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WO1996017869A2 - Antagonistes d'interleukine-6 (il-6) - Google Patents

Antagonistes d'interleukine-6 (il-6) Download PDF

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Publication number
WO1996017869A2
WO1996017869A2 PCT/IT1995/000208 IT9500208W WO9617869A2 WO 1996017869 A2 WO1996017869 A2 WO 1996017869A2 IT 9500208 W IT9500208 W IT 9500208W WO 9617869 A2 WO9617869 A2 WO 9617869A2
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WO
WIPO (PCT)
Prior art keywords
seq
interleukin
sil
receptor
mutant
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/IT1995/000208
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English (en)
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WO1996017869A3 (fr
Inventor
Gennaro Ciliberto
Carlo Toniatti
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.)
Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Original Assignee
Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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 Istituto di Ricerche di Biologia Molecolare P Angeletti SpA filed Critical Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Priority to JP8517466A priority Critical patent/JPH09503232A/ja
Priority to AU41866/96A priority patent/AU4186696A/en
Priority to EP95940401A priority patent/EP0742794A1/fr
Publication of WO1996017869A2 publication Critical patent/WO1996017869A2/fr
Publication of WO1996017869A3 publication Critical patent/WO1996017869A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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 field of immunology. More specifically, the subject of the present invention are mutants- of the soluble forms of receptor ⁇ of interleukin 6 that interfere in a negative manner in the formation of the dimeric receptor complex between the monomeric receptor complex IL-6/sIL-6R ⁇ and gp 130. A further subject of the invention is the use of these mutants as interleukin-6 antagonists to control, prevent and treat the diseases caused by abnormal IL-6 activity.
  • Interleukin-6 elicits a variety of biological responses on different target cells. However - while the physiological production of IL-6 regulates B-cells proliferation and maturation, T-cell activation and the production of acute-phase proteins in liver during inflammatory response - disregulated production of the cytokine plays a crucial role in the pathogenesis of many inflammatory, autoimmune and neoplastic diseases.
  • IL-6 the mature human IL-6 protein
  • h IL-6 is a 185 a ino acid polypeptide containing two disulfide bonds (Cys 45 - Cys 51, and Cys 74 - Cys 84) .
  • IL-6 functions through interaction of two binding sites (known as site I and site II) with at least two specific receptors (IL-R ⁇ and gp 130) on the surface of the target cells, creating a trimeric complex IL-6- (receptor) 2 .
  • This complex is formed sequentially: a first receptor (IL-6R ⁇ ) binds with low affinity to site I of IL-6 without transmitting the signal; subsequently a second receptor (gp 130) , after binding with high affinity to site II of IL-6, transduces the signal.
  • a first receptor IL-6R ⁇
  • gp 130 second receptor
  • hIL-6 mutants have been designed that are capable of binding a first receptor to site I, but incapable of dimerising the receptor because of mutations that sterically inhibit binding of the second receptor to site II. Mutants of this type have been described in WO 94/09138 (Cetus Oncology Corporation), and WO 94/011402 and PCT/IT 94/00095 (Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A. ) .
  • soluble forms of the receptor ⁇ of IL-6 (sIL-6R ⁇ ) containing one or more mutations in the region interfacing with gp 130 are antagonists of interleukin 6.
  • Figure 5 shows resolution on gel of the complex formed by APRF with the DNA binding site (SIE, Serum Inducible Element) .
  • SIE Serum Inducible Element
  • Antagonists of IL- ⁇ according to the invention may be produced synthetically or using recombinant techniques.
  • the cDNA coding for sIL- 6R ⁇ can be incorporated in a plasmid before being expressed in procaryotic or eukaryotic cells. Bacteria are the preferred procaryotic microorganisms.
  • the cDNA coding for the sIL-6R ⁇ mutants according to the invention can be introduced into mammal cells: these mammal cells can be chosen from the group comprising CHO, COS, C127, HepG2, SK Hep.
  • the 3' primer was designed in order to introduce an artificial TAG stop codon at amino acid position 324 preceded by a six- histidine coding sequence. This was done to ensure that the sIL-6R ⁇ and the mutants thereof produced by us have a six histidine "tail" at the carboxy-terminal end of the molecule, which can be useful for purification of the molecule using metal affinity chromatography.
  • the fragment generated was then introduced into the COS-7 cells expression vector pcDNAI (Invitrogen) and sequenced in its entirety, thus obtaining plas id pC6FRH.
  • Plasmid pC ⁇ FRH was in turn used as a template to obtain constructs coding for the following four mutants: Asn230Asp (SEQ ID NO: 1); Asn230Asp/Ala228Asp (SEQ ID NO: 2); His280Ser/Asp281Val (SEQ ID NO 3) and Ala228Asp/Asn230Asp/His280Ser/Asp281Val (SEQ ID NO: 4), by a two-step PCR as described in the past (Landt 0., Grunert H.P., and Hahn, U. (1990) Gene 96, 125-128).
  • the mutants were then expressed in COS-7 cells.
  • the COS-7 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% FCS, plus glutamine and antibiotics, at 5% CO:.
  • 2.5xl0 6 COS-7 cells were seeded in 100-mm tissue culture dishes and the next day transfected with 2 ⁇ g of the various shIL-6R ⁇ expression vectors using the DEAE-dextran technique as described in Seed B., Aruffo A. (1987) Proc. Natl. Acad. Sci. USA 84, 3365- 3369. 16 h after transfection cells were split, replated in 100-mm dishes and grown in complete medium at 37°C.
  • Ala228Asp/Asn230Asp (SEQ ID NO : 2 ) 2 . 0 ⁇ 1 His280Ser/Asp281Val ( SEQ ID NO : 3 ) 4 . 3 ⁇ 2 Ala228Asp/Asn230Asp/ His280Ser/Asp281Val ( SEQ ID NO : 4 ) 2 . 5 ⁇ 1 wild type sIL-6R ⁇ 2 . 0 ⁇ 1
  • IL-6-dependent formation of sIL-6R ⁇ /sgpl30 heterodimers can be easily monitored in vi tro by co- immunoprecipitations with the use of suitable monoclonal antibodies.
  • a selection was therefore made of the mutants showing an IL-6 binding affinity in the same order of magnitude as the wild-type and their binding to sgpl30 was evaluated by co-immunoprecipitation in the presence of IL-6.
  • 35 S-labelled sgp 130 was incubated with 125 I-IL-6 (as an internal standard for the immunoprecipitation) and aliquots of transfected COS-7 cell culture medium, containing either native or mutant receptors.
  • the receptor mutants were also tested for their ability to interact with gpl30 on the cell surface.
  • binding experiments were performed on human melanoma A375 cells which have an excess of gpl30 molecules over IL-6R ⁇ .
  • binding of 125 I-IL-6 to A375 monolayers could be strongly enhanced by addition of the soluble receptor.
  • This phenomenon is due to the ability of the sIL-6R ⁇ to bind 125 I-IL-6 and subsequently to interact with the gpl30 molecules present on the surface of the cells.
  • the specificity of this interaction is demonstrated by the fact that the increased binding of 125 I-IL-6 in the presence of sIL- 6R ⁇ is competed by the addition of an excess of unlabeled human Oncostatin M (OM) (fig.
  • OM Oncostatin M
  • this mutant to be the one that, without any decrease in the affinity for IL-6, has the greatest effect on gpl30 binding.
  • its production and that of the wild type soluble receptor was scaled up using the MaxBac® system (Invitrogen' s Baculovirus Expression System) .
  • the expressed and purified receptors were tested in immunoprecipitation experiments.
  • Sf9 cells grown in Grace's insect medium, were used for transfection of transfer vectors, isolation of recombinant virus and preparation of high-titer virus stocks.
  • High Five® cells (Invitrogen) were instead used for production of proteins. Briefly, 4xl0 7 High Five® cells, grown in complete Grace's insect medium, were seeded into 750 ml flasks and infected with the appropriate recombinant virus at a MOI of 10. After 2 hours, cells were washed and SF-900 serum-free medium was added. The culture supernatants were harvested at 36 hours post-infection, dialyzed against PBS and directly loaded on a Ni 2+ -NTA-agarose column.
  • both wild type shIL-6R ⁇ and mutant were eluted in PBS/80 mM imidazole. Purified protein was dialyzed against PBS and directly used or stored at 4°C for up to three weeks.
  • APRF Acute Phase Response Factor
  • the mutant was added to HepG2 cells induced with the IL-6- related cytokine OM, which is also known to efficiently induce APRF phosphorylation. As shown in figure 5, the mutant did not antagonize OM activity. - -
  • MOLECULE TYPE protein
  • HYPOTHETICAL no
  • NAME Ala228Asp/Asn230Asp/His280Ser/Asp281Val
  • IDENTIFICATION METHOD Electrophoresis on a denaturing SDS/polyacrylamide gel
  • D OTHER INFORMATION: amino acid sequence of a mutant form of the interleukin 6 receptor from position 222 to position 287.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Cell Biology (AREA)
  • Toxicology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Antagonistes d'interleukine-6 (IL-6) caractérisés en ce qu'ils sont constitués de formes solubles du récepteur α de l'IL-6 humaine (shIL-6Rα) renfermant une ou plusieurs mutations au niveau de l'interface de liaison gp130. Selon le mode préféré de réalisation, les mutations sont présentes dans une position choisie dans le groupe qui comporte Ala 228, Asn 230, His 280 et Asp 281. Ces antagonistes sont utilisables comme agents permettant la prophylaxie et le traitement des maladies dues à une activité anormale de l'IL-6. La figure 4 représente l'activité antagoniste du mutant Ala228Asp/Asn 230Asp/His280Ser/Asp281Val en comparaison avec les propriétés agonistes du shIL-6Rα de type sauvage. Cet antagoniste est utilisable dans la préparation de médicaments destinés à la prophylaxie, à la maîtrise et au traitement des maladies dues à une bioactivité anormale de l'IL-6.
PCT/IT1995/000208 1994-12-06 1995-12-05 Antagonistes d'interleukine-6 (il-6) Ceased WO1996017869A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8517466A JPH09503232A (ja) 1994-12-06 1995-12-05 ＧＰ１３０結合界面で突然変異したインターロイキン−６（ＩＬ−６）受容体αの可溶性型であるＩＬ−６アンタゴニスト
AU41866/96A AU4186696A (en) 1994-12-06 1995-12-05 Interleukin-6 (il-6) antagonists
EP95940401A EP0742794A1 (fr) 1994-12-06 1995-12-05 Antagonistes d'interleukine-6 (il-6)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITRM940794A IT1274350B (it) 1994-12-06 1994-12-06 Antagonisti di interleuchina-6(il-6) che consistono di forme solubili del ricettore alfa di il-6, mutate nell'interfaccia che si lega a gp 130
ITRM94A000794 1994-12-06

Publications (2)

Publication Number Publication Date
WO1996017869A2 true WO1996017869A2 (fr) 1996-06-13
WO1996017869A3 WO1996017869A3 (fr) 1996-08-29

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PCT/IT1995/000208 Ceased WO1996017869A2 (fr) 1994-12-06 1995-12-05 Antagonistes d'interleukine-6 (il-6)

Country Status (7)

Country Link
EP (1) EP0742794A1 (fr)
JP (1) JPH09503232A (fr)
CN (1) CN1139933A (fr)
AU (1) AU4186696A (fr)
CA (1) CA2177837A1 (fr)
IT (1) IT1274350B (fr)
WO (1) WO1996017869A2 (fr)

Cited By (30)

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WO1997013781A3 (fr) * 1995-09-28 1997-05-15 Yeda Res & Dev Peptides synthetiques inhibant l'activite de l'interleukine 6
WO1998035694A3 (fr) * 1997-02-11 1998-11-19 Hadasit Med Res Service Composition pharmaceutique de traitement de l'infection par le virus de l'hepatite b (hbv)
WO2000025745A3 (fr) * 1998-11-05 2000-08-24 Omeros Med Sys Inc Solution d'irrigation et methode pour l'inhibition de la douleur et de l'inflammation
US6384193B1 (en) * 1996-10-09 2002-05-07 Imperial College Of Science Technology And Medicine Agents for the regulation of oestrogen synthesis
WO2003025017A1 (fr) * 2001-09-14 2003-03-27 Commonwealth Scientific And Industrial Research Organisation Recepteur de cytokine
US6664374B1 (en) 1999-08-27 2003-12-16 The United States Of America As Represented By The Department Of Health & Human Services Polypeptides comprising IL-6 ligand-binding receptor domains
WO2004073741A1 (fr) 2003-02-24 2004-09-02 Chugai Seiyaku Kabushiki Kaisha Traitement curatif pour les traumatismes medullaires contenant un antagoniste de l'interleukine-6
WO2005037315A1 (fr) 2003-10-17 2005-04-28 Chugai Seiyaku Kabushiki Kaisha Agent de traitement de mesotheliome
WO2005061000A1 (fr) 2003-12-19 2005-07-07 Chugai Seiyaku Kabushiki Kaisha Remede contre l'angor coronarien
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
WO2007043641A1 (fr) 2005-10-14 2007-04-19 Fukuoka University Inhibiteur de dysfonctionnement d'îlots transplantés dans un transplant d'îlots
WO2007046489A1 (fr) 2005-10-21 2007-04-26 Chugai Seiyaku Kabushiki Kaisha Agent therapeutique pour maladie de coeur
WO2007058194A1 (fr) 2005-11-15 2007-05-24 National Hospital Organization Inhibiteur de l'induction des cellules t cytotoxiques
WO2007061029A1 (fr) 2005-11-25 2007-05-31 Keio University Agent thérapeutique pour le cancer de la prostate
WO2007086490A1 (fr) 2006-01-27 2007-08-02 Keio University Remède pour maladie associée avec une angiogenèse choroïdale
WO2007116962A1 (fr) 2006-04-07 2007-10-18 Osaka University Promoteur de régénération musculaire
WO2008090901A1 (fr) 2007-01-23 2008-07-31 Shinshu University Inhibiteur de rejet chronique
EP1972638A1 (fr) 2001-04-02 2008-09-24 Chugai Seiyaku Kabushiki Kaisha Remèdes pour le traitement de l'arthrite chronique juvenile et des maladies apparentées
EP2011514A1 (fr) 1997-03-21 2009-01-07 Chugai Seiyaku Kabushiki Kaisha Agent thérapeutique ou préventif pour les maladies liées aux lymphocytes T sensibilisés comprenant l'antagoniste IL-6 en tant qu'ingrédient actif
WO2009148148A1 (fr) 2008-06-05 2009-12-10 国立がんセンター総長が代表する日本国 Inhibiteur de neuro-invasion
EP2368577A2 (fr) 2003-04-28 2011-09-28 Chugai Seiyaku Kabushiki Kaisha Procédés permettant de traiter les maladies associées à l'interleukine 6
WO2011149051A1 (fr) 2010-05-28 2011-12-01 中外製薬株式会社 Agent améliorant la réponse de lymphocytes t anti-tumoraux
WO2011149046A1 (fr) 2010-05-28 2011-12-01 独立行政法人国立がん研究センター Agent thérapeutique contre le cancer du pancréas
US8440196B1 (en) 1998-08-24 2013-05-14 Chugai Seiyaku Kabushiki Kaisha Treatment for pancreatitis using IL-6 receptor antagonist antibodies
WO2014200018A1 (fr) 2013-06-11 2014-12-18 独立行政法人 国立精神・神経医療研究センター Procédé permettant de prédire le pronostic post-thérapie d'un patient atteint de sclérose en plaques à périodes progressives et rémittentes (spppr) et procédé permettant de déterminer l'applicabilité d'une nouvelle thérapie
EP2898896A1 (fr) 2014-01-22 2015-07-29 Université Pierre et Marie Curie (Paris 6) Agents pour utilisation dans le traitement de l'inflammation de la rétine
WO2018203545A1 (fr) 2017-05-02 2018-11-08 国立研究開発法人国立精神・神経医療研究センター Procédé de prédiction et d'évaluation d'un effet thérapeutique dans des maladies associées à il-6 et à des neutrophiles
WO2019151418A1 (fr) 2018-01-31 2019-08-08 元一 加藤 Agent thérapeutique pour l'asthme contenant un inhibiteur d'il-6
WO2020213665A1 (fr) 2019-04-17 2020-10-22 国立大学法人広島大学 Agent thérapeutique pour cancer urologique caractérisé en ce qu'il est administré avec un inhibiteur de il-6 et un inhibiteur de ccr2 en combinaison
EP4269440A2 (fr) 2015-02-27 2023-11-01 Chugai Seiyaku Kabushiki Kaisha Composition pour le traitement de maladies associées à il-6

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JP4799516B2 (ja) * 1998-08-24 2011-10-26 中外製薬株式会社 Ｉｌ−６アンタゴニストを有効成分として含有する膵炎の予防又は治療剤
JP7439372B2 (ja) * 2018-06-21 2024-02-28 シャタック ラボ，インコーポレイテッド ヘテロ二量体タンパク質及びその使用
CN110133241B (zh) * 2019-05-21 2022-05-27 中国食品药品检定研究院 一种测定重组人可溶性gp130-Fc融合蛋白生物学活性的新方法

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Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
WO1997013781A3 (fr) * 1995-09-28 1997-05-15 Yeda Res & Dev Peptides synthetiques inhibant l'activite de l'interleukine 6
US6384193B1 (en) * 1996-10-09 2002-05-07 Imperial College Of Science Technology And Medicine Agents for the regulation of oestrogen synthesis
US6410009B1 (en) 1997-02-11 2002-06-25 Hadasit Medical Research Services & Development Co., Ltd. Pharmaceutical composition for treating hepatitis B virus (HBV) infection
US6217858B1 (en) 1997-02-11 2001-04-17 Hadasit & Medical Research Services & Development Company, Ltd. Pharmaceutical composition for treating hepatitis B virus (HBV) infection
WO1998035694A3 (fr) * 1997-02-11 1998-11-19 Hadasit Med Res Service Composition pharmaceutique de traitement de l'infection par le virus de l'hepatite b (hbv)
EP2011514A1 (fr) 1997-03-21 2009-01-07 Chugai Seiyaku Kabushiki Kaisha Agent thérapeutique ou préventif pour les maladies liées aux lymphocytes T sensibilisés comprenant l'antagoniste IL-6 en tant qu'ingrédient actif
EP2322216A1 (fr) 1997-03-21 2011-05-18 Chugai Seiyaku Kabushiki Kaisha Agent thérapeutique ou préventif pour les maladies liées aux lymphocytes T sensibilisés comprenant l'antagoniste IL-6 en tant qu'ingrédient actif
US8440196B1 (en) 1998-08-24 2013-05-14 Chugai Seiyaku Kabushiki Kaisha Treatment for pancreatitis using IL-6 receptor antagonist antibodies
WO2000025745A3 (fr) * 1998-11-05 2000-08-24 Omeros Med Sys Inc Solution d'irrigation et methode pour l'inhibition de la douleur et de l'inflammation
US6664374B1 (en) 1999-08-27 2003-12-16 The United States Of America As Represented By The Department Of Health & Human Services Polypeptides comprising IL-6 ligand-binding receptor domains
EP2298812A2 (fr) 2001-04-02 2011-03-23 Chugai Seiyaku Kabushiki Kaisha Remèdes pour maladies associées à l'arthrite chronique chez l'enfant
EP1972638A1 (fr) 2001-04-02 2008-09-24 Chugai Seiyaku Kabushiki Kaisha Remèdes pour le traitement de l'arthrite chronique juvenile et des maladies apparentées
EP3640261A1 (fr) 2001-04-02 2020-04-22 Chugai Seiyaku Kabushiki Kaisha Agent thérapeutique pour arthrites chroniques de maladies infantiles
WO2003025017A1 (fr) * 2001-09-14 2003-03-27 Commonwealth Scientific And Industrial Research Organisation Recepteur de cytokine
WO2004073741A1 (fr) 2003-02-24 2004-09-02 Chugai Seiyaku Kabushiki Kaisha Traitement curatif pour les traumatismes medullaires contenant un antagoniste de l'interleukine-6
EP3167901A1 (fr) 2003-04-28 2017-05-17 Chugai Seiyaku Kabushiki Kaisha Procédés permettant de traiter les maladies associées à l'interleukine 6
EP2368577A2 (fr) 2003-04-28 2011-09-28 Chugai Seiyaku Kabushiki Kaisha Procédés permettant de traiter les maladies associées à l'interleukine 6
EP3903819A1 (fr) 2003-04-28 2021-11-03 Chugai Seiyaku Kabushiki Kaisha Procédés permettant de traiter les maladies associées à l'interleukine 6
EP4098279A1 (fr) 2003-04-28 2022-12-07 Chugai Seiyaku Kabushiki Kaisha Procédés permettant de traiter les maladies associées à l'interleukine 6
WO2005037315A1 (fr) 2003-10-17 2005-04-28 Chugai Seiyaku Kabushiki Kaisha Agent de traitement de mesotheliome
WO2005061000A1 (fr) 2003-12-19 2005-07-07 Chugai Seiyaku Kabushiki Kaisha Remede contre l'angor coronarien
WO2007043641A1 (fr) 2005-10-14 2007-04-19 Fukuoka University Inhibiteur de dysfonctionnement d'îlots transplantés dans un transplant d'îlots
WO2007046489A1 (fr) 2005-10-21 2007-04-26 Chugai Seiyaku Kabushiki Kaisha Agent therapeutique pour maladie de coeur
WO2007058194A1 (fr) 2005-11-15 2007-05-24 National Hospital Organization Inhibiteur de l'induction des cellules t cytotoxiques
WO2007061029A1 (fr) 2005-11-25 2007-05-31 Keio University Agent thérapeutique pour le cancer de la prostate
WO2007086490A1 (fr) 2006-01-27 2007-08-02 Keio University Remède pour maladie associée avec une angiogenèse choroïdale
EP3135298A1 (fr) 2006-01-27 2017-03-01 Keio University Remède pour maladie associée à l'angiogenèse choroïdienne
WO2007116962A1 (fr) 2006-04-07 2007-10-18 Osaka University Promoteur de régénération musculaire
WO2008090901A1 (fr) 2007-01-23 2008-07-31 Shinshu University Inhibiteur de rejet chronique
WO2009148148A1 (fr) 2008-06-05 2009-12-10 国立がんセンター総長が代表する日本国 Inhibiteur de neuro-invasion
WO2011149046A1 (fr) 2010-05-28 2011-12-01 独立行政法人国立がん研究センター Agent thérapeutique contre le cancer du pancréas
WO2011149051A1 (fr) 2010-05-28 2011-12-01 中外製薬株式会社 Agent améliorant la réponse de lymphocytes t anti-tumoraux
EP4115906A1 (fr) 2010-05-28 2023-01-11 Chugai Seiyaku Kabushiki Kaisha Agent améliorant la réponse de lymphocytes t anti-tumoraux
WO2014200018A1 (fr) 2013-06-11 2014-12-18 独立行政法人 国立精神・神経医療研究センター Procédé permettant de prédire le pronostic post-thérapie d'un patient atteint de sclérose en plaques à périodes progressives et rémittentes (spppr) et procédé permettant de déterminer l'applicabilité d'une nouvelle thérapie
US10519232B2 (en) 2014-01-22 2019-12-31 Sorbonne Universite Agents for use in the treatment of retinal inflammation
EP2898896A1 (fr) 2014-01-22 2015-07-29 Université Pierre et Marie Curie (Paris 6) Agents pour utilisation dans le traitement de l'inflammation de la rétine
EP4269440A2 (fr) 2015-02-27 2023-11-01 Chugai Seiyaku Kabushiki Kaisha Composition pour le traitement de maladies associées à il-6
WO2018203545A1 (fr) 2017-05-02 2018-11-08 国立研究開発法人国立精神・神経医療研究センター Procédé de prédiction et d'évaluation d'un effet thérapeutique dans des maladies associées à il-6 et à des neutrophiles
WO2019151418A1 (fr) 2018-01-31 2019-08-08 元一 加藤 Agent thérapeutique pour l'asthme contenant un inhibiteur d'il-6
WO2020213665A1 (fr) 2019-04-17 2020-10-22 国立大学法人広島大学 Agent thérapeutique pour cancer urologique caractérisé en ce qu'il est administré avec un inhibiteur de il-6 et un inhibiteur de ccr2 en combinaison

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CA2177837A1 (fr) 1996-06-07
CN1139933A (zh) 1997-01-08
JPH09503232A (ja) 1997-03-31
WO1996017869A3 (fr) 1996-08-29
EP0742794A1 (fr) 1996-11-20
AU4186696A (en) 1996-06-26
IT1274350B (it) 1997-07-17
ITRM940794A0 (it) 1994-12-06
ITRM940794A1 (it) 1996-06-06

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