medicine", 13th edition, page 570, Gustav Fischer Verlag , Stuttgart, 1984).
Für den komplexen pathophysiologischen Ablauf einer Sepsis wird die Beteiligung einer Reihe von Cytokinen diskutiert. Besonders TNF wird eine wichtige Rolle beim septischen Schock aufgrund tierexperimenteller Daten zugeschrieben (Beutler et al., Science 229, 869-871, 1985) .The involvement of a number of cytokines is discussed for the complex pathophysiological course of sepsis. TNF in particular is attributed an important role in septic shock based on data from animal experiments (Beutler et al., Science 229, 869-871, 1985).
Dies hat letztlich dazu geführt, daß klinische Studien zur Behandlung von Sepsispatienten mit anti -TNF -Antikörpern durchge- führt wurden.Ultimately, this led to clinical studies on the treatment of sepsis patients with anti-TNF antibodies being carried out.
In einer vor kurzem veröffentlichten Mehrzentren-Phase II- Studie zur Behandlung von schwerer Sepsis mit einem murinen monoklonalen anti-TNF-Antikörper wurde allerdings gefunden, daß das Gesamtkol- lektiv (80 Patienten) hinsichtlich Uberlebensrate nicht von der Behandlung mit dem Antikörper profitierte. Lediglich die Patienten mit erhöhten zirkulierenden TNF-Konzentrationen schienen von hochdosierter anti -TNF-Antikörper-Gabe hinsichtlich der Überlebenswahrscheinlichkeit zu profitieren (C.J.Fisher et al . , Critical Care Medicine, Vol. 21, No.3, Seite 318-327). Weiterhin wird in dieser Studie auf eine Korrelation der Plasmawerte von TNF und IL-6 hingewiesen.However, in a recently published multi-center phase II study to treat severe sepsis with a murine monoclonal anti-TNF antibody, it was found that the overall population (80 patients) did not benefit from treatment with the antibody in terms of survival. Only the patients with increased circulating TNF concentrations appeared to be to benefit from high-dose anti-TNF antibody administration with regard to the probability of survival (CJFisher et al., Critical Care Medicine, Vol. 21, No.3, pages 318-327). This study also points to a correlation between the plasma values of TNF and IL-6.
Die Rolle, die das Cytokin Interleukin-6 (IL-6) bei der Sepsis spielt, ist unklar und widersprüchlich. Bei einigen Sepsispatienten wurden erhöhte Serumspiegel an IL-6 gefunden (Hack et al . , Blood 74, Nr.5, 1704-1710, 1989).The role that the cytokine interleukin-6 (IL-6) plays in sepsis is unclear and contradictory. Elevated serum levels of IL-6 have been found in some sepsis patients (Hack et al., Blood 74, No. 5, 1704-1710, 1989).
Waage beschreibt, daß die Konzentrationen der Cytokine IL-6 und IL-8 mit der Schwere des Schocks korrelieren; daß sie aber nicht, weder allein noch in Kombination mit TNF, die Entwicklung eines Schocksyndroms hinsichtlich Lethalität beeinflussen (Waage in "Tumor Necrosis Factors",ed. B.Beutler, Raven Press, New York, 1992, Seite 275-283) .Waage describes that the concentrations of the cytokines IL-6 and IL-8 correlate with the severity of the shock; that they do not, either alone or in combination with TNF, influence the development of a shock syndrome with regard to lethality (Libra in "Tumor Necrosis Factors", ed. B. Beutler, Raven Press, New York, 1992, pages 275-283).
Von einigen Wissenschaftlern wird IL-6 eine günstige Rolle beim septischen Schock zugeschrieben, da IL-6 in Form einer negativen Feedback-Kontrolle die LPS- induzierte TNF Produktion hemmt (Li- bert et al . in "Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance" , ed. W. Fiers, Karger, Basel, 1993, Seite 126-131) .Some scientists attribute IL-6 to a favorable role in septic shock, since IL-6 inhibits LPS-induced TNF production in the form of a negative feedback control (Libert et al. In "Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance ", ed. W. Fiers, Karger, Basel, 1993, pages 126-131).
WO 95/00291 lehrt TNF-Antagonisten als Medikamente zur Behandlung von Sepsis bei solchen Patienten, bei denen Interleukin-6 Serumwerte von 500 pg/ml und mehr auftreten.WO 95/00291 teaches TNF antagonists as medicaments for the treatment of sepsis in those patients in whom interleukin-6 serum values of 500 pg / ml and more occur.
Es zeigte sich jedoch in klinischen Studien, daß die inHowever, it was shown in clinical studies that the in
WO 95/00291 offenbarte Behandlung nicht immer erfolgreich war.Treatment disclosed in WO 95/00291 was not always successful.
Offenbar gibt es Fälle von Sepsis, die mit gutem Erfolg mit TNF- Antagonisten therapierbar sind, während in anderen Fällen eine Behandlung mit TNF-Antagonisten keinen Erfolg zeigt und sogar kontraindiziert ist.Apparently there are cases of sepsis that can be treated successfully with TNF antagonists, while in other cases treatment with TNF antagonists is unsuccessful and is even contraindicated.
Es bestand daher die Aufgabe, innerhalb der an Sepsis erkrankten Patienten diejenigen verläßlich und schnell zu identifizieren, die mit TNF-Antagonisten erfolgreich behandelbar sind.The task was therefore to reliably and quickly identify those who can be successfully treated with TNF-antagonists within the patients suffering from sepsis.
Es wurde gefunden, daß die Behandlung von septischen Erkrankungen bei solchen Patienten erfolgreich ist, die folgende Merkmale aufweisen: Der Interleukin-6 Serumspiegel ist ansteigend, d.h. innerhalb eines Meßintervalls, das mindestens dreißig Minuten beträgt, ist der später gemessene Wert höher als der zuerst gemessene Wert.It has been found that the treatment of septic diseases is successful in those patients who have the following features: The interleukin-6 serum level is increasing, ie within a measurement interval that is at least thirty minutes, the value measured later is higher than the value measured first.
Patienten, die an einer Sepsis erkrankt sind und dieses Kriterium erfüllen, sind für eine Behandlung mit TNF-Antagonisten gut geeignet.Patients with sepsis who meet this criterion are well suited for treatment with TNF antagonists.
Bevorzugt wird die Behandlung bei solchen Patienten durchgeführt, bei denen der Interleukin-6 Serumspiegel im Meßintervall mindestens 500 pg/ml beträgt. Er kann jedoch aber auch deutlich über diesem Wert liegen und bis zu einer Größenordnung von einigen mg/ml betragen.The treatment is preferably carried out in those patients in whom the interleukin-6 serum level in the measurement interval is at least 500 pg / ml. However, it can also be significantly above this value and can be up to the order of a few mg / ml.
Um festzustellen, ob der Interleukin-6 Serumspiegel (IL-6) ansteigend ist, müssen mindestens zwei IL-6 Messungen durchgeführt werden.To determine whether the interleukin-6 serum level (IL-6) is increasing, at least two IL-6 measurements must be carried out.
Der zweite, spätere Meßwert soll in einem Zeitraum von 30 Minuten bis 48 Stunden nach dem ersten IL-6 Meßwert erhoben werden (Meß- intervall) .The second, later measured value should be collected within a period of 30 minutes to 48 hours after the first IL-6 measured value (measuring interval).
Bevorzugt beträgt das Meßintervall 2 - 24, insbesondere 4 - 10 Stunden.The measurement interval is preferably 2 to 24 hours, in particular 4 to 10 hours.
Die zu behandelnden Patienten befinden sich in der Regel unter intensivmedizinischer Behandlung, die ein Einhalten von strikten Meßintervallgrenzen manchmal nicht erlaubt.The patients to be treated are usually under intensive medical treatment, which sometimes does not allow compliance with strict measurement interval limits.
Das Ausmaß des IL- 6 -Serumspiegelanstiegs zwischen den beiden Messungen ist für die erfindungsgemäße Verwendung nicht so entscheidend.The extent of the IL-6 serum level increase between the two measurements is not so critical for the use according to the invention.
Im Falle eines nicht-ansteigenden oder sogar abfallenden IL-6-Se- rumspiegels im Meßintervall ist eine Behandlung mit TNF-Antagonisten nicht zu empfehlen.In the case of a non-rising or even falling IL-6 serum level in the measurement interval, treatment with TNF antagonists is not recommended.
Die Serumkonzentrationen an IL-6 lassen sich mit üblichen Nachweisverfahren wie RIA oder ELISA bestimmen. Ein gut geeignetes NachweisSystem ist beispielsweise das "IL-6-EASIA" der Fa. Medgenix.The serum concentrations of IL-6 can be determined using standard detection methods such as RIA or ELISA. A well-suited detection system is, for example, the "IL-6-EASIA" from Medgenix.
Die Konzentration an IL-6 kann auch über einen Aktivitätstest, bei dem beispielsweise C-reaktives Protein getestet wird, bestimmt werden. Da unterschiedliche Meßverfahren oder Testsysteme bei der gleichen Messung manchmal voneinander abweichende Ergebnisse liefern, empfiehlt es sich, entweder das gleiche Meßverfahren bzw. Test- system für die Bestimmung der IL-6 Werte einzusetzen oder - bei Verwendung unterschiedlicher Systeme - diese gegeneinander zu eichen.The concentration of IL-6 can also be determined using an activity test in which, for example, C-reactive protein is tested. Since different measurement methods or test systems sometimes produce different results for the same measurement, it is recommended either to use the same measurement method or test system to determine the IL-6 values or - if different systems are used - to calibrate them against each other.
Als TNF-Antagonisten geeignet sind anti -TNF-Antikörper, TNF- Rezeptoren und lösliche Fragmente davon, TNF-Bindeproteine oder solche TNF-Derivate, die noch TNF-Rezeptorbindung besitzen, aber keine TNF-Aktivität mehr aufweisen. Solche TNF-Antagonisten sind dadurch gekennzeichnet, daß sie bereits gebildetes TNF abfangen und nicht an den TNF-Rezeptor gelangen lassen oder daß sie mit TNF um den Rezeptor konkurrieren.Suitable TNF antagonists are anti-TNF antibodies, TNF receptors and soluble fragments thereof, TNF binding proteins or TNF derivatives which still have TNF receptor binding but no longer have TNF activity. Such TNF antagonists are characterized in that they capture already formed TNF and do not allow them to reach the TNF receptor or that they compete with TNF for the receptor.
Geeignet für die erfindungsgemäße Verwendung sind aber auch TNF- Antagonisten, die die Bildung oder Freisetzung von TNF verhindern. Solche Substanzen inhibieren beispielsweise die Genexpression von TNF oder die Freisetzung von TNF aus Vorlauferformen. Geeignete TNF-Antagonisten sind beispielsweise Inhibitoren der TNF-Convertase.However, TNF antagonists which prevent the formation or release of TNF are also suitable for the use according to the invention. Such substances inhibit, for example, the gene expression of TNF or the release of TNF from precursor forms. Suitable TNF antagonists are, for example, inhibitors of TNF convertase.
TNF-antagonistischen Aktivitäten sind beispielsweise von Xanthin- derivaten, Glucocorticoiden, Prostaglandin E 2, Thalidomid, In- terleukin-4, Interleukin-10, Granulozyten Stimulating FactorTNF-antagonistic activities include xanthine derivatives, glucocorticoids, prostaglandin E 2, thalidomide, interleukin-4, interleukin-10, granulocyte stimulating factor
(G-CSF) , Cyclosporin, α-Antitrypsin beschrieben. Daher sind auch solche Verbindungen als TNF-Antagonisten geeignet.(G-CSF), cyclosporin, α-antitrypsin. Such compounds are therefore also suitable as TNF antagonists.
Die für die erfindungsgemäße Verwendung geeigneten TNF-Antagoni- sten sind beispielsweise von Mariott et al. DDT, Vol. 2, No. 7, July 1997 und in der dort zitierten Literatur beschrieben.The TNF antagonists suitable for the use according to the invention are described, for example, by Mariott et al. DDT, Vol. 2, No. 7, July 1997 and described in the literature cited there.
Besonders bevorzugt für die erfindungsgemäße Verwendung sind anti -TNF-Antikörper und deren Fragmente.Anti-TNF antibodies and their fragments are particularly preferred for the use according to the invention.
Die zur erfindungsgemäßen Verwendung geeigneten anti -TNF-Antikörper sind bekannt (EP 260 610, EP 351 789, EP 218 868). Es können sowohl polyklonale als auch monoklonale Antikörper verwendet werden. Weiterhin sind auch TNF-bindende Antikörper- fragmente wie Fab- oder F (ab' ) 2-Fragmente oder single-chain- Fv-Fragmente geeignet.The anti-TNF antibodies suitable for use according to the invention are known (EP 260 610, EP 351 789, EP 218 868). Both polyclonal and monoclonal antibodies can be used. TNF-binding antibody fragments such as Fab or F (ab ') 2 fragments or single-chain Fv fragments are also suitable.
Ferner sind auch humanisierte oder humane anti -TNF-Antikörper oder deren TNF-bindende Fragmente gut geeignet, da diese Moleküle in menschlichen Patienten keine anti-Maus -Antigenizität verursachen sollten. Es können auch Gemische von verschiedenen anti-TNF-Antikörpern oder von anti-TNF-Antikörpern und TNF-Rezeptor-Fragmenten als Wirkstoff verwendet werden.Furthermore, humanized or human anti-TNF antibodies or their TNF-binding fragments are also well suited, since these molecules should not cause anti-mouse antigenicity in human patients. Mixtures of various anti-TNF antibodies or of anti-TNF antibodies and TNF receptor fragments can also be used as the active ingredient.
Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nicht-toxischen, inerten pharmazeutisch geeigneten Trägerstof en die anti-TNF-Antikörper enthalten, sowie Verfahren zur Herstellung dieser Zubereitungen.The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the anti-TNF antibodies and processes for the preparation of these preparations.
Die Formulierung der anti -TNF-Antikörper geschieht in für biotechnisch hergestellte Wirkstoffe üblicher Weise, in der Regel als Flüssigformulierung oder Lyophilisat (siehe z.B. Hagers Handbuch der pharmazeutischen Praxis, Bd. 2, 5. Auflage, 1991, S. 720, ISBN 3-540-52459-2). Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirkstoffe mit dem oder mit den Trägerstoffen.The anti-TNF antibodies are formulated in a manner customary for biotechnologically produced active ingredients, generally as a liquid formulation or lyophilisate (see, for example, Hagers Handbuch der Pharmaceutical Praxis, Vol. 2, 5th Edition, 1991, p. 720, ISBN 3- 540-52459-2). The pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient or excipients.
Im allgemeinen hat es sich als vorteilhaft erwiesen, den oder die für die erfindungsgemäße Verwendung geeigneten Wirkstoffe in Gesamtmengen von etwa 0,1 bis etwa 100, vorzugsweise 0,1 bis 10 mg/kg Körpergewicht je 24 Stunden, ggf. in Form mehrerer Einzelgaben oder als Dauerinfusion und ggf. über eine Therapiedauer von mehreren Tagen hinweg zur Erzielung der gewünschten Ergebnisse zu verabreichen. Die Applikation kann als intravenöse Kurzinfusion der Einzelgaben oder als kontinuierliche Langzeitinfusion der Tagesdosis über 24 Stunden erfolgen. Eine Einzelgabe enthält den oder die Wirkstoffe vorzugsweise in Mengen von etwa 0,1 bis etwa 10 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen und zwar in Abhängigkeit von Alter und Größe des zu behandelnden Patienten sowie der Art und der Schwere der zugrundeliegenden Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. Die Erfindung ist in dem folgenden Beispiel weiter veranschaulicht.In general, it has proven to be advantageous to use the active ingredient (s) suitable for the use according to the invention in total amounts of about 0.1 to about 100, preferably 0.1 to 10 mg / kg of body weight per 24 hours, optionally in the form of several individual doses or to be administered as a continuous infusion and possibly over a therapy period of several days to achieve the desired results. The application can be carried out as an intravenous short infusion of the individual doses or as a continuous long-term infusion of the daily dose over 24 hours. A single dose contains the active ingredient (s) preferably in amounts of about 0.1 to about 10 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the age and size of the patient to be treated as well as the type and severity of the underlying disease, the type of preparation and application of the drug, and the period or interval within which is administered. The invention is further illustrated in the following example.
Beispielexample
Behandlung von Sepsispatienten mit einem murinen anti -TNF-Antikörperfragment (F(ab')2), genannt MAK 195F (INN: AFELIMOMAB).Treatment of sepsis patients with a murine anti-TNF antibody fragment (F (ab ') 2 ) called MAK 195F (INN: AFELIMOMAB).
In einer multizentrischen klinischen Studie wurden insgesamt 251 Patienten mit schwerer Sepsis analysiert, die entweder mit einem anti -TNF-A tikörperfragment (Afelimomab) oder als Kontrollpatienten behandelt wurden. Von den 251 Patienten hatten 47 einen ansteigenden, 178 einen absteigenden IL-6 Serumspiegel.A multi-center clinical study analyzed a total of 251 patients with severe sepsis who were treated either with an anti-TNF antibody fragment (afelimomab) or as control patients. Of the 251 patients, 47 had an increasing IL-6 serum level, 178 a decreasing one.
Die Figur zeigt, daß in der Gruppe mit ansteigendem IL-6 Wert durch die Behandlung eine Senkung der Mortalität erreichbar ist (55,6 % Mortalität gegenüber 69 % bei Kontrolle) .The figure shows that in the group with increasing IL-6 value a reduction in mortality can be achieved by treatment (55.6% mortality compared to 69% in control).
Bei der Gruppe, die einen abfallenden IL-6 Serumspiegel aufwies, ist durch die Behandlung mit MAK 195 F kein Erfolg sichtbar; es zeigt sich im Gegenteil sogar ein negativer Einfluß durch die Behandlung (Mortalität beträgt 54,7 % gegenüber 50,6 % bei der Kontroll-Gruppe) .In the group that had a decreasing IL-6 serum level, no success is visible through treatment with MAK 195 F; on the contrary, there is even a negative influence from the treatment (mortality is 54.7% compared to 50.6% in the control group).
Die Behandlungsgruppe erhielt zusätzlich zur Standardtherapie der Sepsis das Prüfpräparat Afelimomab über einen Zeitraum von 3 Tagen als insgesamt neunmalige Kurzinfusion über 15 Minuten in jew. achtstündigen Abständen in der Einzeldosis von jeweils 1 mg/kg Körpergewicht. Die Kontrollgruppe erhielt neben der Standardtherapie der Sepsis zusätzlich ein pharmakologisch unwirksames Scheinpräparat (Placebo) in gleichem Applikationsschema.In addition to the standard therapy for sepsis, the treatment group received the investigational drug afelimomab over a period of 3 days as a total of nine short infusions over 15 minutes at eight-hour intervals in a single dose of 1 mg / kg body weight. In addition to the standard therapy for sepsis, the control group also received a pharmacologically ineffective sham preparation (placebo) in the same application scheme.
Das Ergebnis dieser klinischen Studie belegt deutlich, daß die Behandlung von schwerer Sepsis mit anti -TNF-Antikörpern besonders erfolgreich verläuft, wenn solche Sepsispatienten behandelt wer- den, die einen ansteigenden IL-6 Serumspiegel aufweisen. Patienten, die einen abfallenden IL- 6 -Serumspiegel aufweisen, sollten demzufolge nicht mit TNF-Antagonisten behandelt werden. The result of this clinical study clearly shows that the treatment of severe sepsis with anti-TNF antibodies is particularly successful when treating those sepsis patients who have an increasing IL-6 serum level. Patients with a decreasing IL-6 serum level should therefore not be treated with TNF-antagonists.

Claims

Patentansprüche claims
1. Verwendung von TNF-Antagonisten zur Herstellung von Arznei - mittein zur Behandlung von solchen septischen Erkrankungen, die durch einen ansteigenden Verlauf des Interleukin-6 Serumspiegels in einem Meßintervall von mindestens dreißig Minuten gekennzeichnet sind.1. Use of TNF-antagonists for the manufacture of medicinal products - for the treatment of such septic diseases which are characterized by an increasing course of the interleukin-6 serum level in a measuring interval of at least thirty minutes.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß der2. Use according to claim 1, characterized in that the
Interleukin-6 Serumspiegel im Meßintervall 500 pg/ml und darüber beträgt.Interleukin-6 serum level in the measurement interval is 500 pg / ml and above.
3. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß das Meßintervall 4 - 10 Stunden beträgt.3. Use according to claim 1, characterized in that the measuring interval is 4 - 10 hours.
4. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß als TNF-Antagonist ein F (ab' ) 2-Fragment eines monoklonalen anti- TNF-Antikörpers verwendet wird.4. Use according to claim 1, characterized in that an F (ab ') 2 fragment of a monoclonal anti-TNF antibody is used as the TNF antagonist.
5. Handelspackung enthaltend einen TNF-Antagonisten zusammen mit Instruktionen für die Verwendung dieses TNF-Antagonisten bei der Behandlung von septischen Erkrankungen, die durch einen ansteigenden Verlauf des IL-6 Serumspiegels in einem Meßin- tervall von mindestens dreißig Minuten gekennzeichnet sind.5. Commercial package containing a TNF antagonist together with instructions for the use of this TNF antagonist in the treatment of septic diseases, which are characterized by an increasing course of the IL-6 serum level in a measuring interval of at least thirty minutes.
6. Handelspackung nach Anspruch 5, dadurch gekennzeichnet, daß als TNF-Antagonist ein monoklonaler anti -TNF-Antikörper verwendet wird.6. Commercial package according to claim 5, characterized in that a monoclonal anti-TNF antibody is used as TNF antagonist.
7. Verfahren zur Ermittlung, ob ein an Sepsis erkrankter Patient mit TNF-Antagonisten behandelt werden soll, das folgende Schritte enthält:7. A method of determining whether a patient with sepsis should be treated with TNF antagonists comprising the following steps:
(a) Bestimmung des Interleukin- 6 Serumspiegels des Patienten zu einem ersten Zeitpunkt t1 (b) Bestimmung des Interleukin-6 Serumspiegels zu einem zweiten Zeitpunkt t , der mindestens 30 Minuten nach dem ersten Zeitpunkt ti liegt und Bestimmung des Verhältnisses(a) Determination of the patient's interleukin 6 serum level at a first time t 1 (b) Determination of the interleukin-6 serum level at a second point in time t which is at least 30 minutes after the first point in time ti and determination of the ratio
IL-6 Wert (t2) V =IL-6 value (t 2 ) V =
IL-6 Wert (ti)IL-6 value (ti)
(c) für den Fall, daß V > 1 ist erfolgt eine Behandlung mit TNF-Antagonisten. (c) in the event that V> 1, treatment with TNF antagonists takes place.
EP98955459A 1997-10-23 1998-10-15 Application of tnf antagonists as medicaments for treating septic diseases Withdrawn EP1024831A2 (en)

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DE19746868 1997-10-23
DE19746868A DE19746868A1 (en) 1997-10-23 1997-10-23 Use of tumour necrosis factor antagonists
PCT/EP1998/006545 WO1999021582A2 (en) 1997-10-23 1998-10-15 Application of tnf antagonists as medicaments for treating septic diseases

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UA76640C2 (en) * 2002-08-02 2006-08-15 Олєг Ільіч Епштєйн Method for correcting pathological immune responses and homeopathic medicinal agent
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BR112013000842A2 (en) 2010-07-15 2016-06-07 Oleg Lliich Epshtein pharmaceutical compositions, method of treating the condition of functional etiology of the gastrointestinal tract, and use of activated potentiated antibody form s-100, activated potentiated antibody form histamine and activated potentiated antibody form tnf-alpha.
KR20140014059A (en) 2010-07-15 2014-02-05 올레그 일리치 엡쉬테인 A method of increasing the effect of an activated-potentiated form of an antibody
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