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WO1999021582A2 - Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques - Google Patents

Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques Download PDF

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Publication number
WO1999021582A2
WO1999021582A2 PCT/EP1998/006545 EP9806545W WO9921582A2 WO 1999021582 A2 WO1999021582 A2 WO 1999021582A2 EP 9806545 W EP9806545 W EP 9806545W WO 9921582 A2 WO9921582 A2 WO 9921582A2
Authority
WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/EP1998/006545
Other languages
German (de)
English (en)
Other versions
WO1999021582A3 (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
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
Priority to EP98955459A priority Critical patent/EP1024831A2/fr
Application filed by Knoll GmbH filed Critical Knoll GmbH
Priority to AU12284/99A priority patent/AU756167B2/en
Priority to JP2000517740A priority patent/JP2001521009A/ja
Priority to HU0100105A priority patent/HUP0100105A3/hu
Priority to IL13508398A priority patent/IL135083A0/xx
Priority to KR1020007004361A priority patent/KR20010024549A/ko
Priority to CA002306790A priority patent/CA2306790A1/fr
Priority to BR9813114-1A priority patent/BR9813114A/pt
Publication of WO1999021582A2 publication Critical patent/WO1999021582A2/fr
Publication of WO1999021582A3 publication Critical patent/WO1999021582A3/fr
Priority to NO20001894A priority patent/NO20001894D0/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K39/395—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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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Utilisation d'antagonistes du TNF pour la préparation de médicaments destinés à traiter les maladies septiques caractérisées par une augmentation du taux sérique d'interleukine-6 pendant un intervalle de mesure d'au moins trente minutes.
PCT/EP1998/006545 1997-10-23 1998-10-15 Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques Ceased WO1999021582A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BR9813114-1A BR9813114A (pt) 1997-10-23 1998-10-15 Uso de antagonistas tnf para produzir medicamentos, pacote comercial, e, processo para estabelecer se um paciente que esteja sofrendo de sépsis deva ser tratado com os antagonistas tnf
AU12284/99A AU756167B2 (en) 1997-10-23 1998-10-15 Application of TNF antagonists as medicaments for treating septic diseases
JP2000517740A JP2001521009A (ja) 1997-10-23 1998-10-15 敗血性疾患を治療するための医薬品としてのｔｎｆ拮抗物質の使用
HU0100105A HUP0100105A3 (en) 1997-10-23 1998-10-15 Application of tnf antagonists as medicaments for treating septic diseases
IL13508398A IL135083A0 (en) 1997-10-23 1998-10-15 Application of tnf antagonists as medicaments for treating septic diseases
EP98955459A EP1024831A2 (fr) 1997-10-23 1998-10-15 Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques
CA002306790A CA2306790A1 (fr) 1997-10-23 1998-10-15 Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques
KR1020007004361A KR20010024549A (ko) 1997-10-23 1998-10-15 Ｔｎｆ 길항제의 패혈증 치료를 위한 약제로서의 용도
NO20001894A NO20001894D0 (no) 1997-10-23 2000-04-12 Anvendelse av TNF-antagonister som medikamenter for behandling av septiske sykdommer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19746868.3 1997-10-23
DE19746868A DE19746868A1 (de) 1997-10-23 1997-10-23 Verwendung von TNF-Antagonisten als Arzneimittel zur Behandlung von septischen Erkrankungen

Publications (2)

Publication Number Publication Date
WO1999021582A2 true WO1999021582A2 (fr) 1999-05-06
WO1999021582A3 WO1999021582A3 (fr) 1999-07-15

Family

ID=7846420

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/006545 Ceased WO1999021582A2 (fr) 1997-10-23 1998-10-15 Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques

Country Status (13)

Country Link
EP (1) EP1024831A2 (fr)
JP (1) JP2001521009A (fr)
KR (1) KR20010024549A (fr)
CN (1) CN1163272C (fr)
AU (1) AU756167B2 (fr)
BR (1) BR9813114A (fr)
CA (1) CA2306790A1 (fr)
DE (1) DE19746868A1 (fr)
HU (1) HUP0100105A3 (fr)
IL (1) IL135083A0 (fr)
NO (1) NO20001894D0 (fr)
WO (1) WO1999021582A2 (fr)
ZA (1) ZA989615B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700096B2 (en) 2002-08-02 2010-04-20 Oleg Iliich Epshtein Medicinal agent for treating erectile dysfunction
US8535664B2 (en) 2000-06-20 2013-09-17 Oleg I. Epshtein Method of treating a pathological syndrome and a pharmaceutical agent
US8637030B2 (en) 2010-07-15 2014-01-28 Oleg I. Epshtein Combination pharmaceutical composition and methods of treating functional diseases or conditions of gastrointestinal tract
US9308275B2 (en) 2010-07-15 2016-04-12 Oleg Iliich Epshtein Method of increasing the effect of an activated-potentiated form of an antibody
US9522116B2 (en) 2006-03-13 2016-12-20 Oleg Iliich Epshtein Solid oral form of a medicinal preparation and a method for the production thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA76640C2 (uk) * 2002-08-02 2006-08-15 Олєг Ільіч Епштєйн Спосіб корекції патологічних імунних реакцій та гомеопатичний лікарський засіб
EP2415461B1 (fr) * 2010-07-24 2012-10-31 Roche Diagnostics GmbH Stabilisation d'interleukine 6 dans des solutions à base de sérum

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ229922A (en) * 1988-07-18 1992-04-28 Chiron Corp Monoclonal antibodies specifically binding cachectin (tumor necrosis factor) and compositions
GB9109645D0 (en) * 1991-05-03 1991-06-26 Celltech Ltd Recombinant antibodies
NZ278607A (en) * 1994-02-07 1999-05-28 Knoll Ag Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8535664B2 (en) 2000-06-20 2013-09-17 Oleg I. Epshtein Method of treating a pathological syndrome and a pharmaceutical agent
US8871203B2 (en) 2000-06-20 2014-10-28 Oleg I. Epshtein Method of treating a pathological syndrome and a pharmaceutical agent
US8894995B2 (en) 2000-06-20 2014-11-25 Oleg Iliich Epshtein Method of treating a disorder or condition of viral etiology
US9200081B2 (en) 2000-06-20 2015-12-01 Oleg Iliich Epshtein Method for administering homeopathically potentiated antibodies against mediator of inflammation
US9228024B2 (en) 2000-06-20 2016-01-05 Oleg Iliich Epshtein Method of treating hypertension disorder and a pharmaceutical agent
US9303091B2 (en) 2000-06-20 2016-04-05 Oleg Iliich Epshtein Method of treating disorders of the cardiovascular system and a pharmaceutical agent
US9303090B2 (en) 2000-06-20 2016-04-05 Oleg Iliich Epshtein Method of treating a pathological syndrome and a pharmaceutical agent
US7700096B2 (en) 2002-08-02 2010-04-20 Oleg Iliich Epshtein Medicinal agent for treating erectile dysfunction
US8168182B2 (en) 2002-08-02 2012-05-01 Oleg Iliich Epshtein Method for treating erectile dysfunction
US9522116B2 (en) 2006-03-13 2016-12-20 Oleg Iliich Epshtein Solid oral form of a medicinal preparation and a method for the production thereof
US8637030B2 (en) 2010-07-15 2014-01-28 Oleg I. Epshtein Combination pharmaceutical composition and methods of treating functional diseases or conditions of gastrointestinal tract
US9308275B2 (en) 2010-07-15 2016-04-12 Oleg Iliich Epshtein Method of increasing the effect of an activated-potentiated form of an antibody

Also Published As

Publication number Publication date
CA2306790A1 (fr) 1999-05-06
NO20001894L (no) 2000-04-12
CN1163272C (zh) 2004-08-25
KR20010024549A (ko) 2001-03-26
EP1024831A2 (fr) 2000-08-09
JP2001521009A (ja) 2001-11-06
IL135083A0 (en) 2001-05-20
HUP0100105A3 (en) 2003-08-28
BR9813114A (pt) 2000-08-15
AU1228499A (en) 1999-05-17
HUP0100105A2 (hu) 2001-05-28
ZA989615B (en) 2000-04-20
AU756167B2 (en) 2003-01-09
NO20001894D0 (no) 2000-04-12
CN1277556A (zh) 2000-12-20
DE19746868A1 (de) 1999-04-29
WO1999021582A3 (fr) 1999-07-15

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