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WO1992004913A1 - Procede d'augmentation de la production de globules rouges par traitement a l'aide d'activine ou de peptides apparentes a l'activine - Google Patents

Procede d'augmentation de la production de globules rouges par traitement a l'aide d'activine ou de peptides apparentes a l'activine Download PDF

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Publication number
WO1992004913A1
WO1992004913A1 PCT/US1991/006487 US9106487W WO9204913A1 WO 1992004913 A1 WO1992004913 A1 WO 1992004913A1 US 9106487 W US9106487 W US 9106487W WO 9204913 A1 WO9204913 A1 WO 9204913A1
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WO
WIPO (PCT)
Prior art keywords
inhibin
activin
chain
mammal
red blood
Prior art date
Application number
PCT/US1991/006487
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English (en)
Inventor
Susan P. Perrine
Original Assignee
Children's Hospital Medical Center Of Northern California
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 Children's Hospital Medical Center Of Northern California filed Critical Children's Hospital Medical Center Of Northern California
Publication of WO1992004913A1 publication Critical patent/WO1992004913A1/fr

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Classifications

    • 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
    • A61K38/22—Hormones

Definitions

  • the present invention is directed to a method for increasing the production of red blood cells.
  • the present invention is directed to a method for treatment of diseases or conditions associated with deficient or defective red blood cells by introducing activin to a mammal, such as, for treatment of anemia.
  • the present invention is particularly directed to treatment of anemias which are not effectively treated by erythropoietin, such as A2T- induced anemia.
  • Anemias and other diseases associated with lowered or defective red blood cells may be treated with erythropoietin.
  • some anemias such as anemia induced by AZT intake for therapy against HIV infection, is not effectively counteracted with erythropoietin.
  • red blood cell enhancement is desirable pre- operatively for autologous transfusions, as well as in conditions causing red cell failure states, when erythropoietin elevation in an attempt to raise red blood cell level is usually to no avail. Red blood cell enhancement is also often needed in conjunction with chemotherapy or in recovery from bonemarrow transplant.
  • Hydroxyurea frequently used in anemia treatment, is too toxic for some patients. It is thus an object of the present invention to provide a method for increasing production of red blood cells by administering activin or an activin-related peptide, particularly in individuals with anemias or in need of enhanced red blood cell levels.
  • Activin a hormone, sometimes also referred to as erythroid differentiation factor (EDF) or follicle- stimulating hormone releasing protein (FRP) , is a homodimer consisting of eithertwo ⁇ A subunits of inhibin (Activin A) , two 3 B subunits of inhibin (Activin B) , or a subunit each of ⁇ A and ⁇ B (Activin AB) .
  • Inhibin is another hormone which, among other effects, suppresses secretion of FSH (follicle-stimulatinghormone) fromthe pituitary gland.
  • Inhibin is a protein consisting of ⁇ and ⁇ A subunits linked by disulfide bonds.
  • Activin is present, in analogous forms, in mammals and have been reported, for instance, in human, porcine, and bovine follicular fluid. Porcine inhibin has been purified and sequenced from porcine follicular fluid as described in U.S. Patent 4,740,587. The DNA encoding the prepro inhibin ⁇ and ⁇ chains of porcine or human inhibin has been isolated, ligated into expression vectors and expressed in mammalian culture. See European Patent Application No. 222,491, published Hay 20, 1987. Activin A has been shown to induce hemoglobin accumulation in a human erythroleukaemic cell line and to induce the proliferation of erythroid progenitor cells in human bone marrow culture.
  • the present invention provides a method for enhancing red blood cell production vivo or in vitro comprising the step of introducing to a mammal or to erythroid culture, a compound selected from the group consisting of activin, inhibin, an inhibin chain and mixtures thereof, in an effective amount sufficient to increase red blood cell production.
  • the method according to the present invention is particularly useful for ameliorating in humans the clinical effects of anemias.
  • the present invention provides a method for increasing the production i_ ⁇ vivo or in vitro of red blood cells.
  • activin, inhibin, in any of their analogous mammalian forms, or mixtures of these are introduced to the subject (or culture) receiving enhancement of red blood cell production, such as in the case of anemic subjects.
  • biological sample means any cells or body fluid from a mammal that can be diagnosed, including blood erythroid progenitors.
  • activin or inhibin will be utilized alone or in mixtures with each other, or with activin and/or inhibin.
  • activin and/or inhibin it is meant the dimers of ⁇ and ⁇ -chains of inhibin, prepro forms, and their prodomains, together with glycosylation and/or amino acid sequence variants thereof.
  • the precursor may be used with or without the mature protein, and, after cleavage from the mature protein, may be non-covalently associated with the mature protein.
  • inhibitor chain it is meant to include, but not to be limited to, the ⁇ and ⁇ chains of inhibin, as well as their prepro for s and their prodomains, together with glycosylation and/or amino acid sequence variants of each chain thereof.
  • amino acid sequence variants will be substantially homologous with the relevant portion of the porcine or human ⁇ or ⁇ chain sequences set forth in the aforementioned European Patent Application 222,491, which is incorporated herein by reference in its entirety.
  • Substantially homologous means that greater than about 60% of the primary amino acid sequence of the homologous polypeptide corresponds to the sequence of the porcine or human chain when aligned in order to maximize the number of amino acid residue matches between the two proteins. Alignment to maximize matches of residue includes shifting the amino and/or car oxy1 terminus, introducing gaps as required and/or deleting residues present as inserts in the candidate. Typically, amino acid sequences variants will be greater than about 70% homologous with the corresponding native sequences.
  • Variants that are not hormonally-active fall within the scope of this invention, and include polypeptides that may or may not be substantially homologous with either a mature inhibin chain or prodomain sequence, but which are (l) immunologically cross-reactive with antibodies raised against the native counterpart or (2) capable of competing with such native counterpart polypeptides for cell surface receptor binding.
  • Hormonally inactive variants are produced by the recombinant or organic synthetic preparation of fragments, in particular the isolated B chains of inhibin, or by introducing amino acid sequence variations so that the molecules no longer demonstrate hormonal activity as defined above.
  • Immunological or receptor cross-reactivity means that the candidate polypeptide is capable of competitively inhibiting the binding of thehormonally-active analogue to its receptor and/or to polyclonal antisera raised against the hormonally-active analogue.
  • antisera are prepared in conventional fashion by injecting goats or rabbits S.C. with the hormonally-active analogue or derivative in complete Freunds adjuvant, followed by booster intraperitoneal or S.C. injections in incomplete Freunds.
  • the variants of inhibin include the pro and/or prepro sequences of the inhibin ⁇ or ⁇ chain precursors, or their immunologically or biologically active fragments, substantially free of the corresponding mature inhibin chains.
  • the sequences for porcine and human inhibin are known, for example, as published in European Patent Application 222,491.
  • the prepro sequence for the porcine a subunit precursor is the polypeptide comprised by residues 1 to about 230, while the ⁇ A subunit pro sequence is comprised by residues 1 to about 308. These sequences encompass prodo ain sequences.
  • the intact isolated prepro or prodomain ⁇ A , B B or ⁇ sequences are best synthesized in reco binant cell culture and the individual subcomponent domains are synthesized by routine methods of organic chemistry or by recombinant cell culture, for example as described in European Patent Application 222,491.
  • the site for introducing a sequence variation is predetermined, it is unnecessary that the mutation per sg be predetermined.
  • random mutagenesis may be conducted at the target codon or region and the expressed inhibin mutants screened for the optimal combination of desired activity.
  • Techniques formaking substitutionmutations atpredetermined sites in DNA having a known sequence are well known, for example Ml3 primer mutagenesis.
  • Mutagenesis is conducted by making amino acid insertions, usually on the order of about from 1 to 10 amino acid residues, or deletions of about from 1 to 30 residues. Substitutions, deletions, insertions or any subco bination may be combined to arrive at a final construct. Preferably, however, only substitution mutagenesis is conducted. Obviously, the mutations in the encoding DNA must not place the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure.
  • Covalentmodifications of inhibin, activin orprodomains are included within the scope hereof and include covalent or aggregative conjugates with other chemical moieties.
  • Covalent derivatives are prepared by linkage of functionalities to groups which are found in the inhibin ' amino acid side chains or at the N- or C- termini, by means known in the art.
  • these derivatives will include: aliphatic esters or amides of the carboxyl terminus or residues containing carboxyl side chains, a.g., aspartyl residues; O-acylderivatives of hydroxyl group-containing residues such as seryl or alanyl; and N-acyl derivatives of the amino terminal amino acid or a ino-group containing residues, ⁇ .g.
  • the acyl group is selected from the group of alkyl-moieties (including C3 to CIO normal alkyl) , thereby forming alkanoyl species,- and carbocyclic or heterocyclic compounds, thereby forming aroyl species.
  • the reactive groups preferably are difunctional compounds known per se for use in cross- linking proteins to insoluble matrices through reactive side groups, a.g. m-Maleimidobenzoyl-N-hydroxy succinimide ester. Preferred derivatization sites are at histidine residues.
  • activin-related peptides All of these variants of activin and inhibin, as well as inhibin itself, are intended to be within the scope of the term "activin-related peptides.”
  • the method used to introduce the compound will be any convenient method normally used to introduce pharmaceuticals into the bloodstream, such as by injection, bolus, infusion, and the like. Parenteral administration may also be utilized.
  • an effective dose of a compound according to the method of the present invention will depend on a number of factors, including the particular recipient and the severity of condition; thus the route of administration will be ultimately at the discretion of the attendant physician.
  • the diseases or conditions which may be treated include, but are not limited to, anemias, including AZT-induced anemia and chemotherapy- induced anemia, Diamond-Blackf n anemia, and the like.
  • the treatment may also be used in non-disease related conditions, such as during patient recovery after bone- marrow transplant, or to induce a pre-operative boost in red blood cells preparatory to antologous transfusions.
  • the formulation of the present invention comprises a compound as previously described together with one or more acceptable carriers therefor and, optionally other therapeutic ingredients.
  • the carriers must be acceptable in the sense of being compatible with other ingredients of the formulation and not deleterious to the recipient.
  • Activin or an activin-related peptide may be administered to the patient by any suitable technique, including parenteral, sublingual, topical intrapulmonary, and intranasal administration.
  • parenteral administration include intramuscular, subcutaneous, intravenous, intraarterial, and intraperitoneal administration.
  • compositions to be used in the therapy will be formulated and dosed in a fashion consistent with good medical practice taking into account the clinical condition of the individual patient, the cause of the condition in need of therapy, the site of delivery of the composition, the method of administration, the scheduling of administration, and other factors known to practitioners.
  • the "effective amount" for purposes herein is thus determined by such considerations.
  • the total pharmaceutically effective amount of the activin and/or activin-related peptide administered parenterally per dose will be in the range of about 50 ⁇ g/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to a great deal of therapeutic discretion.
  • the key factor in selecting an appropriate dose is the result obtained, as measured by increase in red blood cell production, which may be measured, for example by in vitro analysis of erythroids of the patient evidencing increase in the number of colonies/culture and/or the number of cells/colony after treatment.
  • the composition herein is also suitably administered by sustained release systems.
  • sustained release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma- ethyl-L-glutamate (U. Sidman, t al « / Biopolvmers. 22, 547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer, at al « . J. Biomed. Mater. Res. , __ ⁇ 161-211 (1981), and R. Langer, Chem.
  • Sustained release compositions also include liposomally entrapped activin or inhibin or a mixture thereof.
  • Such compositions are prepared by methods known per se: DE 3,218,121; Epstein, at al- , Proc. Natl. Acad. Sci. U.S.A., _Z ⁇ 3688-3692 (1985); Hwang, atal- , Proc. Natl. Acad. Sci. U.S.A.
  • the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal therapy.
  • the activin or activin- related peptide is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion) with a pharmaceutically acceptable carrier, i «a « , one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • a pharmaceutically acceptable carrier i «a « , one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the formulation preferablydoes not include oxidizing agents and other compounds that are known to be deleterious to polypeptides.
  • the formulations are prepared by contacting the activin or inhibin uniformly and intimately with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient.
  • carrier vehicles include water, saline. Ringer's solution, dextrose solution, and 5% human serum albumin.
  • Nonaqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.
  • the carrier can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g.
  • the activin is typically formulated into such vehicles at a concentration of about 10/ ⁇ g/ml to 100 ⁇ g/ml at physiological pH.
  • Activin for use in therapeutic administration must be sterile. Sterility is readily accomplished by sterile filtration through (a.g., 0.2 micron) membranes. Activin B ordinarily will be stored in unit or multidose containers, for example, sealed ampoules or vials, as an aqueous solution, as it is highly stable to thermal and oxidative denaturation. Lyophilized formulations for reconstitution are also acceptable.
  • Preferred unit dosage formulations are those containing a daily dose or a unit daily subdose, or an appropriate fraction thereof.
  • they may be added vitro to cell cultures taken from patients and the increase in the amount of red blood cell production measured to determine the potential efficacy of further treatment for the disorders.
  • the compounds may be thus used in vitro in cell cultures from patients to determine whether further addition of one of the compounds would result in continued increase or maintenance of red blood cell production.
  • the frequency and dosages of administration of the above compounds will depend upon when the compound is introduced, whether the subject is a fetus, infant or adult, the size and weight of the subject, the condition of the patient, and the like. Generally, injections or activin and/or activin-related peptide beginning at a dosage of about 50 ⁇ g/kg-10 mg/kg; and often as low as 50 ⁇ g/kg-100 ⁇ g/kg body weight per day during gestation, particularly prior to the thirty-second week of gestation in humans, will delay the ⁇ to ⁇ switching. Dosages, up to about 10 g/kg/day may be utilized at the discretion of the physician.
  • the method according to the present invention may be utilized i vivo, or in vitro as a diagnostic test by measuring the increase in red blood cell production in the culture as compared to a control sample cultured in absence of the activin, inhibin, or inhibin chain.
  • erythroid cultures such as that obtained from cord blood mononuclear cells in Iscove's ModifiedDulbcco'sMediumwith 0.9%methylcellulose, may be used as described by Stamatoyannopoulous et al., Blood. 54. 440-450 (1979) and Friedman et al., J. Clin. Invest.. 75. 1359-1368 (1985).
  • the following examples are provided by way of illustration, however, the invention is not intended to be limited in any manner thereby.
  • EXAMPLE Recombinantly produced human activin (produced as described in EP Publication No. 222,491, supra.) was used to test effect on cell colony growth in erythroid cultures from cord blood of normal infants. Samples were prepared containing 100 nanograms/ml activin and control. The results below show that activin consistently enhanced red blood cell production.

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Abstract

Procédé d'augmentation de la production de globules rouges. Le procédé est particulièrement adapté au traitement des symptomes cliniques de l'anémie, et il consiste à administrer au sujet une dose efficace d'activine, d'inhibine, d'une chaîne d'inhibine ou de mélanges de ces dernières.
PCT/US1991/006487 1990-09-13 1991-09-13 Procede d'augmentation de la production de globules rouges par traitement a l'aide d'activine ou de peptides apparentes a l'activine WO1992004913A1 (fr)

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US58264290A 1990-09-13 1990-09-13
US582,642 1990-09-13

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WO1992004913A1 true WO1992004913A1 (fr) 1992-04-02

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Cited By (31)

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GB2306481A (en) * 1995-10-21 1997-05-07 Univ Manchester Pharmaceutical comprising a stimulator of activin and/or inhibin
US5700640A (en) * 1994-09-16 1997-12-23 Basf Aktiengesellschaft Inducers of gamma globin gene expression and screening assays therefor
WO1998047526A1 (fr) * 1997-04-23 1998-10-29 Monash University Modulation de la croissance cellulaire par l'inhibine
US6011000A (en) * 1995-03-03 2000-01-04 Perrine; Susan P. Compositions for the treatment of blood disorders
US7265153B2 (en) 1998-02-11 2007-09-04 Faller Douglas V Compositions and methods for the treatment of cystic fibrosis
JP2010513506A (ja) * 2006-12-18 2010-04-30 アクセルロン ファーマ， インコーポレイテッド アクチビン−ＡｃｔＲＩＩアンタゴニストおよび赤血球レベルを増加させるためのその使用
US7910624B1 (en) 1995-03-03 2011-03-22 The Trustees Of Boston University Compositions for the treatment of blood disorders
EP2303917A4 (fr) * 2008-06-26 2012-01-25 Acceleron Pharma Inc Antagonistes d actriib et utilisations pour augmenter les taux d érythrocytes
US8252900B2 (en) 2004-07-23 2012-08-28 Acceleron Pharma Inc. Actriib-Fc polynucleotides, polypeptides, and compositions
US8343933B2 (en) 2007-02-02 2013-01-01 Acceleron Pharma, Inc. Variants derived from ActRIIB and uses therefor
EP2340031A4 (fr) * 2008-08-14 2013-01-09 Acceleron Pharma Inc Utilisation de pièges à gdf pour augmenter les taux d érythrocytes
US8367611B2 (en) 2007-09-18 2013-02-05 Acceleron Pharma Inc. Activin-actriia antagonists for inhibiting germ cell maturation
US8486403B2 (en) 2005-11-23 2013-07-16 Acceleron Pharma, Inc. Method of promoting bone growth by an anti-activin A antibody
US8618068B2 (en) 2009-12-08 2013-12-31 Trustees Of Boston University Methods and low dose regimens for treating red blood cell disorders
US8629109B2 (en) 2005-11-23 2014-01-14 Acceleron Pharma Inc. Method for promoting bone growth using activin-actriia antagonists
US8710016B2 (en) 2009-11-17 2014-04-29 Acceleron Pharma, Inc. ActRIIB proteins and variants and uses therefore relating to utrophin induction for muscular dystrophy therapy
US8895016B2 (en) 2006-12-18 2014-11-25 Acceleron Pharma, Inc. Antagonists of activin-actriia and uses for increasing red blood cell levels
US8993581B2 (en) 2009-09-24 2015-03-31 Trustees Of Boston University Methods for treating viral disorders
US9181533B2 (en) 2009-06-12 2015-11-10 Acceleron Pharma, Inc. Truncated ACTRIIB-FC fusion protein
US9439945B2 (en) 2008-08-14 2016-09-13 Acceleron Pharma Inc. Isolated nucleotide sequences encoding GDF traps
US9493556B2 (en) 2010-11-08 2016-11-15 Acceleron Pharma Inc. Actriia binding agents and uses thereof
US9526759B2 (en) 2007-02-01 2016-12-27 Acceleron Pharma Inc. Activin-actriia antagonists and uses for treating or preventing breast cancer
US9572865B2 (en) 2005-11-23 2017-02-21 Acceleron Pharma Inc. Activin-actriia antagonists and uses for treating multiple myeloma
US9790284B2 (en) 2009-06-08 2017-10-17 Acceleron Pharma Inc. Methods for increasing thermogenic adipocytes
US9850298B2 (en) 2014-06-13 2017-12-26 Acceleron Pharma Inc. Methods for treating ulcers in thalassemia syndrome with an ActRIIB polypeptide
US10195249B2 (en) 2012-11-02 2019-02-05 Celgene Corporation Activin-ActRII antagonists and uses for treating bone and other disorders
US10857152B2 (en) 2010-03-11 2020-12-08 Trustees Of Boston University Methods and compositions for treating viral or virally-induced conditions
US10953011B2 (en) 2019-05-31 2021-03-23 Viracta Therapeutics Inc. Methods of treating virally associated cancers with histone deacetylase inhibitors
US11471510B2 (en) 2014-12-03 2022-10-18 Celgene Corporation Activin-ActRII antagonists and uses for treating anemia
US11813308B2 (en) 2014-10-09 2023-11-14 Celgene Corporation Treatment of cardiovascular disease using ActRII ligand traps
US12194076B2 (en) 2016-07-27 2025-01-14 Acceleron Pharma Inc. Methods and compositions for treating myelofibrosis

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Cited By (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5700640A (en) * 1994-09-16 1997-12-23 Basf Aktiengesellschaft Inducers of gamma globin gene expression and screening assays therefor
US6011000A (en) * 1995-03-03 2000-01-04 Perrine; Susan P. Compositions for the treatment of blood disorders
US7910624B1 (en) 1995-03-03 2011-03-22 The Trustees Of Boston University Compositions for the treatment of blood disorders
US7713933B2 (en) 1995-10-21 2010-05-11 Renovo Limited Pharmaceutical composition containing an activin or inhibin stimulator
GB2306481A (en) * 1995-10-21 1997-05-07 Univ Manchester Pharmaceutical comprising a stimulator of activin and/or inhibin
WO1998047526A1 (fr) * 1997-04-23 1998-10-29 Monash University Modulation de la croissance cellulaire par l'inhibine
EP1011715A4 (fr) * 1997-04-23 2003-09-24 Prostate Diagnostics Pty Ltd Modulation de la croissance cellulaire par l'inhibine
US7265153B2 (en) 1998-02-11 2007-09-04 Faller Douglas V Compositions and methods for the treatment of cystic fibrosis
US8252900B2 (en) 2004-07-23 2012-08-28 Acceleron Pharma Inc. Actriib-Fc polynucleotides, polypeptides, and compositions
US9138459B2 (en) 2004-07-23 2015-09-22 Acceleron Pharma Inc. ACTRIIB-FC polynucleotides, polypeptides, and compositions
US10239940B2 (en) 2005-11-23 2019-03-26 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
US9163075B2 (en) 2005-11-23 2015-10-20 Acceleron Pharma Inc. Isolated polynucleotide that encodes an ActRIIa-Fc fusion polypeptide
US11129873B2 (en) 2005-11-23 2021-09-28 Acceleron Pharma Inc. Method for promoting bone growth using activin-actriia antagonists
US9572865B2 (en) 2005-11-23 2017-02-21 Acceleron Pharma Inc. Activin-actriia antagonists and uses for treating multiple myeloma
US8486403B2 (en) 2005-11-23 2013-07-16 Acceleron Pharma, Inc. Method of promoting bone growth by an anti-activin A antibody
US9480742B2 (en) 2005-11-23 2016-11-01 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
US8629109B2 (en) 2005-11-23 2014-01-14 Acceleron Pharma Inc. Method for promoting bone growth using activin-actriia antagonists
US10071135B2 (en) 2005-11-23 2018-09-11 Acceleron Pharma Inc. Method of identifying an agent that promotes bone growth or increases bone density
JP2017155064A (ja) * 2006-12-18 2017-09-07 アクセルロン ファーマ， インコーポレイテッド アクチビン−ＡｃｔＲＩＩアンタゴニストおよび赤血球レベルを増加させるためのその使用
JP2013127002A (ja) * 2006-12-18 2013-06-27 Acceleron Pharma Inc アクチビン−ＡｃｔＲＩＩアンタゴニストおよび赤血球レベルを増加させるためのその使用
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