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WO2003045430A1 - Inhibiteurs du tnf alpha pour traitement de maladies hepatiques - Google Patents

Inhibiteurs du tnf alpha pour traitement de maladies hepatiques Download PDF

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Publication number
WO2003045430A1
WO2003045430A1 PCT/GB2002/005300 GB0205300W WO03045430A1 WO 2003045430 A1 WO2003045430 A1 WO 2003045430A1 GB 0205300 W GB0205300 W GB 0205300W WO 03045430 A1 WO03045430 A1 WO 03045430A1
Authority
WO
WIPO (PCT)
Prior art keywords
tnfα
inhibitor
hepatic disease
treatment
use according
Prior art date
Application number
PCT/GB2002/005300
Other languages
English (en)
Inventor
Gabriel Stavros Panayi
Original Assignee
King's College London
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 King's College London filed Critical King's College London
Priority to AU2002343085A priority Critical patent/AU2002343085A1/en
Publication of WO2003045430A1 publication Critical patent/WO2003045430A1/fr

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Classifications

    • 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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of TNF ⁇ inhibitors in the treatment of hepatic diseases.
  • Hepatic diseases include any inflammatory disease of the liver. In humans the most common cause is viral infection of the liver by viruses such as hepatitis A, B and C, although there are other viruses that cause hepatitis, including yellow fever virus, Epstein-Barr virus and cytomegalo virus. Hepatic diseases cause liver cell damage, necrosis and eventual liver fibrosis or the development of one or more liver hepatomas which may be lethal.
  • Hepatic diseases can also be caused by amoeba infections, alcohol and substance abuse.
  • Amoeba infections can also be caused by amoeba infections, alcohol and substance abuse.
  • Chitturi et al. Semin. Liver Dis., 22, 169-183, 2002.
  • the pathogenesis of the hepatic diseases is a combination of the effects of the causative agent, e.g. the virus, and of the host immune and inflammatory response.
  • the treatment of hepatic diseases, especially viral hepatitis, is difficult, expensive and time consuming. Furthermore, treatments are not always successful.
  • Cytokines are involved in the host's immune response by inducing apoptosis of liver cells but, paradoxically, at the same time inhibiting virus production (Kaplowitz et al., Semin. Liver Dis., 22, 137-144, 2002; Jaeschke et al, Toxicol. ScL, 65, 166-176, 2002; Neuman et al, Alcohol Clin. Exp. Res., 25 (S Suppl ISBRA) 251S-253S, 2001; and Neuman, Crit. Rev. Clin Lab. Sci., 38, 109-166, 2001).
  • TNF ⁇ cytokine tumour necrosis factor ⁇
  • the present invention relates to the use of anti-TNF ⁇ therapy for the treatment of hepatitis D, C, and G, and all other types and forms of viral hepatitis, and alcoholic hepatitis.
  • the present invention provides the use of a TNF ⁇ inhibitor in the treatment of a hepatic disease.
  • the present invention also provides the use of a TNF ⁇ inhibitor in the manufacture of a medicament for the treatment of a hepatic disease.
  • the present invention also provide a method of treating a hepatic disease comprising administrating to a patient in need thereof an effective amount of a TNF ⁇ inhibitor.
  • TNF ⁇ inhibitor refers to any agent that inhibits the inflammatory action of TNF ⁇ .
  • the TNF ⁇ inhibitor may inhibit the production, secretion or activity of TNF ⁇ thereby preventing the inflammatory action.
  • the agent may be a protein, a nucleic acid, a low molecular weight organic or inorganic compound, or a carbohydrate.
  • the agent may directly interact with TNF ⁇ or may inhibit the inflammatory action by blocking the relevant TNF ⁇ receptor or may inhibit the inflammatory action further down the inflammatory pathway.
  • the TNF ⁇ inhibitor may inhibit the production of TNF ⁇ by preventing its expression or secretion.
  • the TNF ⁇ inhibitor may also target TNF ⁇ for degradation reducing the level of active TNF ⁇ in the liver.
  • the TNF ⁇ inhibitor may cause genetic inhibition of TNF ⁇ secretion or action by gene therapy or by interfering with the TNF ⁇ encoding RNA.
  • the TNF ⁇ inhibitor interacts with TNF ⁇ and prevents or reduces its ability to cause inflammation.
  • the TNF ⁇ inhibitor inhibits TNF ⁇ binding to its receptor.
  • the TNF ⁇ inhibitor may do this by interacting with TNF ⁇ or with the receptor.
  • Suitable TNF ⁇ inhibitors include antibody molecules or soluble TNF ⁇ receptors that bind to TNF ⁇ .
  • the soluble TNF ⁇ receptor is a soluble p75 TNF-receptor.
  • the TNF ⁇ inhibitor may be coupled to a moiety that increase the half life in the body and so increases the effectiveness of the inhibitor, decreases the quantity administered and decreases the frequency of administration.
  • suitable moieties include Fc fragments of human immunoglobulins, especially a IgG immunoglobulin Fc fragment, polyethylene glycol (PEG) molecules, etc.
  • the TNF ⁇ inhibitor is an antibody molecule.
  • the antibody molecule may be any antibody molecule capable of specifically binding to TNF ⁇ .
  • the antibody molecule may be a complete polyclonal or monoclonal antibody molecule or antigen binding fragment thereof, such as Fv, Fab, F(ab') 2 fragments and single chain Fv fragments thereof.
  • the antibody molecule may be a recombinant antibody molecule such as a chimeric antibody molecule, preferably having human constant regions and mouse variable regions, or a CDR grafted antibody molecule, or antigen binding fragment thereof. Methods for producing such antibody molecules are well known to those skilled in the art and are described in EP-A-0120694 and EP-A-0125023.
  • the anti-TNF ⁇ therapy may consist of purified antibodies of human or other animal source, genetically engineered complete antibodies or chimeric antibodies or partial forms of antibodies, or constructs of TNF ⁇ soluble receptors with human Fc or chemically modified and small molecular weight compounds that inhibit production or secretion or action of TNF ⁇ .
  • the TNF ⁇ inhibitor is the chimeric (mouse/human) antibody against tumour necrosis factor alpha (TNF ⁇ ) InfliximabTM (Schering-Plough).
  • TNF ⁇ tumour necrosis factor alpha
  • a hepatic disease refers to any hepatic disease, i.e. any disease that causes inflammatory damage to the liver, wherein the damage is accentuated by TNF ⁇ .
  • the hepatic disease may be caused by a viral agent, an amoeba or other parasite, alcoholism, cancers, drug overdoses, narcotic abuse,
  • the hepatic disease is caused by a viral agent.
  • the viral agent is a hepatitis A, B, C, D, E, F or G; Epstein-Barr virus, cytomegalovirus, herpes virus, or the yellow fever virus. It is particularly preferred that the viral agent is hepatitis B, D, C or G, most preferably hepatitis B.
  • the TNF ⁇ inhibitor may be formulated in combination with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • the TNF ⁇ inhibitor may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Preferably the TNF ⁇ inhibitor is administered orally or by injection.
  • the TNF ⁇ inhibitor may be formulated with any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the TNF ⁇ inhibitor may be administered in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
  • the TNF ⁇ inhibitor may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the TNF ⁇ inhibitor may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non- irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non- irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • the TNF ⁇ inhibitor may be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents l ⁇ iown in the art.
  • TNF ⁇ inhibitor The appropriate dosage of the TNF ⁇ inhibitor will vary depending upon, for example, the nature and severity of the disorder to be treated and the mode of administration. For example, a dosage of about lmg/kg to about lOmg/kg body weight given every 2 to 4 weeks will satisfactorily treat a hepatic disease.
  • Figure 1 shows the reduction in hepatitis B DNA levels during treatment with a TNF ⁇ inhibitor.
  • H. pylori positive gastritis Treatment with non-steroidal anti-inflammatory drugs was limited by H. pylori positive gastritis. Intra-muscular injections of methyl prednisolone were initiated. Their benefit was limited. Intra-muscular gold injections were commenced in October 1994 as a result of generally worsening disease activity. He was admitted with severe hip and shoulder disease with an associated dactylitis. The ESR was 88 with an alkaline phosphatase of 138, ALT 35 ( ⁇ 34) and gamma glutamine transferase ( ⁇ GT) 104 ( ⁇ 50). Hepatitis serology gave a positive surface antigen and antibodies to HepBe but no HepBe or Core IgM. This suggested hepatitis B with low infectivity.
  • the dose infused was 3 mg/kg.
  • All measures of disease activity improved (Health Assessment Questionnaire, ESR, CRP, early morning stiffness, global assessment, tender and swollen joint counts and the Ritchie Index). He became pain free. His psoriatic skin disease settled. The liver function tests also returned to within the no ⁇ nal limits. A decision was made to monitor the Hepatitis B DNA levels during treatment. Hepatitis B DNA, measured after the fourth infusion of InfliximabTM, was undetectable.
  • TNF ⁇ may be achieved in a variety of ways.
  • Any agent that is capable of inhibiting the binding of TNF ⁇ to its receptor may be used.
  • agent may be an antibody which is capable of binding to TNF ⁇ or fragment of such antibody or it may be a soluble p75 TNF-receptor or fragment thereof.
  • These agents are capable of binding to TNF ⁇ and inhibiting TNF ⁇ binding to the TNF receptors present on cells.
  • agents may also be coupled to other protein moieties to increase their half life in the body and so increase their effectiveness, by decreasing the quantity administered or the frequency of administration of the reagent to the patient.
  • protein moieties which may be used to have this effect are the Fc fragment of human immunoglobulins especially where such Fc fragment is derived from human immuno globulin and more preferably where the Fc fragment is derived from a human IgG class immunoglobulin.
  • the half life of the agent to be used may also be increased by treating the preparation with polyethylene glycol.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'inhibiteurs du TNFα dans le traitement de maladies hépatiques virales.
PCT/GB2002/005300 2001-11-23 2002-11-25 Inhibiteurs du tnf alpha pour traitement de maladies hepatiques WO2003045430A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002343085A AU2002343085A1 (en) 2001-11-23 2002-11-25 Tnf-alpha inhibitors for the treatment of hepatic diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0128138.5 2001-11-23
GBGB0128138.5A GB0128138D0 (en) 2001-11-23 2001-11-23 Pharmaceutical use

Publications (1)

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WO2003045430A1 true WO2003045430A1 (fr) 2003-06-05

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GB (1) GB0128138D0 (fr)
WO (1) WO2003045430A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117966A1 (fr) * 2004-06-04 2005-12-15 Apoxis Sa Procede visant a reduire l'hepatotoxicite d'agents inducteurs d'apoptose induite par fas
US9028822B2 (en) 2002-06-28 2015-05-12 Domantis Limited Antagonists against TNFR1 and methods of use therefor

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US5753628A (en) * 1995-06-07 1998-05-19 Centocor, Inc. Peptide inhibitors of TNF containing predominantly D-amino acids
WO1998022137A1 (fr) * 1996-11-15 1998-05-28 The Kennedy Institute Of Rheumatology SUPPRESSION DU FNTα ET DE IL-12 EN THERAPIE
WO1999009965A2 (fr) * 1997-08-21 1999-03-04 Takeda Chemical Industries, Ltd. Agent antiinflammatoire
JPH11127882A (ja) * 1997-10-27 1999-05-18 Nippon Kayaku Co Ltd 新規生理活性物質ｎｋ３０４２４ａ，ｎｋ３０４２４ｂ，それらの製造法およびそれらの用途
JPH11228576A (ja) * 1997-12-10 1999-08-24 Japan Tobacco Inc アポトーシス抑制剤
WO1999064419A1 (fr) * 1998-06-10 1999-12-16 Aventis Pharma S.A. Derives du pyrrole, leur preparation et les compositions pharmaceutiques qui les contiennent
US6107273A (en) * 1995-01-24 2000-08-22 Thomas Jefferson University Tumor necrosis factor inhibitors
EP1029851A1 (fr) * 1997-10-14 2000-08-23 Yoshitomi Pharmaceutical Industries, Ltd. Composes de piperazine et utilisation medicale desdits composes
WO2000062790A2 (fr) * 1999-04-19 2000-10-26 Immunex Corporation Traitement de troubles d'ordre medical par un recepteur de facteur de necrose tumorale soluble
JP2001081088A (ja) * 1999-09-10 2001-03-27 Nippon Kayaku Co Ltd 新規生理活性物質ｎｋ３０４２４類縁体とそれらの製造法および用途
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US6107273A (en) * 1995-01-24 2000-08-22 Thomas Jefferson University Tumor necrosis factor inhibitors
US5753628A (en) * 1995-06-07 1998-05-19 Centocor, Inc. Peptide inhibitors of TNF containing predominantly D-amino acids
WO1998022137A1 (fr) * 1996-11-15 1998-05-28 The Kennedy Institute Of Rheumatology SUPPRESSION DU FNTα ET DE IL-12 EN THERAPIE
WO1999009965A2 (fr) * 1997-08-21 1999-03-04 Takeda Chemical Industries, Ltd. Agent antiinflammatoire
EP1029851A1 (fr) * 1997-10-14 2000-08-23 Yoshitomi Pharmaceutical Industries, Ltd. Composes de piperazine et utilisation medicale desdits composes
JPH11127882A (ja) * 1997-10-27 1999-05-18 Nippon Kayaku Co Ltd 新規生理活性物質ｎｋ３０４２４ａ，ｎｋ３０４２４ｂ，それらの製造法およびそれらの用途
JPH11228576A (ja) * 1997-12-10 1999-08-24 Japan Tobacco Inc アポトーシス抑制剤
WO1999064419A1 (fr) * 1998-06-10 1999-12-16 Aventis Pharma S.A. Derives du pyrrole, leur preparation et les compositions pharmaceutiques qui les contiennent
WO2000062790A2 (fr) * 1999-04-19 2000-10-26 Immunex Corporation Traitement de troubles d'ordre medical par un recepteur de facteur de necrose tumorale soluble
JP2001081088A (ja) * 1999-09-10 2001-03-27 Nippon Kayaku Co Ltd 新規生理活性物質ｎｋ３０４２４類縁体とそれらの製造法および用途

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Title
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9028822B2 (en) 2002-06-28 2015-05-12 Domantis Limited Antagonists against TNFR1 and methods of use therefor
WO2005117966A1 (fr) * 2004-06-04 2005-12-15 Apoxis Sa Procede visant a reduire l'hepatotoxicite d'agents inducteurs d'apoptose induite par fas

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GB0128138D0 (en) 2002-01-16

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