EP1024831A2 - 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

Info

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Withdrawn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)
English (en)
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
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP1024831A2 publication Critical patent/EP1024831A2/fr
Withdrawn legal-status Critical Current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 [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Urology & Nephrology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cell Biology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Diabetes (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (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.
EP98955459A 1997-10-23 1998-10-15 Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques Withdrawn EP1024831A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19746868 1997-10-23
DE19746868A DE19746868A1 (de) 1997-10-23 1997-10-23 Verwendung von TNF-Antagonisten als Arzneimittel zur Behandlung von septischen Erkrankungen
PCT/EP1998/006545 WO1999021582A2 (fr) 1997-10-23 1998-10-15 Utilisation d'antagonistes de tnf en tant que medicaments pour traiter les maladies septiques

Publications (1)

Publication Number Publication Date
EP1024831A2 true EP1024831A2 (fr) 2000-08-09

Family

ID=7846420

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98955459A Withdrawn EP1024831A2 (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) NO20001894L (fr)
WO (1) WO1999021582A2 (fr)
ZA (1) ZA989615B (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2181297C2 (ru) 2000-06-20 2002-04-20 Эпштейн Олег Ильич Способ лечения патологического синдрома и лекарственное средство
UA76639C2 (uk) 2002-08-02 2006-08-15 Олєг Ільіч Епштєйн Гомеопатичний лікарський засіб та спосіб лікування еректильних дисфункцій
UA76640C2 (uk) * 2002-08-02 2006-08-15 Олєг Ільіч Епштєйн Спосіб корекції патологічних імунних реакцій та гомеопатичний лікарський засіб
RU2309732C1 (ru) 2006-03-13 2007-11-10 Олег Ильич Эпштейн Спрессованная твердая оральная форма лекарственного препарата и способ получения твердой оральной формы лекарственного препарата
PH12013500107A1 (en) 2010-07-15 2013-03-11 Oleg Iliich Epshtein A method of increasing the effect of an activated-potentiated form of an antibody
JP2013532181A (ja) 2010-07-15 2013-08-15 イリイチ・エプシテイン オレグ 組み合わせ医薬組成物及び胃腸管の機能的な疾患又は状態を治療する方法
ES2398646T3 (es) * 2010-07-24 2013-03-20 F. Hoffmann-La Roche Ag Estabilización de la interleuquina-6 en soluciones de suero

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9921582A2 *

Also Published As

Publication number Publication date
CA2306790A1 (fr) 1999-05-06
AU1228499A (en) 1999-05-17
IL135083A0 (en) 2001-05-20
DE19746868A1 (de) 1999-04-29
KR20010024549A (ko) 2001-03-26
HUP0100105A2 (hu) 2001-05-28
JP2001521009A (ja) 2001-11-06
WO1999021582A2 (fr) 1999-05-06
NO20001894D0 (no) 2000-04-12
CN1277556A (zh) 2000-12-20
BR9813114A (pt) 2000-08-15
NO20001894L (no) 2000-04-12
AU756167B2 (en) 2003-01-09
HUP0100105A3 (en) 2003-08-28
WO1999021582A3 (fr) 1999-07-15
CN1163272C (zh) 2004-08-25
ZA989615B (en) 2000-04-20

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