JP5349448B2 - P.gingivalis抗原組成物 - Google Patents
P.gingivalis抗原組成物 Download PDFInfo
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- JP5349448B2 JP5349448B2 JP2010271343A JP2010271343A JP5349448B2 JP 5349448 B2 JP5349448 B2 JP 5349448B2 JP 2010271343 A JP2010271343 A JP 2010271343A JP 2010271343 A JP2010271343 A JP 2010271343A JP 5349448 B2 JP5349448 B2 JP 5349448B2
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Description
大腸菌(E.coli)における、P.gingivalisプロテイナーゼと付着因子ドメインRgpA45、RgpA44、RgpA27およびRgpA15のクローニングおよび発現、ならびにマウス膿瘍モデルにおける組換えタンパク質のワクチンとしての試験。
単一コロニー形質転換体を使って、50μg/mlカナマイシンを含有するルリア-ベルターニ(Luria-Bertani)ブロス10mlに吸光度(OD600)1.0まで37℃にて接種した。次いでこの種菌を用いてテリフィック(Terrific)ブロス(リン酸カリウムおよび50μg/mlカナマイシンを含有する)500mlに接種した。この培養物のOD600が2.0に達した後、0.1mM IPTGを用いて誘導した。37℃にて4.5時間の誘導期間後に、4000rpmで20分間、4℃にて遠心分離して培養物を回収し、ペレットを-70℃で貯蔵して封入体の抽出に備えた。
細菌ペレットを氷上にて解凍し、結合バッファー(5mMイミダゾール、500nM NaCl、20mM Tris-HCl、pH7.9)に再懸濁し、次いで音波処理し、20,000 x gにて遠心分離して封入体を回収した。ペレットを結合バッファー中に再懸濁し、音波処理および遠心分離のプロセスを2回以上繰り返してタンパク質をさらに遊離させた。次いで、ペレットを6M 尿素を含有する結合バッファー中に再懸濁し、氷上で2〜3時間インキュベートし、攪拌してタンパク質を完全に溶解した。残留する不溶物質は39,000 x gで20分間遠心分離して除去した。上清を0.45μm膜を通して濾過した後、カラムで精製した。
Ni-NTA金属アフィニティクロマトグラフィを使用し、H6タグを介して組換えタンパク質を精製した。簡単に説明すると、タンパク質を平衡化Ni-NTA樹脂(Qiagen)にバッチで結合させ、これを小カラム中に流し込み、そして非結合タンパク質を重力で溶出させた。次に、カラムを10容積の結合バッファー、続いて5カラム容積の洗浄バッファー(60mM イミダゾール、500mM NaCl、20mM Tris-HCl、6M 尿素、pH 7.9)を用いて洗浄した。次いで結合したタンパク質を、1M イミダゾール、500mM NaCl、20mM Tris-HCl、6M 尿素、pH 7. 9を含有するバッファーで溶出した。
NI-NTA樹脂から溶出した画分をプールして、バッファー(0.5M Tris-HCl、50mM NaClおよび8% グリセロール)の尿素含量を6Mから3M、1.5M、0Mへと段階的に変える透析によってリフォールディングした。
SDS-PAGEをLaemmliによる記載のように実施した。サンプルを等容積の2 x サンプル還元バッファーと混合し、10分間95℃にて煮沸し、Tris-グリシン12%ゲル(Novex)上を泳動させた。分子量標準(SeeBlueTM)もNovexから購入した。ウェスタンブロットは、タンパク質をニトロセルロース上に1時間、100ボルトで電気ブロットして調製した。膜を1%カゼイン溶液を用いてブロックした後、1/1000に希釈した一次抗体を用いてインキュベートし、洗浄し、そしてヤギ抗ウサギHRPコンジュゲート(KPL)を用いてインキュベートし、洗浄し、そしてTMB膜ペルオキシダーゼ基質(KPL)を用いて発色させた。
ポリクローナル抗血清は、BALB/cマウスに2 X 20μgの組換えタンパク質を含むフロイント(Freund's)不完全アジュバント(Sigma)を3週間隔てて投与することにより、精製組換えタンパク質に対して産生させた。2回目の投与後1週間にマウスから採血し、そして、産生した抗血清を使い、変性、還元条件下で泳動した全細胞P.gingivalis W50のウェスタンブロットをスクリーニングした。
10匹の雌性BALB/cマウス(6〜8週齢)の各群に、組換えタンパク質r-RgpA45、r-RgpA44、r-RgpA27およびr-RgpAl5、ならびにホルマリン死滅P.gingivalis細胞および大腸菌(全て不完全フロイントアジュバント中に乳化した)を各々皮下注射して免疫感作した(20μg)。免疫感作は尾の基部に与え、P.gingivalisを用いて抗原投与する4週および1週前に行った。投与の2日前にマウスの球後神経叢(retrobulbar plexus)から採血した。BALB/cマウスの腹部にP.gingivalis 33277の7.5 x 109生細胞を皮下注射して投与した。投与後7日間にわたって、マウスの病変部の数とサイズを毎日試験した。マウス腹部に病変が発生し、mm2で表した最大病変サイズを図1に示した。病変サイズの有意な低下は、ホルマリン死滅全P.gingivalis細胞および組換え付着因子r-RgpA44を用いたワクチン接種についてのみ得られた。rgpA遺伝子由来の他の組換えタンパク質は病変サイズを有意に低下しなかった。
先の実施例において、組換え44kDa付着因子がマウス病変モデルにおいてP.gingivalisによる抗原投与から保護することを実証した。しかし、全長44kDa付着因子は、大腸菌で発現した場合、変性溶媒中でのみ可溶性である封入体であることがわかった。このタンパク質の溶解性を改善し、かつ組換えタンパク質の正しいフォールディングを増強する目的で、44kDa付着因子から一連の断片を作製した。44kDa付着因子組換えタンパク質の断片を構築するために使ったオリゴヌクレ
オチドプライマーを表2に示した。
44kDa付着因子の断片を使うだけでなく、1以上の44kDa付着因子の断片を使い、他のP.gingivalisタンパク質由来の他のタンパク質またはタンパク質断片とのキメラタンパク質を構築することができる。配列番号2および4はそのようなキメラ組換えタンパク質の一例であって、44kDa付着因子の断片(断片6、残基192〜290)を、PG33(Genbank登録番号AF175715)由来の別のポルフィロモナス・ジンジバリスタンパク質断片である95残基C末端断片(残基286〜380)と連結して誘導したものである。このキメラタンパク質は、全体で全194残基を有する。
正:5' GGCCCATGGTCGACAATAGTGCAAAGATTGAT 3'
逆:5' CTATCCGGCCGCTTCCGCTGCAGTCATTACTACAA 3'
このPCR産物をpET24bのSalIとNotIの部位中にサブクローニングしてpET24b::PG33Cを作製した。次いで44kDa断片6のPCR産物(プライマーは実施例2を参照)をpET24b::PG33CプラスミドのEcoRIとSalI中にサブクローニングして44kDa/PG33の融合構築物、すなわちpET24b::PG44f6-PG33Cを作製した。このプラスミドを大腸菌(E.coli)BL21(DE3)株に形質転換して実施例1および2に概説したように発現研究を実施すると、高レベルのキメラ44kDa/PG33組換えタンパク質を得て、これを実施例2のように試験すると可溶性であった。
組換え44kDaもしくは組換え44kDaタンパク質断片に対して産生したマウス抗血清はパラホルムアルデヒドで固定した全ポルフィロモナス・ジンジバリス細胞と反応することで、免疫反応性エピトープが組換えタンパク質に保存されていることが示される。
大腸菌(E.coli)における、ポルフィロモナス・ジンジバリスKgp39(Kgp39)およびKgp39断片(Kgp39frag)付着因子ドメインのクローニングおよび発現ならびにELISAによる組換えタンパク質の試験
組換えKgp39およびKgp39断片タンパク質を、rRgp44断片について記載したのと類似した方法論を使い、IPTGを用いた誘導により発現した。簡単に説明すると、単一コロニー形質転換体を使って50μg/mlのカナマイシンを含有するLB5mlに接種し37℃にて軌道式シェーカー上で一夜、インキュベートした。次に、この培養物を使って新しい培地100mlに接種し、中間対数増殖期(OD600=0.6〜1.0)まで増殖させ、0.5mMのIPTGを用いて6時間誘導した。次いで細胞を、6500 x gで遠心分離して回収し、封入体抽出のため、-20℃にて一夜、保存した。
細菌ペレットを氷上で解凍し、バッファーB(20mM Na2HPO4、0.5M NaCl, 8M 尿素)10mlに再懸濁した。再溶解した細胞ペレットを、Branson Sonifier(登録商標)250細胞破砕器(Branson Ultrasonics Corporation, Danbury, CT)を使い、マイクロチップを用いて設定3で、氷上において30秒間隔の3 x 30秒間バーストで超音波処理した。不溶性細胞デブリを39000 x gで30分間、4℃で遠心分離して除去し、上清を回収した。不溶性細胞画分をバッファーB 10mlに再懸濁した。アジ化ナトリウム(0.001% v/v)を全サンプルに加えた後、4℃にて保存した。次にサンプルをSDS-PAGEにより分析した。
タンパク質を、Pharmacia中圧タンパク質液体クロマトグラフィ(Fast Protein Liquid Chromatography;FPLC)計器に接続したPharmacia Biotech HiTrapアフィニティーカラム(1ml)(Amersham Pharmacia Biotech)を使って精製した。カラムは、5カラム体積の0.1M NiS04を用いてコーティングし、次に、10カラム体積のスタートバッファー(20mM Na2HPO4、0.5M NaCl、20mMイミダゾール、8M尿素)を用いて流速1 ml/分で平衡化した。サンプルをカラムに0.5 ml/分の流速でローディングし、次いで10体積のスタートバッファーを用いて1ml/分の速度で洗浄した。タンパク質を、10体積の溶出バッファー(20mM Na2HPO4、0.5M NaCl、200mMイミダゾール、8M尿素)の直線勾配にわたって流速1 ml/分にて溶出した。溶出画分を回収し、各画分のサンプルをSDS-PAGEゲル上で先に記載の通りに分析した。
組換えタンパク質からの8M尿素の除去は、Spectrum-Por(登録商標) Float-A-Lyzer(Alltech、Australia)を使って実施した。サンプル中の尿素のモル濃度は、最初の8Mから4日間にわたって0Mになるよう設定した。rKgp39タンパク質を、バッファー(20mM Na2HPO4、0.5M NaCl)中の尿素含量を8Mから7M、6M、5M、4M、3M、2M、1M、0.5M、0Mへと段階的に変えた透析によりリフォールディングした。
ELISAを実施して、RgpA-Kgp特異的抗血清とrKgp39およびrKgp39断片との結合ならびにrKgp39およびrKgp39断片と歯周マトリックスおよび宿主タンパク質との結合を研究した。
ELISAはまた、rKgp39およびrKgp39断片タンパク質と宿主マトリックスタンパク質フィブリノーゲンおよびコラーゲンV型ならびにヘモグロビンとの結合を調査するためにも実施した。マイクロタイタープレートを、10μg/mlのフィブリノーゲン、コラーゲンV型ならびにヘモグロビンのいずれかを含む0.1M PBSを用いて一夜、RTにてコーティングした。コーティング溶液を除去し、残る未コーティングプラスチックを2%(w/v)のスキムミルクを含む0.1M PBSTを用いて1時間、RTにてブロッキングした。ブロッキング溶液を除去し、5μg/mlのrKgp39またはrKgp39断片タンパク質のいずれかを含む0.1M PBSをウエルに加え、2時間、RTにてインキュベートした。ウエルを0.1M PBSTを用いて4回洗浄し、次いで、1%(w/v)のスキムミルクを含む0.1M PBST中のウサギ抗RgpA-Kgp複合体抗血清の連続希釈物を各ウエルに加え、一夜、RTにてインキュベートした。結合した抗体を、6 x PBST洗浄の後に、1%(w/v)のスキムミルクを含む0.1M PBST中のウサギ免疫グロブリンに対する西洋ワサビペルオキシダーゼコンジュゲートヤギ免疫グロブリン(1:4000希釈)(Sigma, NSW, Australia)とともに、1時間、RTにてインキュベートして検出した。プレートを先に記載のように染色した。
本実施例は、RgpA44またはKgp39またはそれらの部分をコードするヌクレオチド配列は、ファージベクターおよびプラスミドを含む様々なベクター中に挿入して発現できることを説明する。タンパク質およびペプチドの発現を成功するには、遺伝子もしくは遺伝子断片を含むインサート、またはベクター自身が転写および翻訳に必要なエレメントを含有し、そのエレメントが発現に使われる特定の宿主系と共存可能でありかつ前記宿主系により認識されることが必要である。RgpA44もしくはKgp39またはそれらの断片をコードするDNA(例えば、実施例2)、あるいは関連するペプチドもしくはオリゴペプチドまたはキメラタンパク質は、合成または単離して本明細書で説明した方法と配列を使って配列決定分析をすることができる。様々な宿主系を利用してRgpA44もしくはKgp39またはそれらの断片、関連するペプチドもしくはオリゴペプチドまたはキメラを発現することができ、限定されるものでないが、バクテリオファージベクター、プラスミドベクター、またはコスミドDNAを用いて形質転換した細菌;酵母ベクターを含有する酵母;真菌ベクターを含有する真菌;ウイルス(例えばバキュロウイルス)を用いて感染した昆虫細胞系;ならびにプラスミドもしくはウイルス発現ベクターを用いて形質転換した、または組換えウイルス(例えば、ワクシニアウイルス、アデノウイルス、アデノ随伴ウイルス、レトロウイルスなど)を用いて感染した哺乳類動物細胞系が挙げられる。
RgpA44またはKgp39特異的ヌクレオチド配列を分子診断アッセイに利用してP.gingivalisを検出する方法。本発明の核酸配列は、P.gingivalisの遺伝物質を検出するための分子診断アッセイに利用することができる。特に、RgpA44またはKgp39配列特異的オリゴヌクレオチドを合成し、P.gingivalis由来の核酸を増幅するためのプライマーおよび/または増幅した核酸を検出するためのプローブとして、使用することができる。最近の分子生物学の進歩により、核酸配列を酵素的に増幅する複数の方法が提供されている。現在最も一般的に使用される方法、PCRTM(ポリメラーゼ連鎖反応、Cetus社)は、Taqポリメラーゼ、プライマーとしての既知配列、および加熱サイクルを使用して、複製デオキシリボ核酸(DNA)鎖を分離しさらに目的の遺伝子を指数関数的に増幅する。現在開発中の他の増幅法としては、DNAリガーゼおよび増幅すべきDNAの配列と相補的であるDNAセグメントの2つの片鎖から構成されるプローブを利用するLCRTM(リガーゼ連鎖反応、BioTechnica International);相補的RNAを指数関数的に生成するためのDNAテンプレートを作るのに使用される、酵素QBレプリカーゼ(Gene-Trak Systems)およびコピーすべきDNAに相補的なプローブと結合したリボ核酸(RNA)配列テンプレート;ならびに増幅すべき核酸配列としてのRNAまたはDNAについて実施しうるNASBATM(核酸配列に基づく増幅、Cangene Corporation)が挙げられる。
診断用イムノアッセイにおいてRgpA44もしくはKgp39、ペプチドまたはキメラペプチドを使用する方法。
RgpA44もしくはKgp39および関連ペプチドならびにキメラに関連するワクチン製剤用の方法と化合物
本発明のこの実施形態は、P.gingivalisが原因である感染症に対する防御または治療するための能動免疫感作用の予防および/または治療用ワクチン中の免疫原として使用する組換えRgpA44もしくはKgp39タンパク質および/またはそれらのペプチドまたはオリゴペプチドまたはキメラを提供する。ワクチンを目的とする場合、細菌タンパク質を含むP.gingivalisの抗原は、免疫原性であり、かつ無傷の細菌上の表面に露出される1以上の、P.gingivalisの株間に保存されるエピトープに対する機能的抗体を誘導しなければならない。
以下は、抗RgpA44または抗Kgp39抗体を含有する歯磨ペースト製剤の提示例である。
成分 %w/w
リン酸二カルシウム二水和物 50.0
グリセロール 20.0
カルボキシメチルセルロースナトリウム 1.0
ラウリル硫酸ナトリウム 1.5
ラウロイルサルコニサートナトリウム 0.5
香味剤 1.0
ナトリウムサッカリン 0.1
グルコン酸クロルヘキシジン 0.01
デキストラナーゼ 0.01
抗RgpA44または抗Kgp39抗体を含有するヤギ血清 0.2
水 差引残量
以下は、歯磨ペースト製剤の別の提示例である。
成分 %w/w
リン酸二カルシウム二水和物 50.0
ソルビトール 10.0
グリセロール 10.0
カルボキシメチルセルロースナトリウム 1.0
ラウリル硫酸ナトリウム 1.5
ラウロイルサルコニサートナトリウム 0.5
香味剤 1.0
ナトリウムサッカリン 0.1
モノフルオロリン酸ナトリウム 0.3
グルコン酸クロルヘキシジン 0.01
デキストラナーゼ 0.01
抗RgpA(788-1004)を含有するウシ血清 0.2
水 差引残量
以下は、歯磨ペースト製剤の別の提示例である。
成分 %w/w
リン酸二カルシウム二水和物 50.0
ソルビトール 10.0
グリセロール 10.0
カルボキシメチルセルロースナトリウム 1.0
ラウロイルジエタノールアミド 1.0
スクロースモノラウレート 2.0
香味剤 1.0
ナトリウムサッカリン 0.1
モノフルオロリン酸ナトリウム 0.3
グルコン酸クロルヘキシジン 0.01
デキストラナーゼ 0.01
抗RgpA44抗体を含有する牛乳Ig 0.1
水 差引残量
以下は、歯磨ペースト製剤の別の提示例である。
成分 %w/w
ソルビトール 22.0
アイリッシュモス 1.0
水酸化ナトリウム(50%) 1.0
ガントレズ(Gantrez) 19.0
水(脱イオン) 2.69
モノフルオロリン酸ナトリウム 0.76
ナトリウムサッカリン 0.3
ピロリン酸 2.0
水和アルミナ 48.0
芳香油 0.95
抗RgpA44モノクローナル抗体 0.3
ラウリル硫酸ナトリウム 2.00
以下は、歯磨ペースト製剤の別の提示例である。
成分 %w/w
ポリアクリル酸ナトリウム 50.0
ソルビトール 10.0
グリセロール 20.0
香味剤 1.0
ナトリウムサッカリン 0.1
モノフルオロリン酸ナトリウム 0.3
グルコン酸クロルヘキシジン 0.01
エタノール 3.0
抗RgpA(788-1004)を含有するウマIg 0.2
リノール酸 0.05
水 差引残量
以下は口洗浄液製剤の提示例である。
成分 %w/w
エタノール 20.0
香味剤 1.0
ナトリウムサッカリン 0.1
モノフルオロリン酸ナトリウム 0.3
グルコン酸クロルヘキシジン 0.01
ラウロイルジエタノールアミド 0.3
抗RgpA44抗体を含有するウサギIg 0.2
水 差引残量
以下は口洗浄液製剤の提示例である。
成分 %w/w
ガントレズS-97 2.5
グリセリン 10.0
芳香油 0.4
モノフルオロリン酸ナトリウム 0.05
グルコン酸クロルヘキシジン 0.01
ラウロイルジエタノールアミド 0.2
抗RgpA44マウスモノクローナル抗体 0.3
水 差引残量
以下はトローチ製剤の提示例である。
成分 %w/w
砂糖 75〜80
コーンシロップ 1〜20
芳香油 1〜2
NaF 0.01〜0.05
抗RgpA44マウスモノクローナル抗体 0.3
ステアリン酸Mg 1〜5
水 差引残量
以下は歯肉マッサージクリーム製剤の提示例である。
成分 %w/w
白色ワセリン 8.0
プロピレングリコール 4.0
ステアリルアルコール 8.0
ポリエチレングリコール4000 25.0
ポリエチレングリコール400 37.0
モノステアリン酸スクロース 0.5
グルコン酸クロルヘキシジン 0.1
抗RgpA44マウスモノクローナル抗体 0.3
水 差引残量
以下はチューインガム製剤の提示例である。
成分 %w/w
ガムベース 30.0
炭酸カルシウム 2.0
結晶ソルビトール 53.0
グリセリン 0.5
芳香油 0.1
抗RgpA(788-1004)ウサギモノクローナル抗体 0.3
水 差引残量
Claims (8)
- 配列番号3、配列番号3の残基1-290、配列番号3の残基65-290、配列番号3の残基65-419、配列番号3の残基192-290、配列番号3の残基192-419、および配列番号3の残基147-419からなる群から選択される配列からなる組換えタンパク質を含む抗原組成物。
- 1以上のポリペプチド配列と連結された、配列番号3、配列番号3の残基1-290、配列番号3の残基65-290、配列番号3の残基65-419、配列番号3の残基192-290、配列番号3の残基192-419、および配列番号3の残基147-419からなる群から選択される配列からなる組換え融合タンパク質を含む抗原組成物。
- さらにアジュバントを含む、請求項1または2に記載の抗原組成物。
- 融合タンパク質が配列番号4に示される配列を有する、請求項2に記載の抗原組成物。
- 請求項1〜4のいずれかに記載の抗原組成物に対して産生された少なくとも1つの抗体を含む抗体組成物であって、該抗体が、配列番号3、配列番号3の残基1-290、配列番号3の残基65-290、配列番号3の残基65-419、配列番号3の残基192-290、配列番号3の残基192-419、および配列番号3の残基147-419からなる群から選択される配列からなるポリペプチドに特異的に結合することを特徴とする、前記抗体組成物。
- 原核生物または真核生物細胞であって、少なくとも1つの調節エレメントが機能しうる形で連結された、配列番号1、配列番号1のヌクレオチド1-1257、配列番号1のヌクレオチド1-870、配列番号1のヌクレオチド193-870、配列番号1のヌクレオチド193-1257、配列番号1のヌクレオチド574-870、配列番号1のヌクレオチド574-1257、または配列番号1のヌクレオチド439-1257からなるDNA配列を含む、前記原核生物または真核生物細胞。
- 被験者におけるP.gingivalis感染症の発生数または重症度を予防または軽減するための、請求項1〜4のいずれかに記載の抗原組成物。
- 被験者におけるP.gingivalis感染症の発生数または重症度を予防または軽減するための、請求項5に記載の抗体組成物。
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AUPQ4859 | 1999-12-24 | ||
AUPQ4859A AUPQ485999A0 (en) | 1999-12-24 | 1999-12-24 | P. gingivalis antigenic composition |
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JP2010271343A Expired - Fee Related JP5349448B2 (ja) | 1999-12-24 | 2010-12-06 | P.gingivalis抗原組成物 |
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EP (3) | EP2243789B1 (ja) |
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AU (1) | AUPQ485999A0 (ja) |
CA (1) | CA2395423C (ja) |
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AUPQ485999A0 (en) * | 1999-12-24 | 2000-02-03 | Csl Limited | P. gingivalis antigenic composition |
AUPQ718200A0 (en) * | 2000-04-28 | 2000-05-25 | Csl Limited | Porphyromonas gingivalis recombinant proteins and truncations |
JP2006036661A (ja) * | 2004-07-23 | 2006-02-09 | Gen Corp:Kk | 歯周炎を治療又は予防するための組成物 |
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JP2011016843A (ja) * | 2010-10-13 | 2011-01-27 | Gen Corp:Kk | 歯周炎を治療又は予防するための組成物 |
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US20130164298A1 (en) | 2013-06-27 |
JP5209163B2 (ja) | 2013-06-12 |
US8282933B2 (en) | 2012-10-09 |
EP2243789A1 (en) | 2010-10-27 |
DK2243789T3 (da) | 2013-03-04 |
EP1240191A4 (en) | 2005-07-06 |
EP2243789B1 (en) | 2012-12-05 |
AUPQ485999A0 (en) | 2000-02-03 |
CA2395423C (en) | 2013-12-17 |
NZ519365A (en) | 2003-06-30 |
US20030232022A1 (en) | 2003-12-18 |
ES2388895T3 (es) | 2012-10-19 |
JP2003518932A (ja) | 2003-06-17 |
HK1149938A1 (en) | 2011-10-21 |
CA2395423A1 (en) | 2001-07-05 |
US20080175867A1 (en) | 2008-07-24 |
US7419671B2 (en) | 2008-09-02 |
WO2001047961A1 (en) | 2001-07-05 |
JP2011120581A (ja) | 2011-06-23 |
DK1985626T3 (da) | 2012-08-20 |
ES2401043T3 (es) | 2013-04-16 |
EP1985626B1 (en) | 2012-06-06 |
EP1240191A1 (en) | 2002-09-18 |
EP1985626A1 (en) | 2008-10-29 |
US8784831B2 (en) | 2014-07-22 |
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