WO1994020139A1 - Use of anti-tnf antibodies as medicament for the therapy of heart insufficiency (weakness of the heart muscle) - Google Patents

Use of anti-tnf antibodies as medicament for the therapy of heart insufficiency (weakness of the heart muscle) Download PDF

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Publication number
WO1994020139A1
WO1994020139A1 PCT/EP1994/000628 EP9400628W WO9420139A1 WO 1994020139 A1 WO1994020139 A1 WO 1994020139A1 EP 9400628 W EP9400628 W EP 9400628W WO 9420139 A1 WO9420139 A1 WO 9420139A1
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WIPO (PCT)
Prior art keywords
heart
tnf antibodies
weakness
therapy
tnf
Prior art date
Application number
PCT/EP1994/000628
Other languages
German (de)
French (fr)
Inventor
Karl Werdan
Peter Boekstegers
Joachim Kempeni
Martin Kaul
Original Assignee
Knoll Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Knoll Aktiengesellschaft filed Critical Knoll Aktiengesellschaft
Publication of WO1994020139A1 publication Critical patent/WO1994020139A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the use of anti-TNF antibodies in the treatment of heart failure (heart muscle weakness).
  • tumor necrosis factor encompasses two cytotoxic factors (TNF- ⁇ and TNF- ⁇ ), which are largely formed by activated lymphocytes and monocytes.
  • anti-TNF antibodies are described which are used for diseases such as septic shock, transplant rejection, allergies, autoimmune diseases, shock lung, blood clotting disorders or inflammatory bone diseases which are associated with an increase in TNF in the blood Deactivation of TNF can be used.
  • EP 453 898 teaches the use of anti-TNF antibodies for the treatment of ischemia and the associated symptoms.
  • Heart failure is a clinical syndrome that is characterized not only by cardiac symptoms, but also by functional disorders of the periphery of the organ (see Sturm et al, Basic Terms of Internal Medicine, 13th edition, pp. 67-75, Gustav Fischer Verlag, Stuttgart 1984). . It is not possible to adapt the cardiac output to the requirements of the organism sufficiently (see W. Siegenthaler et al., Textbook of Internal Medicine, 2nd edition, pp. 2 - 11, Georg Thieme Verlag, Stuttgart, 1987). In the case of acute life-threatening heart failure, the cardiac output does not suffice to satisfy the organism's need for rest.
  • 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 the. TNF-binding antibody fragments such as Fab or F (ab ') 2 fragments and Fv or single-chain Fv fragments are also suitable. Furthermore, humanized or human anti-TNF antibodies or their TNF-binding fragments are also very suitable.
  • 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 active substances produced in bio-technology, as a rule as a liquid formulation or lyophilisate (see, for example, Hager's Handbook of Pharmaceutical Practice, Vol. 2, 5th Edition, 1991, p. 720 , ISBN 3-540-52459-2).
  • the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients, in particular those known for the treatment of heart failure, such as catecholamines, digitalis, diuretics and vasodilators (e.g. ACE inhibitors).
  • active pharmaceutical ingredients in particular those known for the treatment of heart failure, such as catecholamines, digitalis, diuretics and vasodilators (e.g. ACE inhibitors).
  • the pharmaceutical preparations listed above are prepared in a conventional 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 1000, preferably 0.1 to 10 mg / kg body weight per 24 hours, optionally in the form of several units administered individually or as a continuous infusion and possibly over a therapy period of several days to achieve the desired results.
  • the application can take place 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Anti-TNF antibodies are used, according to the invention, in the therapy of heart insufficiency (weakness of the heart muscle).

Description

Verwendung von anti-TNF-Antikörpern als Arzneimittel bei der Be¬ handlung von Herzinsuffizienz (Herzmuskelschwäche)Use of anti-TNF antibodies as a medicament in the treatment of heart failure (heart muscle weakness)
Beschreibungdescription
Die vorliegende Erfindung betrifft die Verwendung von anti-TNF- Antikörpern bei der Behandlung von Herzinsuffizienz (Herzmuskel¬ schwäche) .The present invention relates to the use of anti-TNF antibodies in the treatment of heart failure (heart muscle weakness).
Es ist bekannt, daß der Begriff Tumor Nekrose Faktor (TNF) zwei zytotoxische Faktoren (TNF-α und TNF-ß) umfaßt, die größtenteils von aktivierten Lymphozyten 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 lymphocytes and monocytes.
In der EP 260 010 werden beispielsweise anti-TNF-Antikörper be¬ schrieben, die bei Krankheiten wie septischer Schock, Trans- plantatabstoßung, Allergien, Autoimmunkrankheiten, Schocklunge, Blutgerinnungsstörungen oder entzündlichen Knochenerkrankungen, die mit einer Erhöhung von TNF im Blut verbunden sind, zur Inak- tivierung von TNF eingesetzt werden können.In EP 260 010, for example, anti-TNF antibodies are described which are used for diseases such as septic shock, transplant rejection, allergies, autoimmune diseases, shock lung, blood clotting disorders or inflammatory bone diseases which are associated with an increase in TNF in the blood Deactivation of TNF can be used.
Von Vincent et al. (Chest 1992, 101, 810 - 815) wurde beschrie¬ ben, daß die Gabe von anti-TNF-Antikörpern die Funktion des lin¬ ken Ventrikels bei Patienten mit septischem Schock verbessert.By Vincent et al. (Chest 1992, 101, 810-815) it was described that the administration of anti-TNF antibodies improves the function of the left ventricle in patients with septic shock.
In der EP 453 898 wird die Verwendung von anti-TNF-Antikörpern zur Behandlung von Ischämien und den damit verbundenen Begleiter¬ scheinungen gelehrt.EP 453 898 teaches the use of anti-TNF antibodies for the treatment of ischemia and the associated symptoms.
Überraschenderweise wurde gefunden, daß anti-TNF-Antikörper bei der Behandlung von Herzinsuffizienz, insbesondere bei akuter, schwerer und lebensbedrohlicher Herzinsuffizienz, eingesetzt wer¬ den können. Unter Herzinsuffizienz versteht man ein klinisches Syndrom, das nicht nur durch kardiale Symptome, sondern durch Funktionsstörungen der Organperipherie gekennzeichnet ist (siehe Sturm et al, Grundbegriffe der Inneren Medizin, 13. Auflage, S. 67 - 75, Gustav Fischer Verlag, Stuttgart 1984) . Dabei ist die Anpassung der kardialen Förderleistung an die Erfordernisse des Organismus nicht ausreichend möglich (siehe W. Siegenthaler et al., Lehrbuch der Inneren Medizin, 2. Auflage, S. 2 - 11, Georg Thieme Verlag, Stuttgart, 1987) . Bei der akuten lebensbedrohli¬ chen Herzinsuffizienz reicht die Förderleistung des Herzens dabei nicht zur Befriedigung des Ruhebedarfs des Organismus.Surprisingly, it was found that anti-TNF antibodies can be used in the treatment of heart failure, in particular in acute, severe and life-threatening heart failure. Heart failure is a clinical syndrome that is characterized not only by cardiac symptoms, but also by functional disorders of the periphery of the organ (see Sturm et al, Basic Terms of Internal Medicine, 13th edition, pp. 67-75, Gustav Fischer Verlag, Stuttgart 1984). . It is not possible to adapt the cardiac output to the requirements of the organism sufficiently (see W. Siegenthaler et al., Textbook of Internal Medicine, 2nd edition, pp. 2 - 11, Georg Thieme Verlag, Stuttgart, 1987). In the case of acute life-threatening heart failure, the cardiac output does not suffice to satisfy the organism's need for rest.
Die zur erfindungsgemäßen Verwendung geeigneten anti-TNF-Antikör¬ per sind bekannt (EP 260 610, EP 351 789, EP 218 868) . Es können sowohl polyklonale als auch monoklonale Antikörper verwendet wer- den. Weiterhin sind auch TNF-bindende Antikörperfragmente wie Fab- oder F (ab' )2-Fragmente sowie Fv oder single-chain-Fv-Frag- mente geeignet. Ferner sind auch humanisierte oder humane anti- TNF-Antikörper oder deren TNF-bindende Fragmente gut 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 the. TNF-binding antibody fragments such as Fab or F (ab ') 2 fragments and Fv or single-chain Fv fragments are also suitable. Furthermore, humanized or human anti-TNF antibodies or their TNF-binding fragments are also very suitable.
Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nicht-toxischen, inerten pharmazeutisch geeigneten Trä¬ gerstoffen 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 bio¬ technisch hergestellte Wirkstoffe üblicher Weise, in der Regel als Flüssigformulierung oder Lyophilisat (siehe z.B. Hagers Hand¬ buch der pharmazeutischen Praxis, Bd. 2, 5. Auflage, 1991, S. 720, ISBN 3-540-52459-2).The anti-TNF antibodies are formulated in a manner customary for active substances produced in bio-technology, as a rule as a liquid formulation or lyophilisate (see, for example, Hager's Handbook of Pharmaceutical Practice, Vol. 2, 5th Edition, 1991, p. 720 , ISBN 3-540-52459-2).
Die oben aufgeführten pharmazeutischen Zubereitungen können außer anti-TNF-Antikörpern auch weitere pharmazeutische Wirkstoffe ent¬ halten, insbesondere solche, die zur Therapie der Herzinsuffi- zienz bekannt sind wie Katecholamine, Digitalis, Diuretika und Vasodilatatoren (z.B. ACE-Hemmer) .In addition to anti-TNF antibodies, the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients, in particular those known for the treatment of heart failure, such as catecholamines, digitalis, diuretics and vasodilators (e.g. ACE inhibitors).
Die Herstellung der oben aufgeführten pharmazeutischen Zuberei¬ tungen erfolgt in üblicher Weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirkstoffe mit dem oder mit den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a conventional 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 1000, vorzugsweise 0,1 bis 10 mg/kg Körpergewicht je 24 Stunden, ggf. in Form mehrerer Ein¬ zelgaben oder als Dauerinfusion und ggf. über eine Therapiedauer von mehreren Tagen hinweg zur Erzielung der gewünschten Ergeb¬ nisse zu verabreichen. Die Applikation kann als intravenöse Kurz- infusion der Einzelgaben oder als kontinuierliche Langzeitinfu¬ sion 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 Verab¬ reichung erfolgt. 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 1000, preferably 0.1 to 10 mg / kg body weight per 24 hours, optionally in the form of several units administered individually or as a continuous infusion and possibly over a therapy period of several days to achieve the desired results. The application can take place 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 the administration takes place.

Claims

PatentanspruchClaim
Verwendung von anti-TNF-Antikörpern zur Herstellung von Arznei- mittein für die Behandlung von Herzinsuffizienz. Use of anti-TNF antibodies for the manufacture of drugs for the treatment of heart failure.
PCT/EP1994/000628 1993-03-10 1994-03-03 Use of anti-tnf antibodies as medicament for the therapy of heart insufficiency (weakness of the heart muscle) WO1994020139A1 (en)

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Cited By (22)

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Publication number Priority date Publication date Assignee Title
WO2004016286A2 (en) 2002-08-16 2004-02-26 Abbott Biotechnology Ltd. Pharmaceutical anti-tnf-alpha antibody formulation
WO2005110452A2 (en) 2004-04-09 2005-11-24 Abbott Biotechnology Ltd. MULTIPLE-VARIABLE DOSE REGIMEN FOR TREATING TNFα-RELATED DISORDERS
EP2196218A2 (en) 2002-04-26 2010-06-16 Abbott Biotechnology Ltd Use of anti-TNFalpha antibodies and another drug
EP2295071A1 (en) 2002-10-24 2011-03-16 Abbott Biotechnology Ltd Low dose methods for treating disorders in which TNF-alpha activity is detrimental
EP2305712A1 (en) 1996-02-09 2011-04-06 Abbott Biotechnology Ltd Human antibodies that bind human TNFalpha
EP2324851A1 (en) 2001-06-08 2011-05-25 Abbott Biotechnology Ltd Methods of administering anti-TNFalpha antibodies
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EP3078675A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
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US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
US9505833B2 (en) 2012-04-20 2016-11-29 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
US9522953B2 (en) 2013-10-18 2016-12-20 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9683033B2 (en) 2012-04-20 2017-06-20 Abbvie, Inc. Cell culture methods to reduce acidic species
US9688752B2 (en) 2013-10-18 2017-06-27 Abbvie Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9708400B2 (en) 2012-04-20 2017-07-18 Abbvie, Inc. Methods to modulate lysine variant distribution
US9708399B2 (en) 2013-03-14 2017-07-18 Abbvie, Inc. Protein purification using displacement chromatography
WO2018124948A1 (en) 2016-12-30 2018-07-05 Закрытое Акционерное Общество "Биокад" AQUEOUS PHARMACEUTICAL COMPOSITION OF A RECOMBINANT MONOCLONAL ANTIBODY TO FNOα

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EP3078676A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
EP3078675A1 (en) 2015-04-10 2016-10-12 Ares Trading S.A. Induction dosing regimen for the treatment of tnf alpha mediated disorders
WO2016162537A1 (en) 2015-04-10 2016-10-13 Ares Trading S.A Induction dosing regimen
WO2018124948A1 (en) 2016-12-30 2018-07-05 Закрытое Акционерное Общество "Биокад" AQUEOUS PHARMACEUTICAL COMPOSITION OF A RECOMBINANT MONOCLONAL ANTIBODY TO FNOα

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