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WO1992001002A1 - Inhibiteur de l'activite du facteur de la necrose tumorale et son procede de preparation - Google Patents

Inhibiteur de l'activite du facteur de la necrose tumorale et son procede de preparation Download PDF

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Publication number
WO1992001002A1
WO1992001002A1 PCT/JP1991/000920 JP9100920W WO9201002A1 WO 1992001002 A1 WO1992001002 A1 WO 1992001002A1 JP 9100920 W JP9100920 W JP 9100920W WO 9201002 A1 WO9201002 A1 WO 9201002A1
Authority
WO
WIPO (PCT)
Prior art keywords
necrosis factor
tumor necrosis
tnf
urine
pro
Prior art date
Application number
PCT/JP1991/000920
Other languages
English (en)
Japanese (ja)
Inventor
Jun Suzuki
Kenji Yone
Noriyuki Tsunekawa
Yataro Ichikawa
Original Assignee
Teijin Limited
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 Teijin Limited filed Critical Teijin Limited
Publication of WO1992001002A1 publication Critical patent/WO1992001002A1/fr

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Classifications

    • 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
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]

Definitions

  • Tumor necrosis factor activity inhibitor and method for producing the same
  • the present invention relates to a novel substance that suppresses the activity of tumor necrosis factor, and the isolation and purification of the substance.
  • Tumor necrosis factor was administered to a CD-1 Swiss mouse with Bacillus Ca1me11e-Gtier II (BCG) bacteria, and two weeks later with bacterial endotoxin (endotoxin) It was discovered as a biologically active substance that appeared in the blood when it was killed, and Carswe! 1 reports [EA Carswe! ! La Pro at! Acad, Sci., USA, 3ot) t U 975:] A bioactive protein whose amino acid sequence was determined in 1985 by Aggarwai et al. [E, B, Aggarwal et al., J. Biol. Diem. 260, 2345 11985). It has been clarified by J.
  • TNF TNF-1 fibroblast growth factor
  • B. Beutler et al., Science, 229, 869 (1985) Induction of inflammatory response to vascular endothelial cells [J Gamble 'et al., Proc. Xa ⁇ i. A cad. Sc ⁇ ., USA, _82 ⁇ _ 8667 (1985)], ripening [A. D are! Io et al., J. Exp. Med. 163. 1443 (1986)], Interleukin, one of the substances causing inflammation :! ['PP Nawroth et al., J. Exp. Med. 1 _ 1363]
  • Noshika has been prepared and is not suitable for administration to the human body Such antibodies are considered to be a major problem.
  • immune complex formation is at least a factor that worsens the condition.
  • anti-Din'F antibody as a substance having anti-NF activity for such diseases. Therefore, if a human body fluid could contain an anti-Fing agent that could be present naturally, it would be a sufficient, effective and safe treatment for TNF-fighting diseases.
  • TNF activity inhibitor also referred to as ⁇ F inhibitor
  • Peetre et al. [Eur. J. Haemalc !, ⁇ , 414 (1988), £ 2, -270 (1989)], P. Secger La
  • the present inventors have conducted research to search for a novel TNF activity inhibitor, and have reached the present invention.
  • An object of the present invention is to provide a novel TNF activity inhibitor, a composition containing the same, and a method for producing the same.
  • the present invention encompasses the following inventions. That is, the present invention relates to H) suppressing the cell killing effect of tumor necrosis factor on L929 cells. • 2) SDS-PAGE has a reduced molecular weight of 34
  • amino acids from the 1st to the Uth from the ⁇ terminus are substances represented by the following sequence Val-Aia-Phe-Thr-Pro-Tr-Aia-Pro-Ala-Pro-Tr is there
  • the substance of the present invention is characterized in that the 11th amino acid from the N-terminus is Va! -AIa-Phe-Tr-Pro-Tyr-Ala-Pro-Ala-? Ro-Thr.
  • the substances of the present invention are described in C. Peetre et al. [Eur. J. Haematol. 11, 414 (1988 ⁇ ). However, the difference is that it is 34 K2 1 KDa.
  • amino acid sequence from the- ⁇ ⁇ end is completely different from the substance TBPI described in H. Engeimann et al., 7. Bio, Chem. 265, 153L 1990].
  • Ding XF is described by Aggarwai et al. Chem. 2345 (1985)] and Shirai et al. [Ature 313. 805: 1985)]. Including natural TNF and recombinant TNF
  • L 929 cells are mice
  • ATC C strain number is CCL-11, registered under the name L 929 (NCTC clone 929)
  • the molecular weight of the substance of the present invention is a substance having a reduced molecular weight in SDS-PAGE of 3'4K / 200 KDa.
  • the reduced state in SDS-PAGE refers to the electrical properties of SDS polyacrylamide gel.
  • a suitable reducing agent for example, 2-mercaptoethanol, dithiothreitol, etc., at 100 ° C for several minutes to obtain the disulfide in the protein.
  • a suitable reducing agent for example, 2-mercaptoethanol, dithiothreitol, etc.
  • the substance of the present invention can be obtained by purifying urine.
  • it can be obtained by purifying the urine of patients with membranous proliferative glomerulonephritis,
  • Membranous proliferative glomerulonephritis clinically involves the deposition of immune complexes in the renal glomeruli, lowering blood complement value, thickening of the glomerular basement membrane, and proliferation of mesangial cells.
  • sycaines especially interleukin 6
  • the inventor of the present invention determined the F content in the blood of patients with various renal diseases and found that high blood levels of TNF were contained in the blood of patients with membranous proliferative glomerulonephritis. Finally, using the urine of the patient with this disease, we examined the ability to inhibit the activity of DNF and found that it had a high ability to inhibit TNF activity.
  • Purification can be performed by combining purification operations such as ion exchange, reversed phase column, and XF immobilization.
  • the present invention relates to a method for producing a tumor necrosis factor activity inhibitor
  • the urine may be any of primary urine, urine collection, and spot urine.
  • urine is collected under aseptic or aseptic conditions as much as possible in order to carry out a bioa / se / se later.
  • a protease inhibitor may be added immediately after urine collection, but these additives are not required if urine is immediately transferred to frozen storage. When these additives are added, it is necessary to remove the additives sufficiently by performing appropriate operations, for example, dialysis, ⁇ extracellular filtration, gel filtration, etc.
  • Purification may be performed by an ordinary protein purification method. Since a low activity is usually observed in the urine stock solution, it is preferable to first concentrate the urine solution.
  • the enrichment method may be based on ordinary biochemical experiment methods such as ultrafiltration, lyophilization, salting out, etc., but in the case of ultrafiltration, salting out, etc., the target substance It is necessary to check in advance the molecular weight and the degree of saltiness that initiates precipitation:
  • the substance of the present invention is subjected to separation and purification by adsorbing to a column to which TNF has been applied after the above-mentioned concentration operation, and then specific eluting by elution with a reversed-phase column.
  • cell is a substance contained in the fraction in two k Lil concentration cell), column nits Lil concentration used varies depending ⁇ cell Tonito Lil ⁇ gradient, Protein C 4, VYDA and 'Company, 0.46: , 25 cm, and a 150-minute linear gradient of 1 ⁇ to 37% acetonitrile, 2? ⁇ 28%,
  • a test sample may be added to a known system for measuring TNF activity.
  • Cell killing effect on various tumor cells in vitro known as the Lysie method, cell growth inhibitory effect, fatty acid metabolism of fat cells _ inhibitory effect
  • Growth promoting effect of normal fibroblasts and 1 L-6 production inducing effect Neutrophil adhesion promoting effect on endothelial cells, superoxide secretion promoting effect, vascular endothelial cell coagulation activity enhancing effect, osteoclasting effect on bone cells, IL in various cells
  • a system for measuring the inducing effect of ⁇ 'mouth mouth staglandins is available. It is particularly preferable to measure the cell killing effect on L929 cells.
  • the tumor necrosis factor activity inhibitor of the present invention includes various types of
  • the pharmaceutical composition used as a therapeutic agent for the disease of the sword is a pharmaceutical composition containing the substance for suppressing tumor necrosis factor activity of the present invention as an active ingredient, and is other pharmaceutically acceptable. It includes a carrier and is good
  • tumors to be used as active ingredients may be used to reduce the antigenicity of the inhibitor of death factor activity or to enhance the physiological activity.
  • polyethylene glycol ⁇ PEG polyethylene glycol ⁇ PEG
  • dextran it can be modified by a known polymer such as poly-DL-alanine.
  • Examples of the form of the pharmaceutical composition include an injectable composition, a suppository and the like, and it is particularly preferable to use the injectable composition as an intravenous composition.
  • an injectable composition it is a mixture of a pharmaceutically effective amount of the tumor necrosis factor activity-inhibiting substance of the present invention and a pharmaceutically acceptable carrier, including amino acids, saccharides, and cellulose.
  • a pharmaceutically acceptable carrier including amino acids, saccharides, and cellulose.
  • activators generally added to injectable compositions, such as derivatives, polyvinylpyrrolidones, and inorganic compounds. Specific examples thereof include glycine and arginine as amino acids. , Alanine and their pharmaceutically acceptable salts, etc.
  • the sugars include mannitol, wild boar, il, xyli, oleoresin, milk, and -7'-coose.
  • Cellulose derivatives include carboxymethyi / rese / relo-t-tris, methyl 'cell'-mouth, etc .: Polyvinylpyrrolidones have a molecular weight of 10 000 ⁇ 1,000, GOO Bolibulpyrrolidone:
  • Examples of the organic acids include ascorbic acid, citric acid, and the salts thereof.
  • Examples of the inorganic compound calcium include 10% of hydrogen phosphate, 10% of hydrogen carbonate, and 10% of acetate. There is a room
  • Solutions for dissolving these excipients include injection ⁇ distillation, saline for injection or Ringer's solution for injection.
  • injections may contain stabilizers, surfactants, tonicity agents, soothing agents, preservatives, buffers, etc. as required.
  • Antioxidants such as deuterium pyrosulfite and perscorbic acid: chelating agents such as DTA and thioglycol agents, etc.
  • Examples of surfactants include phosphorylates and boroxixylene derivatives
  • Non-ionic surfactants such as Examples of the tonicity agent include sodium chloride and the like.
  • Soothing agents include benzyl alcohol, xylocaine, procaine and the like.
  • Preservatives include parabens, chlorobutanol, benzanolone chloride, and thimerosal.
  • buffer examples include sodium salts such as citric acid, acetic acid, and phosphoric acid.
  • a novel substance that suppresses the cell killing effect of tumor necrosis factor (TNF) on cells is provided, and a disease considered to be exerted by TNF, for example, endotoxin shock ⁇ ⁇
  • TNF tumor necrosis factor
  • Many autoimmune diseases such as acute burn, acute liver failure, renal failure and multiple organ failure, rheumatism, SLE, Behcet, V Grade disease at the time of burn, rejection at organ transplantation, coagulation of Kawasaki disease, DIC, etc. It can be used for treating abnormalities, diagnosing abnormalities, etc.
  • Urine from a patient with membranous proliferative glomerulitis was concentrated by ultra-filtration with a silicone (Millipore) to a fraction with a molecular weight of 10,000 or more to a volume of 10 ml Tr !? Changed '.' and 'to pH 8.0 (Sample 2)
  • the concentrated urine sample was applied to a 4 S DEAE-Sepiiarose column equilibrated with ⁇ OraM Tris pH 8.0 ⁇ 1 : Flow rate 40 ⁇ ir .: After washing with 10m Tris pH 8.0 in zjir, 10mM Tri? -LOOm Elution was carried out with NaC! PH G, and the mixture was collected at 400 m!
  • Table 1 shows the cell killing effect of TXF on these L929 cells.
  • the peak fraction was further purified by a TNF affinity column and a reversed-phase column, and the X-terminal amino acid sequence was determined.Asp-Ser-Va! -X-Pro-G ! n-Gl-Lys-T rI I e-His-Pro-Gi QX-Asn-Se rI ⁇ e (X is the residue that was not recognized in the 477A type protein sequencer without beak) It was presumed to be a known TNF inhibitor or a TNF receptor fragment, [I. "01 sson et al., Eur. J. Haemat .. 42, 270 (1989); H. Loetscher et al., Ce. j _ ⁇ _ 351 (1990), T.J, Schail, et al., Cell JJ ⁇ 361 (1990;)
  • TNF_Inhibtition rate is as follows.
  • the final purified product A35G ⁇ was freeze-dried and redissolved in 230 JL St of S. This Sanal 9 ⁇ ! 10 u 2 XSDS—PAGE sample buffer (1 mM Tris — HC] H6.8, 10% Sucrose. 10% SDS, 0.25 mg 'ml bromphenol buffer :), 1 2— After adding mercaptoethanol and heating at 100 ° C for 5 minutes, apply the whole amount to a 10-20 SDS polyacrylamide gradient gel (first character, SDS-PAGPL AT E 10'20>, —) ir. : A fixed Electrophoresis was performed for 120 minutes at a current, and BI-RAD Molecular Weight Standards-Low was used as a molecular weight marker.
  • Figure 1 shows the elution profile of the DEAE crude product when applied to a reversed-phase column.
  • Figure 2 shows the results of SDS-PAGE under reduced conditions of the final purified product A: ⁇ Sequence list>

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un nouvel inhibiteur de l'activité du facteur de la nécrose tumorale qui inhibe l'effet cytocide d'un facteur de nécrose tumorale et qui a une masse molaire d'environ 34 kDa et une séquence de 11 acides aminés au niveau de la terminaison N de Val-Ala-Phe-Thr-Pro-Tyr-Ala-Pro-Ala-Pro-Thr.
PCT/JP1991/000920 1990-07-11 1991-07-10 Inhibiteur de l'activite du facteur de la necrose tumorale et son procede de preparation WO1992001002A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP18148890 1990-07-11
JP2/181488 1990-07-11

Publications (1)

Publication Number Publication Date
WO1992001002A1 true WO1992001002A1 (fr) 1992-01-23

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271346B1 (en) 1989-04-21 2001-08-07 Amgen Inc. TNF Receptors, TNF binding proteins and DNAs coding for them
US6306820B1 (en) 1996-12-06 2001-10-23 Amgen Inc. Combination therapy using a TNF binding protein for treating TNF-mediated diseases
US7238776B2 (en) 1989-04-21 2007-07-03 Amgen Inc. TNF binding proteins
WO2008054603A2 (fr) 2006-10-02 2008-05-08 Amgen Inc. Protéines de liaison à l'antigène du récepteur a de l'il-17
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP2002846A2 (fr) 1996-12-06 2008-12-17 Amgen Inc. Thérapie combinée utilisant un inhibiteur IL-1 pour traiter les maladies liées au IL-1
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
US7732587B2 (en) 1996-07-09 2010-06-08 Amgen Inc. Nucleic acids encoding truncated soluble tumor necrosis factor
WO2011046958A1 (fr) 2009-10-12 2011-04-21 Amgen Inc. Utilisation des proteines se liant a un antigene du recepteur a de l'il-17
WO2013016220A1 (fr) 2011-07-22 2013-01-31 Amgen Inc. Récepteur a de il-il-17 requis pour biologie il-17c
WO2015153144A1 (fr) 2014-03-31 2015-10-08 Kirin-Amgen, Inc. Procédés de traitement du psoriasis des ongles et du cuir chevelu
US10072085B2 (en) 2010-01-15 2018-09-11 Kirin-Amgen, Inc. Method of treating psoriasis using an IL-17 receptor antibody formulation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02117700A (ja) * 1988-03-31 1990-05-02 Glaxo Group Ltd 生物学的に活性な蛋白質
WO1990013575A1 (fr) * 1989-05-09 1990-11-15 Basf Aktiengesellschaft Nouvelles proteines a effet d'inhibition de tnf et leur preparation
JPH0330693A (ja) * 1989-06-29 1991-02-08 Teijin Ltd 新規生理活性ポリペプチド

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02117700A (ja) * 1988-03-31 1990-05-02 Glaxo Group Ltd 生物学的に活性な蛋白質
WO1990013575A1 (fr) * 1989-05-09 1990-11-15 Basf Aktiengesellschaft Nouvelles proteines a effet d'inhibition de tnf et leur preparation
JPH0330693A (ja) * 1989-06-29 1991-02-08 Teijin Ltd 新規生理活性ポリペプチド

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7282483B2 (en) 1989-04-21 2007-10-16 Amgen Inc. Method of ameliorating the harmful effects of TNF using a polypeptide having the ability to bind to TNF
US6294352B1 (en) * 1989-04-21 2001-09-25 Amgen Inc. TNF receptors, TNF binding proteins and DNAs coding for them
US6271346B1 (en) 1989-04-21 2001-08-07 Amgen Inc. TNF Receptors, TNF binding proteins and DNAs coding for them
US6417158B1 (en) * 1989-04-21 2002-07-09 Amgen, Inc. Method of ameliorating the harmful effects of TNF using a polypeptide having the ability to bind to TNF
US6440693B1 (en) 1989-04-21 2002-08-27 Rudolf Hauptmann TNF receptors, TNF binding proteins and DNAS coding for them
US7238776B2 (en) 1989-04-21 2007-07-03 Amgen Inc. TNF binding proteins
US7264944B1 (en) 1989-04-21 2007-09-04 Amgen Inc. TNF receptors, TNF binding proteins and DNAs coding for them
US7732587B2 (en) 1996-07-09 2010-06-08 Amgen Inc. Nucleic acids encoding truncated soluble tumor necrosis factor
EP2002846A2 (fr) 1996-12-06 2008-12-17 Amgen Inc. Thérapie combinée utilisant un inhibiteur IL-1 pour traiter les maladies liées au IL-1
US6306820B1 (en) 1996-12-06 2001-10-23 Amgen Inc. Combination therapy using a TNF binding protein for treating TNF-mediated diseases
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
EP3165539A1 (fr) 2006-10-02 2017-05-10 Kirin-Amgen, Inc. Protéines se liant à des antigènes a du récepteur il-17
WO2008054603A2 (fr) 2006-10-02 2008-05-08 Amgen Inc. Protéines de liaison à l'antigène du récepteur a de l'il-17
US10208122B2 (en) 2006-10-02 2019-02-19 Amgen K-A, Inc. IL-17 receptor A antigen binding proteins
US11180564B2 (en) 2006-10-02 2021-11-23 Amgen K-A, Inc. IL-17 Receptor A antigen binding proteins
US11858999B2 (en) 2006-10-02 2024-01-02 Amgen K-A, Inc. IL-17 receptor A antigen binding proteins
WO2011046958A1 (fr) 2009-10-12 2011-04-21 Amgen Inc. Utilisation des proteines se liant a un antigene du recepteur a de l'il-17
US10072085B2 (en) 2010-01-15 2018-09-11 Kirin-Amgen, Inc. Method of treating psoriasis using an IL-17 receptor antibody formulation
US10808033B2 (en) 2010-01-15 2020-10-20 Amgen K-A, Inc. IL-17 receptor antibody formulation
US11505612B2 (en) 2010-01-15 2022-11-22 Amgen K-A, Inc. Method of treating diseases using an IL-17 receptor antibody formulation
WO2013016220A1 (fr) 2011-07-22 2013-01-31 Amgen Inc. Récepteur a de il-il-17 requis pour biologie il-17c
WO2015153144A1 (fr) 2014-03-31 2015-10-08 Kirin-Amgen, Inc. Procédés de traitement du psoriasis des ongles et du cuir chevelu

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