JP4936341B2 - 細胞増殖方法ならびに組織の修復および再生のための医薬 - Google Patents
細胞増殖方法ならびに組織の修復および再生のための医薬 Download PDFInfo
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Description
本発明は、血清を含む培地中で細胞を増殖させる、前記方法に関する。
本発明はまた、培地中の血清含有量が1〜20容積%である、前記方法に関する。
本発明は、幹細胞を増殖させる、前記方法に関する。
さらに、本発明は、ヒトの細胞を増殖させる、前記方法に関する。
本発明は、幹細胞を未分化な状態で増殖させる、前記方法に関する。
さらに、本発明は、培地の交換を少なくとも週1回は行う、前記方法に関する。
また、本発明は、前記細胞を含む組織修復・再生用医薬に関する。
本発明の方法は、生体から採取された試料中の細胞を、培地中で培養して増殖させる方法であって、同種血清を含む培地において、細胞を抗凝固剤と実質的に接触しない状態で培養することを特徴とする。前記同種血清は血清癌マーカーおよび/または感染因子について陰性であることが検査されていることが好ましく、また細胞を採取した被験者自身の自己血清であることが好ましい。
あるいは、一定の細胞種へ分化した細胞が所望である場合、幹細胞または芽細胞を未分化な状態で大量に増殖させ、次いで、所望の細胞種への分化を誘導する既知の成長因子の添加またはかかる性質を有する遺伝子の導入などによる分化誘導を行うことによって、大量の分化した細胞を得てもよい。
CaCl2(無水物):160〜240
KCL:320〜480
Fe(NO3)3・9H2O:0.08〜1.2
MgSO4(無水物):80〜120
NaCl:5120〜7680
NaHCO3:2960〜4440
NaH2PO4・H2O:100〜150
D−グルコース:3600〜5400
フェノールレッド:12〜18
ピルビン酸ナトリウム:88〜132
L−アルギニン・HCl:67〜101
L−システィン・2HCl:50〜76
L−ヒスチジン・HCl・H2O:34〜50
L−イソロイシン:84〜126
L−ロイシン:84〜126
L−リジン・HCl:117〜175
L−メチオニン:24〜36
L−フェニルアラニン:53〜79
L−セリン:34〜50
L−スレオニン:76〜114
L−トリプトファン:13〜19
L−チロシン(2ナトリウム塩):83〜125
L−バリン:75〜113
塩化コリン:3.2〜4.8
D−Ca−パントテン酸:3.2〜4.8
葉酸:3.2〜4.8
i−イノシトール:5.8〜8.6
ナイアシンアミド:3.2〜4.8
ピリドキサール・HCl:3.2〜4.8
リボフラビン:0.3〜0.5
チアミン・HCl:3.2〜4.8
1.上記のようにヘパリン液にて内壁を濡らしたシリンジにて生体から採取した試料を、100倍以下の希釈率、好ましくは10倍以下の希釈率、さらに好ましくは約2倍〜6倍程度の希釈率で、予め37±0.5℃に保った培地中に加え、培養ディッシュに播種し、37±0.5℃、5%の炭酸ガス中でインキュベートする。培地の交換は少なくとも週1回、典型的には週1〜2回行う。培地は、好適な標準培地に血清および必要な助剤を添加して調製し、ろ過滅菌機により滅菌し、小分けして4℃の保冷庫に保管したものを、予め37±0.5℃に保って使用する。37.5℃を超えると死滅細胞が増え、36.5℃未満では生育が遅い。炭酸ガス濃度は5±1%の範囲が好ましい。全ての工程で細胞に接触する溶液を同様の温度範囲に保つことが、増殖の迅速化を促進する。
内壁を予め微量のヘパリン(骨髄液1mLあたり0.1U)で濡らした採血管を用いて、脳疾患患者から骨髄液を60mL採取し、210mLの培地中に添加し、総量270mLとした。この骨髄液含有培養液を18等分して、15mLずつ150mm径のディッシュ(IWAKI製Tissue culture dish #3030-150)中に播種し、培地を5mLずつ添加して1ディッシュあたり総量20mLとした。播種後、9ディッシュずつ、別々のインキュベーターに静置して、37±0.5℃、5%の炭酸ガス雰囲気下で培養した。骨髄液は、予め末梢血の検査によって、HIV、ATL、HB、HC、梅毒、ヒトパルボウイルスB19等に感染していないことを確認した。
試料中のへパリンの含量を2mL(267U/mL)に変えた他は全て実施例1と同様の条件で培養を行った。結果を図1および図2に示す。ヘパリンを極微量(0.1U/mL)しか添加しない場合、培養開始から4日後で、8×105個の増殖を得、一方、2mLのヘパリンを添加した場合、2×104個の増殖を得、ヘパリンが微量である場合において約40倍の増殖率を得た(図1および図2)。培養を続けた場合、培養開始から12日後での細胞数は、ヘパリンを極微量添加した細胞で1.4×107個まで増加し、一方、ヘパリン2mLを添加した細胞は、2.9×106個であった(図1)。これらの結果は、ヘパリンの添加が細胞増殖に対して阻害効果を及ぼすことを示すとともに、抗凝固剤の添加量がごく微量であるかまたは実質的に添加しなくとも、本発明の方法によって細胞を迅速に増殖させることが可能であることを確認し、さらに、試料中のヘパリンの量を極微量とすることによって、著しい増殖率の改善を得ることを示す。
ヒト末梢血由来の血清の代わりにFBSを用いる他は全て実施例1と同様の条件で、8日間培養を行った。細胞数計測による間葉系幹細胞の増殖速度の比較を、図3に示す。本発明の条件下においてヒト間葉系幹細胞を培養する場合、ヒト成人血清を用いた場合、FBSを用いた場合と比較して、培養開始から5日後で約2.6倍、8日後で約6倍の増殖率を得た。この結果は、ヒト骨髄細胞の培養において、試料中のヘパリンの量を極微量とすることによって、ヒト成人血清を使用してFBSより高い増殖率が得られることを示す。
ラット間葉系幹細胞を用いて実験を行った。ラット大腿骨2本から採取した骨髄細胞を、実施例1と同様の培地にヘパリンをそれぞれ1U/mL、10U/mL、100U、または1000U/mLで添加して培養した。ヒト末梢血由来の血清の代わりにFBSを用いる他は、全て実施例1と同様の条件で培養を行った。結果を図4に示す。培地中のヘパリンの濃度が高くなるほど、増殖に対する阻害効果が高くなることが示された。
ラット間葉系細胞を用いて、以下のように実験を行った。1群:ラット大腿骨1本より、DMEM4mLを用いて骨髄液を押し出し、合計4mL強の試料を得た。この試料を、ヘパリン160Uを添加したDMEM36mLに加え、培養を開始した。培地中のヘパリン濃度は、4U/mLであった。2群:ラット大腿骨1本より、ヘパリン160Uを添加したDMEM4mLを用いて骨髄液を押し出し、合計4mL強の試料を得た。この試料を、このまま高濃度のヘパリンに曝した状態で、5分間室温で放置した後、DMEM36mLに加え、培養を開始した。培地中のヘパリン濃度は、4U/mLであった。これら2群の細胞数の変化を、図5に示す。1群において、2群と比較して著しい増殖率の低下が観察された。この結果は、試料採取の際(または培養に移行する前)に細胞試料にヘパリンを添加した場合、培養時の培地中にヘパリンを添加した場合と比較して、細胞の増殖効率が低下するがことを示唆する。
標準培地としてDMEMの代わりにαMEM培地を使用した他は、全て実施例1と同様の条件で培養を行った。結果を図6に示す。αMEM培地を用いる場合においても、ヘパリンの量を抑えることにより、ヒト血清を用いてFBSよりも迅速な増殖が得られることを確認した。
培地中にグルタミンを含まない以外はすべて実施例1と同様にして7日間培養した。細胞数計測による間葉系幹細胞の増殖速度の比較を、図7に示す。培養開始から1週間後で、グルタミンを使用する場合において約1.6倍の増殖率が観察された。この結果は、間葉系幹細胞の迅速な増殖のために、グルタミンの添加が必要であることを示す。
〔方法〕
ラットの大腿骨3本を採取し、それぞれDMEM(5ml)で骨髄細胞を洗い出し、下記を添加して3群のサンプルを調製した。
(i)DMEM(5ml)
(ii)DMEM(5ml)+ヘパリンを2μl
(iii)DMEM(5ml)+ヘパリンを2μl+プロタミン2μl
各サンプルは、DMEMで洗浄し、10mlの培養液(DMEM+10%FBS+1%penicillin/streptomycin+2mM L-Glutamine)に入れ、10cmディッシュへ播種し、14日間培養した。継代は5,500個/cm2を越えた時点で行った。
図8に示すとおり、ヘパリン処理を経ない細胞は、ヘパリン処理を経た細胞と比較して初期量も多いが、増殖率も高く、それは培養8〜11日において顕著であった。また、ヘパリンの活性を阻害する物質であるプロタミンを加えた細胞も、ヘパリン処理を経た細胞と同様に、初期量も増殖率も低かった。
細胞がヘパリンと実質的に接触しない状態、すなわち低濃度ヘパリン条件下において、自己血清培養した間葉系幹細胞とFBS培養した間葉系幹細胞を比較した。
実施例1の方法にしたがい自己血清含有培地で培養した間葉系幹細胞と、比較例2の方法にしたがいFBS含有培地で培養した間葉系幹細胞を1×107cell/sampleに別々に調整し、それぞれからRNeasy Protect Min Kit (QIGEN,Cat.No.74124)を用いてtotal RNAを抽出した。細胞の破壊にはQIA shredder (QIAGEN,Cat.No.79654)を使用した。得られたRNA溶液を0.5μg/μlに調整し、Agilent 2100 Bioanalyzer (Agilent Technologies)を使用してRNAの品質をチェックした。
MessageAmpII-Biotin Enhanced Kit (Ambion, Catalog#1791)を用いて、IVT反応およびaRNAの精製を行った。具体的には、反応溶液(IV)を37℃にて14時間反応させた後、60μlのNuclease-free Waterを加えて反応を停止させ、キットに付属のaRNA Filter Cartridgeを用いて、最終的に100μlのNuclease-free WaterをFilterに添加して溶出することによってaRNAを精製した。得られたRNA溶液を20μg/32μlに調整し、Agilent 2100 Bioanalyzer (Agilent Technologies)を使用してRNAの品質をチェックした。
MessageAmpII-Biotin Enhanced Kit (Ambion, Catalog#1791)を用いて、aRNAをフラグメント化し、Hybridization Cocktailを調製した。具体的には、反応溶液(V)を94℃にて35分間反応させた後に、GeneChip Expression 3’-Amplification Reagents Hybridization control kit (AFFYMETRIX, P/N900454)を用いてHybridization Cocktailを調製し、99℃にて5分間反応させた後45℃で5分間反応させた。
GeneChip Human Genome U133 Plus 2.0 Array (AFFYMETRIX, P/N900466)を1×Hybridization bufferで満たし、60rpm、45℃にて10分間のprehybridizationを行った。その後、1×Hybridization bufferを除き、調製したHybridization Cocktailで満たして60rpm、45℃にて一晩hybridizationを行った。
Wash Buffer A (6×SSPE, 0.01% Tween-20)、Wash Buffer B (100mM MES,0.1M [Na+], 0.05% Tween-20) およびWaterをFluidics Stationにセットし、GCOS (GeneChip Operating Software)のプログラムよりPrimingを行った。次いで、Hybridization Cocktailを除き、Wash Buffer Aで満たしたArrayならびにSAPE Solution Mix (1×Stain buffer, 2mg/ml BSA, 10μg/ml SAPE)およびAntibody Solution Mix (1×Stain buffer, 2mg/ml BSA, 0.1mg/ml Goat IgG Stock, 3μg/ml biotinylated antibody)をFluidics Stationにセットした。その後、GCOSのプログラムにより洗浄および染色を行った。
Gene Array ScannerにArrayをセットし、スキャンおよび解析を行った。解析結果を表1〜5に示す。
表1には、FBS培養細胞と自己血清培養細胞において5つのケースで共通して増減のみられた細胞表面抗原が示されている。表2には5つのケースで共通して発現に増減のみられた増殖因子関連因子が列挙されている。また表3には、5つのケースで共通して発現に増減のみられたサイトカインが示されている。さらに表4には、5つのケースで共通して発現量に2倍以上の差があった遺伝子群が示されている。
患者(52歳、男性)は、虚血性神経疾患(脳梗塞:右内頸動脈閉塞)で、2007年2月4日に左半身麻痺を発症し、同年2月19日、札幌医科大学付属病院へ転院した。治療前の症状として;左半身麻痺、特に上肢に強い麻痺があり;手を開いたり握ったりすることが全く出来ず;物(積木など)を握ったり離したりすることが出来ず;腕を肩の位置より高く上げることが出来ず;手首を曲げたり伸ばしたりすることも出来なかった。この患者から、実施例1に記載のとおりに間葉系幹細胞を採取して増殖させ、その全量に、凍結保存液(通常の濾過滅菌したRPMI20.5mLと、患者から採取した自己血清20.5mL、デキストラン5mL、DMSO 5mL)を加え、治療薬を製造した。なお、骨髄液は、あらかじめ末梢血の検査によって、HIV、ATL、HB、HC、梅毒、ヒトパルボウイルスB19等に感染していないことを確認した。この治療薬を、3月19日に上記の患者に静脈内に30分間で投与した。副作用は全く認められなかった。
この患者は、細胞治療前は左手指全5指の運動機能不全であったが、細胞投与の翌朝には全く動かなかった左手の指が動くようになり、握ったり開いたりができるようになった。1週間後には運動機能改善が見られ、ステイック運搬運動が可能となった。2週間後には、脳梗塞が著明に縮小していることがMRIによって確認された(図10)。また、手を握ったり開いたりすることが、より早くできるようになり、積木をつまんだり、離したりすることもできるようになった。腕も肩の位置より高く上げ、「バンザイ」することが出来るようになった。肘の曲げ伸ばしおよび手首の曲げ伸ばしも出来るようになった。細胞治療の前後にわたるこの患者の脳梗塞レベルの推移を、脳梗塞の評価のための周知のスケール(NIHSS:米国立衛生研究所脳卒中スケール、JSS:日本脳卒中学会脳卒中スケール、MRS:修正ランキンスケール)を用いて図11に示す。
患者(50代、女性)は、ウィリス動脈輪閉塞症(もやもや病)を長期間患っており、これにより左半身麻痺を発症した。この患者から、実施例1と同様に間葉系幹細胞を採取、培養し、発症から約2ヶ月後に同患者に静脈内投与した。投与後に行ったMRI(PWI)検査により、脳血流の改善が確認された。
患者(60代、男性)は、アテローム血栓症により左半身麻痺を発症した。この患者から、実施例1と同様に間葉系幹細胞を採取、培養し、発症から4ヶ月後に同患者に静脈内投与した。この結果、投与翌日より硬直の緩和と関節可動域の拡大を認め、その後の経過でも筋力の回復が顕著であり、握力の計測も可能となった(4kg)。さらに、投与から約2ヶ月半後には独歩可能となり、左手も実用的に使用できるレベルに回復した。
患者(50代、男性)は、アテローム血栓症により左半身麻痺を発症した。この患者から、実施例1と同様に間葉系幹細胞を採取、培養し、発症から6週後に同患者に静脈内投与した。この結果、投与翌日より指の動きが改善し、その後の経過でも筋力の回復が顕著であり、握力の計測も可能となった(8kg)。また、より細かい作業を、より素早く行えるようになり、割り箸を割ることが可能となるなど、指先の力も回復し、日常生活で役立つ動作が行えるようになった。
患者(60代、男性)は、アテローム血栓症により左半身麻痺を発症した。この患者から、実施例1と同様に間葉系幹細胞を採取、培養し、発症から5週後に同患者に静脈内投与した。この結果、投与当日の夜より、主に下肢の運動の改善が自覚され、投与翌日には、手の運動の改善も自覚された。その後の経過でも運動機能の改善が続いている。
患者(70代、男性)は、ラクナ梗塞により左半身麻痺および構語障害を発症した。この患者から、実施例1と同様に間葉系幹細胞を採取、培養し、発症から8週後に同患者に静脈内投与した。この結果、投与の翌朝より、足の指が動くようになり、肩や肘の動きにも改善が認められた。そして、投与から3日後には、手の指を動かせる程に回復した。
慢性糖尿病患者から、実施例1と同様に間葉系幹細胞を採取、培養し、同患者に静脈内投与した。この結果、投与前は約190mg/dl前後であった血糖値が投与後約1ヶ月で正常値にまで改善したほか、その他の糖尿病指標にも顕著な改善が見られた(図13)。
前立腺肥大患者から、実施例1と同様に間葉系幹細胞を採取、培養し、同患者に静脈内投与した。この結果、前立腺肥大の指標であるPSA値が、投与前と比べると投与後では顕著な改善が見られた(図14)。
肝障害患者から、実施例1と同様に間葉系幹細胞を採取、培養し、同患者に静脈内投与した。この結果、肝障害の指標であるγ−GTP値、GOT値、GPT値が、投与前と比べると投与後では顕著な改善が見られた(図15)。
腎障害患者から、実施例1と同様に間葉系幹細胞を採取、培養し、同患者に静脈内投与した。この結果、腎障害の指標であるβ2-マイクログロブリン値が、投与前と比べると投与後では顕著な改善が見られたほか、その他の腎障害指標(BUN値および/またはクレアチニン値)にも顕著な改善が見られた(図16)。
高脂血症患者から、実施例1と同様に間葉系幹細胞を採取、培養し、同患者に静脈内投与した。この結果、高脂血症の指標である中性脂肪値が、投与前と比べると投与後では顕著な改善が見られたほか、その他の高脂血症指標にも顕著な改善が見られた(図17)。
高次脳機能障害/失語症患者から、実施例1と同様に間葉系幹細胞を採取、培養し、同患者に静脈内投与した。投与前後において、標準失語症検査(SLTA)とウェクスラー成人知能検査(WAIS−R)を実施した。この結果、投与前に比較してSLTAおよびWAIS−Rの値に有意な改善が見られた(図18)。
ヒト健常者から、実施例1と同様に間葉系幹細胞を採取、培養した。ラット脳梗塞モデル(中大脳動脈閉塞モデル)に対して、前述のヒト間葉系幹細胞を調製した。次いで、(i)非移植群、(ii)細胞(1.0×106)静注群、(iii)Angiopoietin遺伝子導入した細胞(1.0×106)静注群、(iv)VEGF遺伝子導入した細胞(1.0×106)静注群、(v)AngiopoietinとVEGF遺伝子導入した細胞(1.0×106)静注群、に分けて治療を行い、治療効果について比較検討を行った。治療効果をMRIで評価した結果(図19A)、(ii)、(iii)、(v)の群で治療効果が見られたが、その治療効果の強さは、(v)>(iii)>(ii)であった。
また、治療効果を行動学的側面からTreadmill stress testを用いて解析した結果(図20)、(ii)、(iii)、(v)の群で治療効果が見られたが、その治療効果の強さは、(v)>(iii)>(ii)であった。
ヒト健常者から、実施例1と同様に間葉系幹細胞を採取、培養した。ラット心肺停止モデルに対して、前述のヒト間葉系幹細胞(1.0×106)を静脈内投与し治療効果を判定した。治療によりアポトーシスが抑制され(Tunnel陽性の細胞数が減少)(図21)、生き残った神経細胞の数も多かった(図22)。また、脳高次機能をMorris water maze testで評価した結果、治療群で改善が見られた。
ヒト健常者から、実施例1と同様に間葉系幹細胞を採取、培養した。Laminectomyしたラット脊髄(Th 11)にNYU imactorを用い、脊髄損傷モデルを作成し、6時間後、1日後、3日後、7日後、14日後に前述のヒト間葉系幹細胞(1.0 x 106)を大腿静脈より移植し、トレッドミルテストにより経時的に運動評価を行った。すなわち、予め、走るのを止めると電気ショックを受けるように設計された20 m/minで動くトレッドミル上で、ラットを1週間に2日、1日20分走らせることを脳梗塞作成前よりトレーニングしておいてから、各群における経時的な回復の程度をグラフ化した。横軸は時間、縦軸はmaximum speed。脊髄損傷後、6時間後および1日後に移植した群で、著明な治療効果が見られた(図23)。
Claims (18)
- 骨髄または血液から採取された試料中の細胞を、培地中で培養して増殖させる方法であって、採取された試料に添加される抗凝固剤の量を該試料の容積に対して0.2U/mL未満として細胞が抗凝固剤と実質的に接触しない状態で採取されたものであり、かつ、培地中に存在する抗凝固剤の量が培地の容積に対して0.02U/mL未満であることを特徴とする、前記方法。
- 同種血清を含む培地において、前記細胞を培養することを特徴とする、請求項1に記載の方法。
- 採取された試料に抗凝固剤を添加しないことを特徴とする、請求項1または2のいずれか1項に記載の方法。
- 同種血清が細胞を採取した被験者の自己血清である、請求項2または3のいずれか1項に記載の方法。
- 前記同種血清が血清癌マーカーおよび/または感染因子について陰性であることが検査されている、請求項2〜4のいずれかに記載の方法。
- 血清癌マーカーが、フェリチン、CEA、AFP、BFP、CA125、CA15−3、CA19−9、CA72−4、STN、DUPAN−2、SLX、ST−439、SPAN−1、SCC、PSA、G−セミノプロテイン、TPA、シフラ、PAP、NSE、C−ペプチド、PIVKA、Pro−GRP、HCGB、エラスターゼ、β2マイクログロブリン、S−NTX、抗p53抗体、HER2からなる群より選ばれる1または2以上である、請求項5に記載の方法。
- 感染因子が、HIV、ATL、HB、HC、梅毒、ヒトパルボウイルスB19からなる群より選ばれる1または2以上である、請求項5または6に記載の方法。
- 抗凝固剤が、ヘパリン、ヘパリン誘導体またはこれらの塩である、請求項1〜7のいずれかに記載の方法。
- 培地中の血清含有量が、1〜20容積%である、請求項1〜8のいずれかに記載の方法。
- 細胞が、幹細胞である、請求項1〜9のいずれかに記載の方法。
- 幹細胞が、間葉系幹細胞である、請求項10に記載の方法。
- 細胞が、ヒト細胞である、請求項1〜11のいずれかに記載の方法。
- 細胞を未分化な状態で増殖させる、請求項1〜12のいずれかに記載の方法。
- 骨髄または血液由来の細胞を含む組織修復・再生用医薬を製造する方法であって、請求項1〜13のいずれかに記載の方法によって骨髄または血液から採取された試料中の細胞を増殖させ、増殖させた細胞を用いて前記医薬を製造することを特徴とし、前記細胞がCD24を発現していないことを特徴とする方法。
- 骨髄または血液由来の細胞を含む組織修復・再生用医薬を製造する方法であって、請求項1〜13のいずれかに記載の方法によって骨髄または血液から採取された試料中の細胞を増殖させ、増殖させた細胞を用いて前記医薬を製造することを特徴とし、前記細胞が表1記載の陽性CD抗原群のうち少なくとも90%が発現し、かつ陰性CD抗原群の少なくとも90%が発現していないことを特徴とする方法。
- 細胞が間葉系幹細胞であり、医薬が静脈内投与、腰椎穿刺投与、脳内投与、脳室内投与、局所投与、または動脈内投与される、損傷部位の修復を幇助するための、もしくは加齢による老化した部位の修復を幇助するための医薬である、請求項14または15に記載の方法。
- 医薬が疾患あるいは障害の亜急性期以降に投与される医薬である、請求項16に記載の方法。
- 損傷部位が脳である、請求項16または17に記載の方法。
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US10328102B2 (en) | 2019-06-25 |
ES2611021T3 (es) | 2017-05-04 |
EP3117828B1 (en) | 2020-02-12 |
JPWO2009034708A1 (ja) | 2010-12-24 |
CA2699236C (en) | 2017-02-28 |
PL3117828T3 (pl) | 2020-05-18 |
PT2194121T (pt) | 2016-12-05 |
KR20170116219A (ko) | 2017-10-18 |
AU2008298816A1 (en) | 2009-03-19 |
CN101802174B (zh) | 2013-06-05 |
KR102087366B1 (ko) | 2020-03-10 |
EP2194121A4 (en) | 2012-03-07 |
US20100254953A1 (en) | 2010-10-07 |
AU2008298816B2 (en) | 2013-09-26 |
US9700582B2 (en) | 2017-07-11 |
ES2776408T3 (es) | 2020-07-30 |
CN101802174A (zh) | 2010-08-11 |
CA2699236A1 (en) | 2009-03-19 |
DK2194121T3 (en) | 2016-12-12 |
US11426432B2 (en) | 2022-08-30 |
KR20100072240A (ko) | 2010-06-30 |
EP2194121A1 (en) | 2010-06-09 |
US20190255118A1 (en) | 2019-08-22 |
WO2009034708A1 (ja) | 2009-03-19 |
PL2194121T3 (pl) | 2017-02-28 |
EP3117828A1 (en) | 2017-01-18 |
KR101614823B1 (ko) | 2016-04-22 |
DK3117828T3 (da) | 2020-03-09 |
EP2194121B1 (en) | 2016-10-26 |
US20170266234A1 (en) | 2017-09-21 |
PT3117828T (pt) | 2020-03-17 |
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