TOP > 外国特許検索 > AGENT TO PROMOTE THE CELL-SURFACE EXPRESSION OR AGENT TO INHIBIT THE CELL-SURFACE EXPRESSION OF PHOSPHATIDYLSERINE, AND AGENT TO INHIBIT THE FORMATION OF LIPID RAFT CLUSTERS

AGENT TO PROMOTE THE CELL-SURFACE EXPRESSION OR AGENT TO INHIBIT THE CELL-SURFACE EXPRESSION OF PHOSPHATIDYLSERINE, AND AGENT TO INHIBIT THE FORMATION OF LIPID RAFT CLUSTERS

外国特許コード F160008668
整理番号 (S2014-0943-N0,S2014-0944-N0,S2014-0945-N0)
掲載日 2016年2月5日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2015JP063840
国際公開番号 WO 2015170778
国際出願日 平成27年5月7日(2015.5.7)
国際公開日 平成27年11月12日(2015.11.12)
優先権データ
  • 特願2014-097201 (2014.5.8) JP
  • 特願2014-097202 (2014.5.8) JP
  • 特願2014-097203 (2014.5.8) JP
発明の名称 (英語) AGENT TO PROMOTE THE CELL-SURFACE EXPRESSION OR AGENT TO INHIBIT THE CELL-SURFACE EXPRESSION OF PHOSPHATIDYLSERINE, AND AGENT TO INHIBIT THE FORMATION OF LIPID RAFT CLUSTERS
発明の概要(英語) Provided are: an agent that promotes the cell surface expression of PS, and that includes a peptide containing the EGF1 domain of factor IX or a peptide containing the EGF3 domain of endothelial cell-1 protein; an agent that inhibits the cell surface expression of PS, and that contains a peptide that includes a portion obtained by removing the trypsin domain (heavy chain) portion and the light chain portion from the full length of factor IX; and an agent for inhibiting the formation of lipid raft clusters, and that contains a peptide that includes a portion obtained by removing the trypsin domain (heavy chain) portion and the light chain portion from the full length of factor IX.
従来技術、競合技術の概要(英語) BACKGROUND ART
Cell surface expression of the promoter><PS hemostatic coagulation factor 9 (F9) that are involved in the coagulation of the long-known is an essential and blood coagulation factors, protein known as the cause of hemophilia. F9 Is, in the course of the coagulation reaction by coagulation factor 11 (F11) the two fragments of the 2 (heavy chain, light chain) or the like can be cleaved by activated, to promote the coagulation reaction (non-patent document 1: Textbook of Medical Physiology,10e.Arthur C. Guyton MD). F9 In, coagulation factor C functions as an important part of the trypsin domain (heavy chain) and of the terminal side, the function of the N-terminal side (light chain) is not well known. In particular, the light chain fragment in a first EGF (F9 - EGF1) (EGF1) the function of the domain is not known in detail much. However, in the treatment of cancer or an agent (anticancer agent) of the radiation used is so much higher cytotoxicity, therapeutic problem is, how the treatment efficacy of a cancer tissue, become concentrated in the cancer cells, reduced side-effects to healthy tissue F_TD. Therefore, the characteristic properties of a cancer cell specific protein binds or as a therapeutic target has been tried. Cancer of the blood vessel tissues of healthy tissues and as a therapeutic target for a different nature are selected, antibody anti-Vascular Endothelial Growth factor (VEGF) a production. Anti-VEGF antibody besides the drugs that target vascular vessel targets, one of them is antiphosphatidylserine antibody (PS). Is a two-layered cell membrane is separated from the lipid membrane, lipid membrane and the inner and outer lipid membrane constituting lipid components is different. In normal cells, included in the lipid membrane and the inner PS (unevenly distributed; are localized) is, on the outside of the endothelial cells of the tumor blood vessels (i.e. outside the cell membrane) lipid membrane the expression. Anti-PS antibodies, coupled to the exposed on PS, immune reaction to attack and destroy the tumor blood vessels. Blood flow has been shut off and tumor cells can be killed, growth is stopped. In fact, anti-PS antibody therapy trials in the second phase, advanced non-small cell lung cancer 11 months 7 months the patient's life prognosis extended. In addition, the application of the anti-PS antibody treatment not only. Antibody conjugated to a radioisotope administered to the patient, the activity on a tumor. When the imaging camera from outside it, the site of a tumor can be evaluated and spreading. As the other applications of anti-PS antibody, possible treatment of a viral infection. Cells infected with the virus, since PS is exposed outside, tumor endothelial cells of blood vessels in the same manner as anti-PS antibody therapy is applied. Since the virus to propagate in cells, the growth of the virus to kill infected cells before once, viral proliferation is inhibited. The anti-viral drugs are currently used, have been developed for each type of virus is often, no effect on the other viruses. On the other hand, viruses by anti-PS antibody treatment, according to an experiment animal, AIDS virus, influenza virus, coxsackie virus, hepatitis C virus, lassa fever virus and the like, a wide range to be effective against the virus infection has been confirmed. However, the above-all endothelial cells of blood vessels of the tumor, the exposed PS on the cell surface does not. PS is exposed on the cell surface of tumor vascular endothelial cells and 15-40% have been reported. Therefore, promote the expression of cell surface PS which has the effect of radiation or anti-cancer, are currently used for the treatment of cancer, for use with anti-PS antibody results in advantages of the present invention, as is well known, it is resistant to treatment with radiation or anticancer drug side effects. Therefore, such treatment may be, and is a limitation in the treatment of cancer, cannot be used in the treatment of virus. Expression of cell surface<PS>hemostatic coagulation that are involved in the coagulation inhibitor 9 (F9) is an essential factor of the long-known and blood coagulation factors, protein known as the cause of hemophilia. F9 Is, in the course of the coagulation reaction (F11) coagulation factor 11 by the two fragments of the 2 (heavy chain, light chain) or the like can be cleaved by activated, to promote the coagulation reaction (mentioned Non-Patent Documents 1). F9 In, coagulation factor C functions as an important part of the trypsin domain (heavy chain) and of the terminal side, the function of the N-terminal side (light chain) is not well known. In particular, the light chain fragment in a first EGF (F9 - EGF1) (EGF1) the function of the domain is not known in detail much. However, in the treatment of cancer or an agent (anticancer agent) of the radiation used is so much higher cytotoxicity, therapeutic problem is, how the treatment efficacy of a cancer tissue, become concentrated in the cancer cells, reduced side-effects to healthy tissue F_TD. Therefore, the characteristic properties of a cancer cell specific protein binds or as a therapeutic target has been tried. Cancer of the blood vessel tissues of healthy tissues and as a therapeutic target for a different nature are selected, antibody anti-Vascular Endothelial Growth factor (VEGF) a production. Anti-VEGF antibody besides the drugs that target vascular vessel targets, one of them is antiphosphatidylserine antibody (PS). Is a two-layered cell membrane is separated from the lipid membrane, lipid membrane and the inner and outer lipid membrane constituting lipid components is different. In normal cells, included in the lipid membrane and the inner PS (unevenly distributed; are localized) is, on the outside of the endothelial cells of the tumor blood vessels (i.e. outside the cell membrane) lipid membrane the expression. Anti-PS antibodies, coupled to the exposed on PS, immune reaction to attack and destroy the tumor blood vessels. Blood flow has been shut off and tumor cells can be killed, growth is stopped. In fact, anti-PS antibody therapy trials in the second phase, advanced non-small cell lung cancer 11 months 7 months the patient's life prognosis extended. In addition, the application of the anti-PS antibody treatment not only. Antibody conjugated to a radioisotope administered to the patient, the activity on a tumor. When the imaging camera from outside it, the site of a tumor can be evaluated and spreading. As the other applications of anti-PS antibody, possible treatment of a viral infection. Cells infected with the virus, since PS is exposed outside, tumor endothelial cells of blood vessels in the same manner as anti-PS antibody therapy is applied. Since the virus to propagate in cells, the growth of the virus to kill infected cells before once, viral proliferation is inhibited. The anti-viral drugs are currently used, have been developed for each type of virus is often, no effect on the other viruses. On the other hand, viruses by anti-PS antibody treatment, according to an experiment animal, AIDS virus, influenza virus, coxsackie virus, hepatitis C virus, lassa fever virus and the like, a wide range to be effective against the virus infection has been confirmed. However, the above-all endothelial cells of blood vessels of the tumor, the exposed PS on the cell surface does not. PS is exposed on the cell surface of tumor vascular endothelial cells and 15-40% have been reported. Therefore, promote the expression of cell surface PS which has the effect of radiation or anti-cancer, are currently used for the treatment of cancer, for use with anti-PS antibody results in advantages of the present invention, as is well known, it is resistant to treatment with radiation or anticancer drug side effects. Therefore, such treatment may be, and is a limitation in the treatment of cancer, cannot be used in the treatment of virus. Inhibitor & gt<clustering of lipid rafts; 9 Hemostatic clotting factors that are involved in the coagulation (F9) is an essential long-known and blood coagulation factors, protein known as the cause of hemophilia. F9 Is, in the course of the blood coagulation reaction, clotting factors and clotting factors 7 11, the heavy chain and the heavy chain (trypsin domain) present between the intermediate portion (Activation peptide (F9-AP) ) is cut off, is activated. Heavy and light chains after cutting is also connected by a disulfide bond and, as a single molecule of 1, to promote blood coagulation reaction (mentioned Non-Patent Documents 1). However, the function of the peptides in the middle is reported F9-AP is little. However, many of the conventional therapeutic agents for infections, pathogen (virus, bacteria, protozoa and the like) target the proteins derived from, by inhibition of its function and it exerts an effect. In addition, conventional cancer cell inhibition of information transfer from the target agent is a molecular target, to inhibit the function of the protein that are involved in the transmission of information, effect in many cases. However, a single protein inhibitor for the individual is being developed to a protein of a pathogen, the pathogen is different from that of becomes invalid. Further, the greatest disadvantage is that of drug resistance is established. Pathogens and cancer cells, and the variation of the protein target of the inhibitor, other signal transduction pathway in the alternative, neutralizes the attack agent. Is tolerated, as well as severe disease, long-term development of waste of the effort and cost. Now, the cell membranes are, typically, of the two layers formed from the lipid membrane. Therein, and sphingolipids or cholesterol-rich region, this region is referred to as lipid rafts. Lipid rafts are, in the required structure for a phagocytosis (endocytosis). In addition, a number of lipid rafts gather and a membrane protein, of a variety of biological and the sites for reaction. Is endocytosis by cells, and the material of the information into the cell from outside the cell entrance. Virus, bacteria, protozoa and the like, many of the pathogens, lipid rafts of the cell membrane occurs goes into cells using endocytosis. Therefore, suppressing the cluster formation of lipid rafts, via endocytosis and growth of pathogens can be suppressed. And the other function of lipid rafts, from outside the cell into the cell a cell membrane receptor is to be transmission of information via, suppressing the cluster formation of lipid rafts, a plurality of information is transmitted via the receptor can be blocked at the same time.
In such a situation, the segregation of the lipid membrane and the inside of the cell membrane phosphatidylserine (PS) to expose the outer lipid membrane can be (so-called everting), expression of cell surface PS development accelerator has been desired. In particular, in endothelial cells of blood vessels or virus - infected tumor cells, the expression of cell surface PS can be promoted effectively, the development of the exposed promoter has been desired. In addition, the inside of the cell membrane lipid membrane is unevenly distributed in the outer lipid membrane phosphatidylserine (PS) (so-called everting) of the expression can be suppressed, the expression of cell surface PS development inhibitor has been desired. In particular, and to the development of antigen PS APS in patients, the expression of cell surface PS effectively suppressed, an autologous immune response can be important for suppressing, the expression of the inhibitor of the development is strongly desired. Further, cluster formation of lipid rafts cell membrane can be suppressed effectively, the clustering of lipid rafts is the development of inhibitors has been desired. The present invention is, as described above and there is a need with an object, shown below, promoter and expression of cell surface PS, such as a pharmaceutical composition comprising the exposed promoter; PS inhibitor or the expression of the cell surface, such as a pharmaceutical composition comprising the expression inhibitor; and clustering of lipid rafts and inhibitor, a pharmaceutical composition comprising the inhibitor system according to the invention and the like. & Gt<PS promoter expression of cell surface; blood clotting factors (1-1) a peptide containing the 9 EGF1 domain, EGF3 domain or endothelial cells a peptide containing the locus of the -1 protein, a derivative thereof, or salts thereof characterized in that, the expression of the promoter to the surface of phosphatidylserine. (A) (1-2) or less, (c) or (b) the peptide, its derivatives or salts thereof characterized in that, the expression of the promoter to the surface of phosphatidylserine. (a) Shown in SEQ ID NO:8 or 16 comprising an amino acid sequence. (b) Amino acid sequence shown in SEQ ID NO:8 or 16 in 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, to the surface of phosphatidylserine promotes expression of a peptide having the activity. (c) Amino acid sequence shown in SEQ ID NO:8 or 16 and 80% or higher identity with the amino acid sequence having (homology), and, to the surface of phosphatidylserine promotes expression of a peptide having the activity. (1-2) (1-1) and the expression of the promoter in, for promotion of the expression of cell surface phosphatidylserine is, for example, endothelial cells of blood vessels in the tumor or viral infected cells exposed to the surface of phosphatidylserine facilitation. (1-1) (1-3) the animals (1-2) or the expression of the promoter and administering, to a method for enhancing the expression of phosphatidylserine on the cell surface. As the method of the above (1-3), for example, endothelial cells of blood vessels in the tumor or viral infected cells and the expression of phosphatidylserine to the surface and promoting. (1-1) (1-4) or (1-2) the expression of the use of the accelerator, the pharmaceutical composition. The pharmaceutical composition of the above (1-4), for example, comprise further antiphosphatidylserine antibody may be. (1-4) of the pharmaceutical composition may include, for example, cancer or viral infection or the like of a pharmaceutical composition for the treatment of, cancer or viral infection a pharmaceutical composition for the diagnosis and the like. Inhibitor & gt<PS cell surface expression of; blood clotting factor 9 (2-1) trypsin domain of the total length of the part except the part portion and a light chain peptide comprising, derivatives thereof, or salts thereof characterized in that, the expression of the inhibitor to the surface of phosphatidylserine. (A) the following (2-2), (b) or (c) peptide, its derivatives or salts thereof characterized in that, the expression of the inhibitor to the surface of phosphatidylserine. (a) Comprising the amino acid sequence shown in SEQ ID NO:26 peptide. (b) 26 In the amino acid sequence shown in SEQ ID NO:1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, of phosphatidylserine exposed to the surface of an active peptide. (c) And 26 amino acid sequence shown in SEQ ID NO:80% comprises the amino acid sequence identity or more, and, of phosphatidylserine exposed to the surface of an active peptide. (2-1) (2-3) animals (2-2) or of the expression inhibitor and administering, to a method for inhibition the expression of cell surface phosphatidylserine. (2-4) or (2-2) (2-1) of the expression inhibitor, the pharmaceutical composition. (2-4) of the pharmaceutical composition may include, for example, anti-phospholipid antibody syndrome (APS) used for the treatment or prevention of pharmaceutical compositions, excessive thrombosis or embolization due to the formation of various diseases (for example, existing anti-platelet agent is applied to a variety of disease) used for the treatment or prevention of a pharmaceutical composition and the like. Inhibitor & gt<clustering of lipid rafts; blood clotting factor 9 (3-1) trypsin domain of the total length of the part except the part portion and a light chain peptide comprising, derivatives thereof, or salts thereof characterized in that, the clustering of lipid rafts inhibitor. (A) (3-2) or less, (c) or (b) the peptide, its derivatives or salts thereof characterized in that, the clustering of lipid rafts inhibitor. (a) Comprising the amino acid sequence shown in SEQ ID NO:38 peptide. (b) 38 In the amino acid sequence shown in SEQ ID NO:1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, the clustering of lipid rafts an active peptide. (c) And 38 amino acid sequence shown in SEQ ID NO:80% comprises the amino acid sequence identity or more, and, the clustering of lipid rafts an active peptide. Blood clotting factor 9 (3-3) trypsin domain of the total length of the part except the part portion and a light chain peptide comprising, derivatives thereof, or salts thereof and, cell endocytosis inhibitor. (A) (3-4) or less, (c) or (b) the peptide, its derivatives and salts thereof, inhibitor endocytosis by cells. (a) Comprising the amino acid sequence shown in SEQ ID NO:38 peptide. (b) 38 In the amino acid sequence shown in SEQ ID NO:1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, a peptide having the activity to suppress the endocytosis by cells. (c) And 38 amino acid sequence shown in SEQ ID NO:80% comprises the amino acid sequence identity or more, and, a peptide having the activity to suppress the endocytosis by cells. Blood clotting factor 9 (3-5) trypsin domain of the total length of the part except the part portion and a light chain peptide comprising, derivatives thereof, or salts thereof characterized in that, a cell membrane receptor mediated cell information into transfer inhibiting agent. (A) (3-6) or less, (c) or (b) the peptide, its derivatives and salts thereof, cell membrane receptors information into the cell via the transfer inhibiting agent. (a) Comprising the amino acid sequence shown in SEQ ID NO:38 peptide. (b) 38 In the amino acid sequence shown in SEQ ID NO:1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, a cell membrane receptor information into the cell via the transfer inhibiting peptide having the activity. (c) And 38 amino acid sequence shown in SEQ ID NO:80% comprises the amino acid sequence identity or more, and, a cell membrane receptor information into the cell via the transfer inhibiting peptide having the activity. (3-1) (3-7) animals (3-2) or of the inhibitor and administering, to a method for inhibition cluster formation of lipid rafts. (3-3) (3-8) animals (3-4) or of the inhibitor and administering, to a method for inhibition of receptor-mediated endocytosis by the cells. (3-5) (3-9) animals (3-6) or of the inhibitor and administering, cell membrane receptors information into the cell via the transfer inhibiting method. (3-1) - (3-6) (3-10) according to any of the above-mentioned inhibitor, the pharmaceutical composition. (3-10) of the pharmaceutical composition may include, for example, be one that can be the treatment or prevention of infection, the cell via the cell membrane receptors transmit information into the treatment or prevention of conditions or diseases caused by and used.
  • 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
  • NIHON UNIVERSITY
  • 発明者(英語)
  • HIDAI, Chiaki
  • KITANO, Hisataka
  • MAMIYA, Atsushi
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 IR IS KE KG KN KP KR KZ LA LC LK LR LS 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 SA 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 ST TD TG
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