JP2011518133A - Sykチロシンキナーゼタンパク質が関与している代謝経路を阻害する分子および前記分子を同定するための方法 - Google Patents
Sykチロシンキナーゼタンパク質が関与している代謝経路を阻害する分子および前記分子を同定するための方法 Download PDFInfo
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Abstract
Description
(i) 抗体断片 G4G11(配列番号 2),または
(ii) 抗体断片 G4E4(配列番号 3),または
(iii) ヒト Syk チロシンキナーゼ タンパク質と、配列番号 1で表されるヒト Syk チロシンキナーゼ タンパク質のアミノ酸配列の残基65から74の少なくとも一つを含むエピトープ上で結合する抗体または抗体断片,または
(iv) ヒト Syk チロシンキナーゼ タンパク質と結合し、抗体断片G4G11またはG4E4とヒト Syk チロシンキナーゼ タンパク質 (配列番号 1)との結合を少なくとも10%阻害する抗体または抗体断片、
とヒト Syk チロシンキナーゼ タンパク質または動物における任意のそのバリアント(例えば、マウスの Syk チロシンキナーゼ タンパク質)との結合であり、前記配列は図 8B (配列番号 4)に記載され、これはヒトまたは動物においてSykが関与している代謝経路に依存する状態の予防または治療のための医薬品として用いられる。
R1は、任意に置換された芳香族基,または任意に置換された少なくとも 一つのS, OまたはN 原子を含んでいる複素環であり;
R2は、任意に置換された芳香族基, 任意に置換された複素環, アミン基を含んでいる任意に飽和の炭素鎖, 任意に置換された芳香族基を含んでいる任意に飽和の炭素鎖または少なくとも 一つのS, OまたはN 原子を含んでいる任意に置換された複素環を含んでいる任意に飽和の炭素鎖であり;
R3は、任意に置換されたフェニル, 2-ピリジニル, 3-ピリジニルまたは4-ピリジニル基であり;
n = 0または1; n' = 0または1であり;
R4は、1 から5の炭素原子を含み、任意に芳香族基で置換された任意で飽和の炭素鎖;
R5は、任意に置換された芳香族基または任意に置換されたアミン基であり;
R6は、水素原子, アルコキシ 基, アルキル基またはハロゲンであり;
R7は、水素原子, アルコキシ 基, アルキル基またはハロゲンであり;
R8は、水素原子, アルコキシ 基, アルキル基またはハロゲンであり;
m = 0, 1または2であり;
R9は水素原子であり、R10は任意に置換されたフェニル基であり,またはR9およびR10は同じ任意に置換された複素環の部分であり,またはR9およびR10は同じ任意に置換された芳香族基の部分であり;
R11は、水素原子, アルコキシ基またはアルキル基であり;
R12は、水素原子, アルコキシ基またはアルキル基であり;
R13は、水素原子またはアルキルまたはアルコキシ基であり;
R14は、水素原子またはアルキルまたはアルコキシ基であり;
Aは、酸素またはイオウ原子であり;
R15は、1, 2または3つの炭素原子を含み、任意に置換された芳香族基, 任意に置換された複素環または任意に置換された複素環に属しているアミン 基で任意に置換された任意に飽和の炭素鎖であり;
R16は、水素原子, ハロゲンまたはアルコキシ基であり;
R17は、水素原子, アルコキシ基またはアセトキシ基である。
FまたはCl 原子, メチルまたはエチル基, N,N-ジメチル-スルホンアミドまたはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基から選択される二つの基で任意に置換されたフェニル基,
以下の基,
メチル, エチル, ヒドロキシ, メトキシまたはエトキシ基で任意に置換されたチオフェン基;
式 (I)を有している分子のR2基は、以下に記載する基から選択される、即ち:
以下の基,
以下の基,
以下の基,
非置換の2-ピリジニル, 3-ピリジニルまたは4-ピリジニル基,
ベンゾキシ基, および/またはヒドロキシル基, および/またはメチル基, および/またはエチル基, および/またはプロピル基, および/または一または二のBr, FまたはCl 原子, および/または一ないし三のヒドロキシル, メトキシまたはエトキシ基で任意に置換されたフェニル基。
式 (III)を有している分子のR9基は水素原子であり、R10基は任意に置換されたフェニル基であり,またはR9およびR10基は2の窒素原子および4の炭素原子を含んでいる同じ任意に置換された複素環に属し;
式 (III)を有している分子のR11基は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
式 (III)を有している分子のR12基は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
式 (III)を有している分子のR13基は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
および式 (III)を有している分子のR14基は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基である。
これらの分子の何れかである場合、糖質コルチコイド アゴニストと組み合わせて使用されない。
a) 50 および2500 Daの間の分子量を有している候補の有機分子バンクから、Syk タンパク質とSyk タンパク質の立体的な腔において結合しやすく、上記の式 C-13, I, II, III, IVまたは1 から87を有している分子から選択される分子をスクリーニングすることと;
b) a)で同定された分子から、抗体または抗体断片 (i), (ii), (iii)または(iv) とSyk タンパク質との結合をインビトロで少なくとも 5%, 好ましくは 少なくとも 10%、例えば、 少なくとも 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80または85 %阻害する能力のあるものから選択すること。
例 1 アナフィラキシーショックを予防するための経口投与に潜在的に適切な分子 C-13の同定。
発明者は、scFv G4G11 とSykとの会合を置換する能力のある小分子を同定するためのADA (抗原置換アッセイ)法を開発した。3000の化学的な分子バンクのメンバーのなかで、15の小分子がscFv G4G11およびSykの結合と競合する能力があることが証明された。これらの化合物のなかで以下C-13 (図 1A)と称される化合物は、推定のIC50が4 μM の最大の阻害ポテンシャルを示した(図 1B)。この結果は、蛍光分光学 (または分光蛍光分析)の手段でC-13のSykに対するインビトロ親和性を測定することで得られた4.8 μMと等しい解離定数値 (またはKd)と一致している(図 1B)。C-13の作用様式を理解するため、発明者は最初にSPOT法を用いてG4G11の結合サイトを同定した16。SykのN末端 SH2 ドメインに位置し、アミノ酸 65-74を含み、マウス, ラット およびヒトの配列において100%保存されたエピトープが同定された。
G4G11との機能的な類似性を検査するために、発明者はマスト細胞の活性化におけるC-13の生物学的効果を探索した。RBL-2H3 細胞をC-13とインキュベーションすることによって、Sykのリン酸化およびFcεRI-誘導性のキナーゼ活性は影響されなかった(図2A)。それ故、基本的にSyk-依存性であることが知られている全ての細胞タンパク質のチロシンリン酸化の全体的なレベルは正常であった(図2B, C)。イントラボディーG4G11と類似して、C-13は、Btkのリン酸化およびFcεRI-誘導性のキナーゼ活性(図2A)およびPLC-γ1 および PLC-γ2(マスト細胞に発現される二つのPLC-γ アイソフォーム)のリン酸化を阻害した(図2A, C)。PTK Lynは、Syk および Btkの双方をリン酸化し、完全な活性化を生じ、引き続きPLC-γのリン酸化を生じる18。C-13がFcεRI-依存性の Lyn 活性化に影響しないならば(図2A)、Btk および PLC-γ リン酸化のレベルの減少が上流のPTKの近傍におけるそれらの正しい位置に関連する欠陥に起因させることができることを結論付けることができる。
マスト細胞において、シグナル伝達 カスケード Fyn/Gab2/PI3Kは、PI3Kの活性化および原形質膜にプレクストリン相同ドメイン (PH)を含んでいる幾つかのタンパク質(Btk および PLC-γを含む)をリクルートするPI-3,4,5-P3の産生を生じる19。Akt(PI3Kの活性マーカー)のリン酸化の分析によって、C-13が、Fyn-依存的な カスケードに影響しないことが示され(図2B, C)、Btk および PLC-γのリン酸化のレベルの減少はそれらの膜の配置における欠陥が原因ではないことを示唆している(これはカルシウム流の増加に必須の因子であることが知られている)20。
SLP-76 とVav および/または Nckとの会合は、マスト細胞における至適な MAPキナーゼ 活性化に役割がある27。C-13が僅かにMAPキナーゼ活性化に影響することを発明者は実証した(リン酸化 レベルを介した評価)、つまり: 高い C-13 濃度はERK1/2のリン酸化レベルを減少させ、他方でp38 および JNKのリン酸化レベルは正常なままである(図2B, C)。
Btk および VavとSLP-76の結合は、膜, カルシウムの移動性および顆粒のエキソサイトーシスにおけるPLC-γ 活性の制御に重要である27, 28。PLC-γ とLATの会合がC-13で用量依存的な様式で阻害されたことを発明者は実証した(図2A)。PLC-γ1およびPLC-γ2 のリン酸化における欠陥と一致して、マスト細胞は、FcεRI 結合に応答したカルシウム流の範囲が減少したこと(図3A)、BMMC (「骨髄由来のマスト細胞」)細胞における及びRBL-2H3 細胞株における早期及び遅延性のFcεRI-誘導性のアレルギー応答も、β-ヘキソサミニダーゼ 放出およびTNF-α 分泌の測定に基づいて、用量依存的な様式で弱くなったことを示した(図3B, C, D)。また、C-13がマスト細胞に毒性作用がないことを結果は実証した。実際、イオノマイシン-誘導性の脱顆粒 (図3B),またはBMMC 細胞の生存度 (図 10を参照されたい)は、C-13での治療により検出可能な程度に影響されなかった。さらにまた、マスト細胞の活性化で観察された欠陥は、FcεRI 表面発現のレベルの減少が原因ではなく、フローサイトメトリー分析はC-13とインキュベーションした細胞が対照細胞のものと類似するFcεRIレベルを発現することを指摘している(図3E)。
最終的に、これらの観察をインビボでのマスト細胞の機能に拡張するために、発明者は、BALB/cマウスにおいてDNP-特異的な IgE 分子の投与とつづくDNP-KLH ハプテンでの静脈内刺激により誘導した受動性の全身 (PSA) および 皮膚のアナフィラキシー (PCA)におけるC-13の効果を試験した。これによって、即時型の心肺の変化および血管透過性の増加により示されるような全身性アナフィラキシーが模倣された。全身性アナフィラキシーの強度は、抗原投与につづく体温の降下および血管透過性の増加の両方を測定することによって決定された。C-13の経口投与後(抗原刺激の前)、動物は、毒性の明らかな兆候もなく健常であるように思われた。100 mg/kgのC-13の単一経口用量の投与によって、低体温が阻止され、動物の回復が促進された(図4A)。エバンスブルーの血管外遊出の定量に基づいて、C-13が血管透過性の増加を110 mg/kgの推定IC50で阻害することが決定された(図4B および 4C)。C-13は、25 μMの推定IC50のPCAにおける阻害効果を実証した(図4D)。
CB ref: ChemBridge reference;
Rank: インシリコドッキング後の1000の最良の分子のリストにおける各分子のランク;
In vit. inhib.: 各分子でのscFv G4G11 とSykとのインビトロ結合の置換をADA法で取得した際の平均阻害%;
Degran.IC50: マスト細胞の脱顆粒を50%阻害する濃度;
Kd: Sykについてインビトロで分光蛍光分析で測定された解離定数
No.: 発明者により割り当てられたナンバー;
Gp: 分子が所属するグループ。
薬学的な標的になりそうな立体的な腔を、Q-SiteFinder 12 および ICM 13を用いて予測した。分子 C-13を、LigおよびFit 14 およびSurflex 15を用いてドッキングさせた。最初の 20 ポジションを分析し、コンセンサスポジションを図1Aに示した。イメージをPyMolで作製した。
平均の数値データを、平均±標準偏差(SD)として表した。スチューデントのt-検定を使用して、グループ間の統計学的な有意差を決定した。
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Claims (30)
- ヒト Syk タンパク質のポジション 68に位置するアルギニン残基およびポジション121 および 155に位置する二つのグルタミン酸残基を含んでいる立体的な腔においてSyk チロシンキナーゼ タンパク質(その配列は配列番号 1に示される)と結合し、少なくとも 10%のインビトロ結合を阻害する能力があり、該インビトロ結合は、
(i) 抗体断片 G4G11(配列番号 2),または
(ii) ヒト Syk チロシンキナーゼ タンパク質と、配列番号 1で表されるヒト Syk チロシンキナーゼ タンパク質のアミノ酸配列の残基65から74の少なくとも一つを含むエピトープで結合する抗体または抗体断片,または
(iii) ヒト Syk チロシンキナーゼ タンパク質と結合し、抗体断片G4G11とヒト Syk チロシンキナーゼ タンパク質 (配列番号 1)との結合を少なくとも10%阻害する抗体または抗体断片、
とヒト Syk チロシンキナーゼ タンパク質または動物における任意のそのバリアントとの結合であり、ヒトまたは動物においてSykが関与している代謝経路に依存するコンディションの予防または治療のための分子であって、次の式を有している分子 C-13;
R1は、任意に置換された芳香族基,または任意に置換された少なくとも 一つのS, OまたはN 原子を含んでいる複素環であり;
R2は、任意に置換された芳香族基, 任意に置換された複素環, アミン基を含んでいる任意に飽和の炭素鎖, 任意に置換された芳香族基を含んでいる任意に飽和の炭素鎖または少なくとも 一つのS, OまたはN 原子を含んでいる任意に置換された複素環を含んでいる任意に飽和の炭素鎖であり;
R3は、任意に置換されたフェニル, 2-ピリジニル, 3-ピリジニルまたは4-ピリジニル基であり;
又は
n = 0または1; n' = 0または1であり;
R4は、1 から5の炭素原子を含み、任意に芳香族基で置換された任意で飽和の炭素鎖;
R5は、任意に置換された芳香族基または任意に置換されたアミン基であり;
R6は、水素原子, アルコキシ 基, アルキル基またはハロゲンであり;
R7は、水素原子, アルコキシ 基, アルキル基またはハロゲンであり;
R8は、水素原子, アルコキシ 基, アルキル基またはハロゲンであり;
又は
m = 0, 1または2であり;
R9は水素原子であり、R10は任意に置換されたフェニル基であり,またはR9およびR10は同じ任意に置換された複素環の部分であり,またはR9およびR10は同じ任意に置換された芳香族基の部分であり;
R11は、水素原子, アルコキシ基またはアルキル基であり;
R12は、水素原子, アルコキシ基またはアルキル基であり;
R13は、水素原子またはアルキルまたはアルコキシ基であり;
R14は、水素原子またはアルキルまたはアルコキシ基であり;
又は
Aは、酸素またはイオウ原子であり;
R15は、1, 2または3つの炭素原子を含み、任意に置換された芳香族基, 任意に置換された複素環または任意に置換された複素環に属しているアミン 基で任意に置換された任意に飽和の炭素鎖であり;
R16は、水素原子, ハロゲンまたはアルコキシ基であり;
R17は、水素原子, アルコキシ基またはアセトキシ基であり;
又は
- 請求項1に記載の分子であって、Syk チロシンキナーゼ タンパク質とその触媒ドメインの外側に位置する部位で結合する分子。
- 前記抗体または抗体断片は、ヒト Syk チロシンキナーゼ タンパク質と、配列番号 1に表されるヒト Syk チロシンキナーゼ タンパク質のアミノ酸配列の残基65から74の少なくとも5つを含むエピトープ上で結合する、請求項1または2に記載の分子。
- 請求項1, 2または3に記載の分子であって、前記立体的な腔は、更にヒト Syk タンパク質のポジション9に位置するセリン残基, ポジション 43に位置するグルタミン残基, ポジション51に位置するフェニルアラニン残基, ポジション66に位置するイソロイシン残基, ポジション 67 および 69に位置するグルタミン酸残基, ポジション 70に位置するロイシン残基, ポジション 71に位置するアスパラギン残基, ポジション 72に位置するグリシン残基, ポジション 73に位置するスレオニン残基, ポジション 74に位置するチロシン残基およびポジション 75に位置するアラニン残基を含む(その配列は配列番号 1で示される)分子。
- 請求項1〜4の何れか一項に記載の分子であって、I型過感受性反応の予防または治療のため使用される分子。
- 請求項5に記載の分子であって、IgE-依存的なマスト細胞の脱顆粒を阻害する分子。
- 請求項6に記載の分子であって、1ng/ml および 1 mg/mlの間の濃度でインビトロでマスト細胞の脱顆粒を50%阻害(IC50)する能力がある分子。
- 請求項5〜7の何れか一項に記載の分子であって、前記Sykが関与している代謝経路は、マスト細胞または好塩基球の活性化経路である分子。
- 請求項5〜8の何れか一項に記載の分子であって、前記コンディションは、アレルギー性喘息, アレルギー性結膜炎, アレルギー性鼻炎, アナフィラキシー, 血管性浮腫, じんま疹, 好酸球増加症または抗生物質のアレルギーである分子。
- 請求項5〜9の何れか一項に記載の分子であって、マスト細胞の脱顆粒および/または I型過感受性反応を生じるもの以外のヒト Syk タンパク質 (配列番号 1)が関与している代謝経路に影響を有さない分子。
- 請求項10に記載の分子であって、胸腺依存性の抗原による免疫化につづく抗体応答または好中球依存的Sykリクルートに影響を有さない分子。
- 請求項1〜4の何れか一項に記載の分子であって、前記Sykが関与している代謝経路は、Bリンパ球, Tリンパ球, 好中球, 好酸球, NK細胞, 血小板, 赤血球, 破骨細胞, 上皮細胞または癌細胞の活性化経路である分子。
- 請求項12に記載の分子であって、前記コンディションは、関節リウマチ, 自己免疫疾患, 炎症または癌である分子。
- 請求項1〜13の何れか一項に記載の分子であって、更なる治療上の分子と組み合わせて使用される分子。
- 請求項14に記載の分子であって、前記更なる治療上の分子は、Sykが関与している代謝経路に依存するコンディションの予防または治療にも使用される分子。
- 前記更なる治療上の分子はSykが関与している代謝経路に非依存のコンディションの予防または治療のため使用される分子である、請求項14に記載の分子。
- 請求項1〜16の何れか一項に記載の分子であって、口, 舌下, 鼻, 眼球, 局所, 静脈内, 腹腔内, 皮下の経路, エアロゾルまたは吸入で投与されることが意図される分子。
- 請求項1〜17の何れか一項に記載の分子であって、成人, 子供または新生児のヒトの患者に投与されることが意図される分子。
- 請求項1〜18の何れか一項に記載の分子であって、0.01 mg/kg および 200mg/kgの間の用量で投与されることが意図される分子。
- 請求項19に記載の分子であって、前記均等な分子は、以下の式の何れかを有している分子から選択される分子:
式 (I) 中で
R1 は、
FまたはCl 原子, メチルまたはエチル基, N,N-ジメチル-スルホンアミドまたはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基から選択される二つの基で任意に置換されたフェニル基, または
以下の基
メチル, エチル, ヒドロキシ, メトキシまたはエトキシ基で任意に置換されたチオフェン基であり;
R2 は、
以下の基
以下の基
以下の基
非置換の2-ピリジニル, 3-ピリジニルまたは4-ピリジニル基,
ベンゾキシ基, および/またはヒドロキシル基, および/またはメチル基, および/またはエチル基, および/またはプロピル基, および/または一または二のBr, FまたはCl 原子, および/または一ないし三のヒドロキシル, メトキシまたはエトキシ基で任意に置換されたフェニル基である,
又は、
式 (II) 中で
R4 は、1, 2または3の炭素原子を含んでいる任意で飽和の炭素鎖であり;
R5 は、フェニル基または任意に置換されたフェニル基で,または以下の基で置換された二級アミン基であり;
R7 は、水素または塩素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
R8 は、水素または塩素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
又は、
式 (III) 中で、
R9 は水素原子であり、R10基は任意に置換されたフェニル基であり,またはR9およびR10基は2の窒素原子および4の炭素原子を含んでいる同じ任意に置換された複素環に属し;
R11 は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
R12 は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
R13 は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
R14 は、水素原子またはメチル, エチル, ヒドロキシ, メトキシまたはエトキシ基であり;
又は、
式 (IV) 中で
A は、酸素またはイオウ原子であり;
R15 は、以下の基であり;
R17 は、メチル, エチル, ヒドロキシ, メトキシ, エトキシ, アセトキシ, メトキシカルボニルまたはエトキシカルボニル基である。 - Syk タンパク質に対する前記分子のインビトロ親和性が25 μM未満である、請求項1〜21の何れか一項に記載の分子。
- ヒトまたは動物においてSykが関与している代謝経路に依存するコンディションの予防または治療のための、請求項1〜22の何れか一項に記載の分子および薬理学的に許容される賦形剤を含んでいる組成物。
- 請求項23に記載の組成物であって、さらなる治療上の分子を含む組成物。
- Syk チロシンキナーゼタンパク質と結合し、50 および2500 ダルトンの間の分子量を有し、少なくとも10%のインビトロ結合を阻害する能力のある有機分子を同定するための方法であって、該インビトロ結合は、
(i) 抗体断片 G4G11(配列番号 2),または
(ii) ヒト Syk チロシンキナーゼ タンパク質と、配列番号 1で表されるヒト Syk チロシンキナーゼ タンパク質のアミノ酸配列の残基65から74の少なくとも一つを含むエピトープ上で結合する抗体または抗体断片,または
(iii) ヒト Syk チロシンキナーゼ タンパク質と結合し、抗体断片G4G11とヒト Syk チロシンキナーゼ タンパク質 (配列番号 1)との結合を少なくとも10%阻害する抗体または抗体断片、
とヒト Syk チロシンキナーゼ タンパク質または動物における任意のそのバリアントとの結合であり、少なくとも以下の工程を含む方法:
a) 50 および2500 Daの間の分子量を有している候補の有機分子バンクから、Syk タンパク質とSyk タンパク質の立体的な腔において結合しやすく、上記の式 C-13, I, II, III, IVまたは1 から87を有している分子から選択される分子をスクリーニングすることと;
b) a)で同定された分子から、抗体または抗体断片(i)または(ii)とSyk タンパク質との結合をインビトロで少なくとも 10%阻害する能力のあるものを選択すること。 - 工程 a)における分子は分子C-13, 分子(59)または分子(61)である、請求項25に記載の方法。
- 請求項25または26に記載の方法であって、付加的に工程 a)の前に、式 C-13, I, II, III, IVまたは1 から87を有している分子から選択される分子のSyk タンパク質における立体的な腔を同定するための工程を含む方法。
- 前記の前の工程はインシリコ ドッキングで実施される、請求項27に記載の方法。
- 請求項25〜28の何れか一項に記載の方法であって、付加的に1ng/ml および 1mg/mlの間の濃度でマスト細胞の脱顆粒を50%阻害(IC50)する能力があるものをb)において同定された分子から選択するための工程 c)を含む方法。
- ヒトまたは動物においてSykが関与している代謝経路に依存するコンディションの予防または治療のための医薬品を製造するための、請求項1〜22の何れか一項に記載の分子の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0801959A FR2929851B1 (fr) | 2008-04-09 | 2008-04-09 | Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules |
FR08/01959 | 2008-04-09 | ||
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US9504676B2 (en) | 2016-11-29 |
CA2720908C (fr) | 2018-04-03 |
ES2537518T3 (es) | 2015-06-09 |
WO2009133294A2 (fr) | 2009-11-05 |
CA2720908A1 (fr) | 2009-11-05 |
WO2009133294A3 (fr) | 2010-04-08 |
JP5666423B2 (ja) | 2015-02-12 |
US20140179679A1 (en) | 2014-06-26 |
US20110112098A1 (en) | 2011-05-12 |
FR2929851A1 (fr) | 2009-10-16 |
FR2929851B1 (fr) | 2012-11-30 |
EP2285366A2 (fr) | 2011-02-23 |
EP2285366B1 (fr) | 2015-02-25 |
JP2015061837A (ja) | 2015-04-02 |
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