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THERAPEUTIC AGENT, TREATMENT METHOD AND TEST METHOD FOR DISEASES ASSOCIATED WITH ACTIVATION OF NEUTROPHILS

外国特許コード F130007801
整理番号 S2012-0798-N0
掲載日 2013年12月18日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2013JP064779
国際公開番号 WO 2013183494
国際出願日 平成25年5月28日(2013.5.28)
国際公開日 平成25年12月12日(2013.12.12)
優先権データ
  • 特願2012-129232 (2012.6.6) JP
発明の名称 (英語) THERAPEUTIC AGENT, TREATMENT METHOD AND TEST METHOD FOR DISEASES ASSOCIATED WITH ACTIVATION OF NEUTROPHILS
発明の概要(英語) Provided are a therapeutic agent, a treatment method and a test method for diseases associated with the activation of neutrophils. More specifically, the present invention relates to a neutrophil activation regulator comprising a histidine-rich glycoprotein (HRG) as an active ingredient, and provides: a therapeutic agent for diseases associated with the activation of neutrophils, which comprises the neutrophil activation regulator; a method for treating a disease associated with the activation of neutrophils; and a method for testing for diseases associated with the activation of neutrophils. A neutrophil activation regulator comprising a HRG as an active ingredient. The present invention also provides: a neutrophil-vascular endothelial cell interaction inhibitor comprising the HRG according to the present invention as an active ingredient; and a method for treating diseases associated with the activation of neutrophils and/or inflammatory diseases accompanied by the activation of neutrophils. The present invention further provides a method for testing for inflammatory diseases accompanied by the activation of neutrophils by measuring a HRG level in blood.
従来技術、競合技術の概要(英語) BACKGROUND ART
Is in the blood, cellular components as red blood cells, white blood cells, platelets present. Wherein the white blood cells, granulocytes (neutrophils, eosinophils, basophils), lymphocytes, monocytes are classified into 5 types. Neutrophils in humans most of a large number of cell type, tissue damage or bacterial infection in a living body of the first line of defense function is well known. Neutrophils, bacteria (for example, Lipopolysaccharide: LPS) cell body components and bacteria derived peptide, complement C5a, activated by IL-8 and the like. Granulocytic leukocytes neutrophils are one of the principal components of 1, foreign substances such as bacteria penetration within the living body, that migrated to the site, phagocytized foreign substances such as bacteria, to produce active oxygen. Further, lysozyme, defensin protein release (degranulation) etc. and the sterilization and, their effect and further such as by the action of the acidic hydrolysis of the various enzymes play an important role for eliminating the foreign particles are. However, excessively protein or disinfection of the active oxygen released outside of the cell and tissue damage and is thus, in some cases caused by the intrusion of foreign matter further exacerbate acute inflammation. Also acute lung injury, acute respiratory distress syndrome, neutrophil involvement of other specific diseases such as inflammation such as in the case of the action of neutrophils is adversely affects the disease is known.
Is neutrophil elastase, molecular weight of about 3 million and the neutral protease, present in the azurophilic granules (lysosomes). Neutrophil elastase is, physiological state, in neutrophils, bacteria and foreign substances in the phagocytosis, digestion, decomposition, on the outside of the neutrophils, elastin, collagen (type III, type IV), fibronectin, immunoglobulin, such as blood clotting factor XIII to decompose, adjusting the tissue biosynthesis. Is neutrophil elastase, the release of excess, such as α1-AT(α1-antitrypsin) inhibitors of the lack of, the decomposed biological components, the risk of tissue damage of its own. In the case of inflammation, neutrophils infiltrate the nest is inflammation, such as elastase, material produced by leukocytes, rather, caused in view of inflammation. In recent years particularly in a clinical setting, the kinetics of the neutrophil elastase and various disease has attracted attention. Neutrophil elastase is, has a resolution of a strong and a wide range of proteins, particularly over the extracellular matrix components such as collagen, elastin, proteoglycans and the like from decomposing, tissue damage has been considered as one of the factors. Therefore, focused on inhibition of neutrophil elastase is currently under development of a pharmaceutical. For example H2 receptor antagonists are ranitidine hydrochloride (drug name: zantac), neutrophils of intracellular Ca2+ by decreasing the concentration, release of neutrophil elastase, which has been reported to suppress. In addition, sivelestat sodium (pharmaceutical name: erasuporu) is, from neutrophils released into the extracellular specific inhibitor of elastase and, in Japan respiratory syndrome or acute lung injury has been approved for the application of the therapeutic agent. These agents are, essentially suppressing the activation of neutrophils without drugs, activated neutrophils release not only with respect to one of the factors act, by inhibiting their enzymatic activity, is expected for anti-inflammatory effects.
As described above, activated neutrophils release to cause the factors, and inhibiting the activity of materials will be those reports, little is known about suppression mechanism of neutrophils is not. In particular, neutrophils in the circulating blood in order to prevent runaway activation, neutrophils in a deactivated state needs to be maintained. However, neutrophils were maintained in a deactivated state, no report of factors can be controlled.
Is HRG(Histidine-rich glycoprotein), year 1972 identified by Heimburger et al (1972) plasma protein of molecular weight of about 80kDa. A total of 507 amino acids, wherein the histidine 66 and histidine-containing proteins present in high, mainly synthesized in the liver, as high as about 100-150μg/ml in human plasma at a concentration believed to be present. HRG is, adjustment of the fibrinolytic system of coagulation line involved in the regulation of angiogenesis is known (non-patent document 1). Further, the polypeptide of HRG method of inhibiting angiogenesis by, HRG polypeptide, the receptor and antibodies that bind the polypeptide HRG, HRG-deficient plasma and polynucleotides, encoding a polypeptide HRG including vector and a host cell, the product and a pharmaceutical formulation comprising the disclosed (patent document 1). In addition, relates to the field of angiogenesis, including subfragments of the central region of the HRG derived from anti-angiogenic activity of the substantially pure polypeptide is disclosure relating to the use of continuous (Patent Document 2).
However, affecting the control of the neutrophils with HRG for, not reported.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY
  • 発明者(英語)
  • NISHIBORI, Masahiro
  • MORI, Shuji
  • WAKE, Hidenori
  • TAKAHASHI, Hideo
  • LIU, Keyue
  • TESHIGAWARA, Kiyoshi
  • SAKAGUCHI, Masakiyo
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN TD TG

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