JP2001500362A - 増殖因子に対する高親和性オリゴヌクレオチドリガンド - Google Patents
増殖因子に対する高親和性オリゴヌクレオチドリガンドInfo
- Publication number
- JP2001500362A JP2001500362A JP08536646A JP53664696A JP2001500362A JP 2001500362 A JP2001500362 A JP 2001500362A JP 08536646 A JP08536646 A JP 08536646A JP 53664696 A JP53664696 A JP 53664696A JP 2001500362 A JP2001500362 A JP 2001500362A
- Authority
- JP
- Japan
- Prior art keywords
- nucleic acid
- ligand
- pdgf
- hkgf
- tgfβ1
- 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.)
- Granted
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- 229960000278 theophylline Drugs 0.000 description 1
- 238000005382 thermal cycling Methods 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. TGFβに対する核酸リガンドの同定方法であって、 a) 核酸の候補混合物をTGFβに接触させ、ここで候補混合物よりTGF βへの親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、TGFβへの結合について比較的高 い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうして TGFβの核酸リガンドを同定する工程、 からなる上記方法。 2. d)工程a)、b)およびc)を繰り返す工程を、さらに含む請求の範囲 第1項に記載の方法。 3. 核酸の候補混合物は1本鎖核酸からなる、請求の範囲第1項に記載の方法 。 4. 1本鎖核酸はリボ核酸である、請求の範囲第3項に記載の方法。 5. 核酸は修飾核酸からなる、請求の範囲第4項に記載の方法。 6. 核酸は、2’−アミノ(2’−NH2)修飾リボ核酸である、請求の範囲 第5項に記載の方法。 7. 核酸は2’−F修飾リボ核酸である、請求の範囲第5項に記載の方法。 8. 核酸は2’−NH2−UTP、2’−F−CTP修飾リボ核酸である、請 求の範囲第5項に記載の方法。 9. 核酸は2’−F−UTP、2’−NH2−CTP修飾リボ核酸である、請 求の範囲第5項に記載の方法。 10.1本鎖核酸はデオキシリボ核酸である、請求の範囲第3項に記載の方法。 11.TGFβ核酸リガンドの薬剤として有効な量を投与することからなる、T GFβ媒介疾患の治療方法。 12.TGFβ核酸リガンドは、請求の範囲第1項に記載の方法により同定され る、請求の範囲第11項に記載の方法。 13.TGFβ1核酸リガンドの薬剤として有効な量を投与することからなる、 TGFβ1媒介疾患の治療方法。 14.TGFβ1核酸リガンドは、請求の範囲第1項に記載の方法により同定さ れる、請求の範囲第13項に記載の方法。 15.リガンドは表3と6に記載のリガンド(配列番号12〜42;55〜89 )から選択される、請求の範囲第14項に記載の方法。 16.精製され単離された、天然に存在しない、TGFβに対する核酸リガンド 。 17.精製され単離された、天然に存在しない、TGFβ1に対する核酸リガン ド。 18.核酸リガンドは1本鎖である、請求の範囲第17項に記載の、精製され単 離された、天然に存在しない核酸リガンド。 19.核酸リガンドはリボ核酸である、請求の範囲第18項に記載の、精製され 単離された、天然に存在しない核酸リガンド。 20.核酸リガンドはデオキシリボ核酸である、請求の範囲第18項に記載の、 精製され単離された、天然に存在しない核酸リガンド。 21.a)核酸の候補混合物をTGFβに接触させ、ここで候補混合物よりTG Fβへの親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、TGFβへの結合について比較的高 い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうして TGFβの核酸リガンドを同定する工程、 からなる方法により同定されるTGFβに対する核酸リガンド。 22.a)核酸の候補混合物をTGFβ1接触させ、ここで候補混合物よりTG Fβ1への親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、TGFβ1への結合について比較的 高い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうし てTGFβ1の核酸リガンドを同定する工程、 からなる方法により同定されるTGFβ1に対する核酸リガンド。 23.リガンドは、表3に記載の配列(配列番号12〜42)よりなる群から選 択される、請求の範囲第19項に記載の、精製され単離された、天然に存在しな い、TGFβ1に対するリボ核酸リガンド。 24.リガンドは、表3に記載の配列(配列番号12〜42)よりなる群から選 択されるリガンドと、実質的に相同的であり、TGFβ1に結合する実質的に同 じ能力を有する、請求の範囲第19項に記載の、精製され単離された、天然に存 在しない、TGFβ1に対するリボ核酸リガンド。 25.リガンドは、表3に記載の配列(配列番号12〜42)よりなる群から選 択されるリガンドと、実質的に同じ構造を有し、TGFβ1に結合する実質的に 同じ能力を有する、請求の範囲第19項に記載の、精製され単離された、天然に 存在しない、TGFβ1に対するリボ核酸リガンド。 26.リガンドは、表6に記載の配列(配列番号55〜89)よりなる群から選 択される、請求の範囲第20項に記載の、精製され単離された、天然に存在しな い、TGFβ1に対するデオキシリボ核酸リガンド。 27.リガンドは、表6に記載の配列(配列番号55〜89)よりなる群から選 択されるリガンドと、実質的に相同的であり、TGFβ1に結合する実質的に同 じ能力を有する、請求の範囲第20項に記載の、精製され単離された、天然に存 在しない、TGFβ1に対するデオキシリボ核酸リガンド。 28.リガンドは、表6に記載の配列(配列番号55〜89)よりなる群から選 択されるリガンドと、実質的に同じ構造を有し、TGFβ1に結合する実質的に 同じ能力を有する、請求の範囲第20項に記載の、精製され単離された、天然に 存在しない、TGFβ1に対するデオキシリボ核酸リガンド。 29.PDGFに対する核酸リガンドの同定方法であって、 a) 核酸の候補混合物をPDGFに接触させ、ここで候補混合物よりPDG Fへの親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、PDGFへの結合について比較的高 い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうして PDGFの核酸リガンドを同定する工程、 からなる上記方法。 30.d)工程a)、b)およびc)を繰り返す工程を、さらに含む請求の範囲 第29項に記載の方法。 31.核酸の候補混合物は1本鎖核酸からなる、請求の範囲第29項に記載の方 法。 32.1本鎖核酸はリボ核酸である、請求の範囲第31項に記載の方法。 33.1本鎖核酸はデオキシリボ核酸である、請求の範囲第31項に記載の方法 。 34.核酸は修飾核酸からなる、請求の範囲第32項に記載の方法。 35.核酸は、2’−アミノ(2’−NH2)修飾リボ核酸である、請求の範囲 第34項に記載の方法。 36.核酸は2’−フルオロ(2’−F)修飾リボ核酸である、請求の範囲第3 4項に記載の方法。 37.PDGFの核酸リガンドの薬剤として有効な量を投与することからなる、 PDGF媒介疾患の治療方法。 38.核酸リガンドは、請求の範囲第29項に記載の方法により同定される、請 求の範囲第37項に記載の方法。 39.核酸リガンドは、表8と13、および図3、4、と10に記載のリガンド (配列番号93〜124;128〜176)の1つから選択される、請求の範囲 第38項に記載の方法。 40.精製され単離された、天然に存在しない、PDGFに対する核酸リガンド 。 41.核酸リガンドは1本鎖である、請求の範囲第40項に記載の、精製され単 離された、天然に存在しない核酸リガンド。 42.核酸リガンドはリボ核酸である、請求の範囲第41項に記載の、精製され 単離された、天然に存在しない核酸リガンド。 43.核酸リガンドはデオキシリボ核酸である、請求の範囲第41項に記載の、 精製され単離された、天然に存在しない核酸リガンド。 44.a)核酸の候補混合物をPDGFに接触させ、ここで候補混合物よりPD GFへの親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、PDGFへの結合について比較的高 い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうして PDGFの核酸リガンドを同定する工程、 からなる方法により同定されるPDGFに対する核酸リガンド。 45.リガンドは、表13に記載の配列(配列番号128〜170)よりなる群 から選択される、請求の範囲第42項に記載の、精製され単離された、天然に存 在しない、PDGFに対するリボ核酸リガンド。 46.リガンドは、表13に記載の配列(配列番号128〜170)よりなる群 から選択されるリガンドと、実質的に相同的であり、PDGFに結合する実質的 に同じ能力を有する、請求の範囲第42項に記載の、精製され単離された、天然 に存在しない、PDGFに対するリボ核酸リガンド。 47.リガンドは、表13に記載の配列(配列番号128〜170)よりなる群 から選択されるリガンドと、実質的に同じ構造を有し、PDGFに結合する実質 的に同じ能力を有する、請求の範囲第42項に記載の、精製され単離された、天 然に存在しない、PDGFに対するリボ核酸リガンド。 48.リガンドは、表8と9、および図3、4、と10に記載の配列(配列番号 93〜124、171〜176)よりなる群から選択される、請求の範囲第43 項に記載の、精製され単離された、天然に存在しない、PDGFに対するデオキ シリボ核酸リガンド。 49.リガンドは、表8と9、および図3、4、と10に記載の配列(配列番号 93〜124、171〜176)よりなる群から選択されるリガンドと、実質的 に相同的であり、PDGFに結合する実質的に同じ能力を有する、請求の範囲第 43項に記載の、精製され単離された、天然に存在しない、PDGFに対するデ オキシリボ核酸リガンド。 50.リガンドは、表8と9、および図3、4、と10に記載の配列(配列番号 93〜124、171〜176)よりなる群から選択されるリガンドと、実質的 に同じ構造を有し、PDGFに結合する実質的に同じ能力を有する、請求の範囲 第43項に記載の、精製され単離された、天然に存在しない、PDGFに対する デオキシリボ核酸リガンド。 51.図3(配列番号171)に記載の保存構造からなる、請求の範囲第40項 に記載の、精製され単離された、天然に存在しない、PDGFに対する核酸リガ ンド。 52.hKGFに対する核酸リガンドの同定方法であって、 a) 核酸の候補混合物をhKGFに接触させ、ここで候補混合物よりhKG Fへの親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、hKGFへの結合について比較的高 い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうして hKGFの核酸リガンドを同定する工程、 からなる上記方法。 53.d)工程a)、b)およびc)を繰り返す工程を、さらに含む請求の範囲 第52項に記載の方法。 54.核酸の候補混合物は1本鎖核酸からなる、請求の範囲第52項に記載の方 法。 55.1本鎖核酸はリボ核酸である、請求の範囲第54項に記載の方法。 56.核酸は修飾核酸からなる、請求の範囲第55項に記載の方法。 57.核酸は、2’−アミノ(2’−NH2)修飾リボ核酸である、請求の範囲 第56項に記載の方法。 58.核酸は2’−F修飾リボ核酸である、請求の範囲第56項に記載の方法。 59.hKGF核酸リガンドの薬剤として有効な量を投与することからなる、h KGF媒介疾患の治療方法。 60.核酸リガンドは、請求の範囲第52項に記載の方法により同定される、請 求の範囲第59項に記載の方法。 61.核酸リガンドは、表16と23に記載のリガンド(配列番号189〜26 2、272〜304)の1つから選択される、請求の範囲第60項に記載の方法 。 62.hKGF受容体媒介細胞増殖を阻害する能力について試験化合物を測定す る方法であって、 a)試験化合物をhKGF核酸リガンドおよびケラチン細胞増殖因子と接触させ る工程;および b)hKGF核酸リガンドとケラチン細胞増殖因子の間の結合を阻害する試験化 合物の能力を検出する工程、 からなる上記方法。 63.増殖因子とその原形質膜結合受容体との相互作用を阻害する能力について 試験化合物を測定する方法であって、 a) 原形質膜結合受容体を含有する細胞を可溶化する工程; b) 細胞の原形質膜結合抽出物を作成する工程; c) 抽出物を、標識された増殖因子のみおよび試験化合物の存在下で反応さ せて、複合体を形成させる工程; d) 複合体を電気泳動により未変性の条件下で解析する工程; e) イメージングにより複合体を可視化する工程;および e) 抽出物と標識した増殖因子とのイメージを、試験化合物の存在下での抽 出物のイメージと比較して、試験化合物が増殖因子と原形質膜結合受容体との間 の相互作用を阻害したか否かを測定する工程、 からなる、上記方法。 64.増殖因子はhKGFである、請求の範囲第63項に記載の方法。 65.細胞はPC−3細胞である、請求の範囲第63項に記載の方法。 66.試験化合物は小分子、ペプチド、および抗体よりなる群から選択される、 請求の範囲第63項に記載の方法。 67.イメージングは、オートラジオグラフィーおよびホスホルイメージングよ りなる群から選択される、請求の範囲第63項に記載の方法。 68.細胞が増殖因子原形質膜結合受容体を発現するかどうかを調べるために細 胞を測定する方法であって、 a) 細胞を可溶化する工程; b) 細胞の原形質膜抽出物を作成する工程; c) 原形質膜抽出物を標識した増殖因子と反応させる工程; d) 原形質膜抽出物と標識した増殖因子との間の反応を、未変性条件下の電 気泳動で解析する工程; e) 工程d)の電気泳動を標識した増殖因子の電気泳動と比較する工程;お よび f) 標識した増殖因子単独の移動度に比較して、変化した移動度を有する複 合体が形成されたかどうかを調べるために、電気泳動の結果を可視化する工程、 からなる上記方法。 69.精製され単離された、天然に存在しない、hKGFに対する核酸リガンド 。 70.核酸リガンドは1本鎖である、請求の範囲第69項に記載の、精製され単 離された、天然に存在しない核酸リガンド。 71.核酸リガンドはリボ核酸である、請求の範囲第70項に記載の、精製され 単離された、天然に存在しない核酸リガンド。 72.a)核酸の候補混合物をhKGFに接触させ、ここで候補混合物よりhK GFへの親和性が上昇している核酸を、残りの候補混合物から分離する工程、 b) 残りの候補混合物から親和性が上昇した核酸を分離する工程、および c) 親和性が上昇した核酸を増幅して、hKGFへの結合について比較的高 い親和性と特異性を有する核酸配列が濃縮された核酸の混合物を得て、こうして hKGFの核酸リガンドを同定する工程、 からなる方法により同定されるhKGFに対する核酸リガンド。 73.リガンドは、表16と23に記載の配列(配列番号189〜262、27 2〜304)よりなる群から選択される、請求の範囲第71項に記載の、精製さ れ単離された、天然に存在しない、hKGFに対するリボ核酸リガンド。 74.リガンドは、表16と23に記載の配列(配列番号189〜262、27 2〜304)よりなる群から選択されるリガンドと、実質的に相同的であり、h KGFに結合する実質的に同じ能力を有する、請求の範囲第71項に記載の、精 製され単離された、天然に存在しない、hKGFに対するリボ核酸リガンド。 75.リガンドは、表16と23に記載の配列(配列番号189〜262、27 2〜304)よりなる群から選択されるリガンドと、実質的に同じ構造を有し、 hKGFに結合する実質的に同じ能力を有する、請求の範囲第71項に記載の、 精製され単離された、天然に存在しない、hKGFに対するリボ核酸リガンド。 76.リガンドは、配列番号267に示す配列を有する、精製され単離された、 天然に存在しない、hKGFに対するリボ核酸リガンド。
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US6207816B1 (en) | 2001-03-27 |
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WO1996038579A1 (en) | 1996-12-05 |
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EP0828849A4 (en) | 2005-01-19 |
CA2221318A1 (en) | 1996-12-05 |
EP1741780A2 (en) | 2007-01-10 |
EP0828849A1 (en) | 1998-03-18 |
JP4531132B2 (ja) | 2010-08-25 |
AU5883996A (en) | 1996-12-18 |
US20030180744A1 (en) | 2003-09-25 |
US20060229273A1 (en) | 2006-10-12 |
DE69636656T2 (de) | 2007-10-04 |
EP0828849B1 (en) | 2006-10-25 |
ATE343638T1 (de) | 2006-11-15 |
JP2007049997A (ja) | 2007-03-01 |
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