JP2007537980A - 高次構造的に制約された副甲状腺ホルモン(pth)アナログ - Google Patents
高次構造的に制約された副甲状腺ホルモン(pth)アナログ Download PDFInfo
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- JP2007537980A JP2007537980A JP2006520353A JP2006520353A JP2007537980A JP 2007537980 A JP2007537980 A JP 2007537980A JP 2006520353 A JP2006520353 A JP 2006520353A JP 2006520353 A JP2006520353 A JP 2006520353A JP 2007537980 A JP2007537980 A JP 2007537980A
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Abstract
Description
本発明は、高次構造的に制約された副甲状腺ホルモン(PTH)および副甲状腺ホルモン関連タンパク質(PTHrT)アナログ、ならびにこれらのアナログの調製方法および使用方法に関する。
米国特許審査便覧310の下での言及。米国政府は、本発明における一括払いライセンス、および米国国立衛生研究所によって授与された補助金番号DK-11794の規約によって提供されるような道理にかなった規約に基づいて他者にライセンスを与えるよう特許権者に要求するために限定された状況における権利を有する。
副甲状腺ホルモン
副甲状腺ホルモン(PTH)(84アミノ酸ペプチド)は、ヒト体内のイオン化血液カルシウムの主要なレギュレーターである(Kronenberg, H.M., et al.、Handbook of Experimental Pharmacology, Mundy, G.R. and Martin, T.J. (編)、pp.185-201、Springer-Verlag, Heidelberg (1993))。カルシウム濃度の調節は、胃腸、骨格、神経、神経筋、および心臓血管の系の通常の機能のために必要である。PTHの合成および放出は主に血清カルシウムレベルによって制御され;低レベルはホルモンの合成と放出の両方を刺激し、高レベルはそれらを抑制する。PTHは、次に、カルシウム交換の3つの部位:腸、骨、および腎臓において、血液へのカルシウムの流入を直接的または間接的に促進することによって、血清カルシウムレベルを維持する。PTHは、活性型ビタミンDの腎臓合成を促進することによって、正味の胃腸のカルシウム吸収に寄与する。PTHは、骨再吸収細胞である破骨細胞の分化を刺激することによって間接的にカルシウム再吸収を促進する。これはまた、腎臓に対する少なくとも3つの主要な効果:尿細管カルシウム再吸収の刺激、リン酸クリアランスの増強、および活性型ビタミンDの合成を完成する酵素の増加の促進を媒介する。PTHは、主としてアデニル酸シクラーゼおよび/またはホスホリパーゼCのレセプター媒介活性化を通してこれらの効果を発揮すると考えられている。
PTH誘導体は、アミノ酸置換を有するポリペプチドを含むか、または全長分子と比較して短縮される。PTHの14アミノ酸、21アミノ酸、および34アミノ酸のアミノ末端短縮型、ならびにC末端短縮型が研究された。さらに、短縮型ポリペプチド中のアミノ酸置換もまた研究された。
PTHおよびPTHrPの最初の34アミノ酸は、高親和性P1R結合およびP1R媒介シグナル伝達応答の強力な誘導のために必要な情報を含む(Nerr, RM, et al., N.E.J.M. 344:1434-1441 (2001))。PTHの短いN末端フラグメント、例えば、PTH(1-14)およびPTH(1-11)は極度に弱い結合親和性を示すが(Kd>>100μM)、それにも関わらず、PTH(1-34)の効力(EC50〜2nM)よりも実質的に弱い効力(EC50s≧100μM)であるが、cAMPシグナル伝達応答を誘発することが可能である(Luck, MD et al., Molecular Endocrinology 13:670-680 (1999))。一連の修飾されたPTH(1-14)およびPTH(1-11)アナログが、PTH(1-34)の効力に近いか、または完全に等しい程のシグナル伝達効力を示すことが最近発見されている(Shimizu, M. et al., Endocrinology 142:3068-3074 (2001); Shimizu, M. et al., J. Biol. Chem. 276:490003-49012 (2001); Shimizu, M. et al., J. Biol. Chem. 275:21836-21843 (2000))。
本発明は新規なP1Rポリペプチドアンタゴニストを提供する。これらのアンタゴニストは、短縮型PTHおよびPRHrPポリペプチド中の選択された位置にアミノ酸置換を含み、かつレセプターの膜近傍(「J」)ドメインに選択的に結合する。このJドメインは、7つの膜貫通ヘリックスおよび細胞外ループを含むレセプター(P1R)の領域である。P1RのJドメインに結合する、本発明のN末端PTHアンタゴニストアナログは、PTH/P1R機能亢進に関連する状態(例えば、原発性副甲状腺機能亢進症、ヤンセン軟骨形成不全症)を治療するために有用である。さらに、これらのアナログは、P1Rに結合する他のリガンド(例えば、低分子PTH模倣化合物)を同定するために有用である(例えば、高スループットスクリーニングを利用して)。さらに、これらのアナログは、それらの選択性について、例えば、Jドメインについて、P1Rリガンドを薬理学的に分析するために使用可能である。
からなる群より選択されるペプチド;アミノ酸1〜9、1〜10、1〜11、1〜12、もしくは1〜13を含むそれらのフラグメント;それらの薬学的に許容される塩;およびそれらのN-もしくはC-誘導体に関し:ここでX01およびX03はα-ヘリックス安定化残基(例えば、Ac5c、Ac3c、Deg、AibまたはAc5c、Ac3c、Deg、もしくはAibのデサミノ型)であり;X02はTrp、Bpa、ArgまたはValであり;X04はMetまたはNleであり;X05はGln、DegまたはAsnであり;X06はHarまたはLeuであり;X07はα-ヘリックス安定化残基(例えば、Aib)、AlaまたはGlyであり;およびX08はα-ヘリックス安定化残基(例えば、Aib)、Trp、TyrまたはHisである。本発明の1つの態様において、上記のペプチドは
;アミノ酸1〜9、1〜10、1〜11、1〜12、もしくは1〜13を含むそれらのフラグメント;それらの薬学的に許容される塩;およびそれらのN-もしくはC-誘導体から本質的になり、ここでX01およびX03はα-ヘリックス安定化残基(例えば、Ac5c、Ac3c、Deg、AibまたはAc5c、Ac3c、Deg、もしくはAibのデサミノ型)であり;X02はTrp、Bpa、ArgまたはValであり;X04はMetまたはNleであり;X05はGln、DegまたはAsnであり;X06はHarまたはLeuであり;X07はα-ヘリックス安定化残基(例えば、Aib)、AlaまたはGlyであり;およびX08はα-ヘリックス安定化残基(例えば、Aib)、Trp、TyrまたはHisである。
に及ぶ。本発明はさらに、上記のペプチドの薬学的に許容される塩およびそれらのペプチドのN-またはC-誘導体を含む。本発明の態様は、上記に列挙されたポリペプチドのいずれかに及び、ここで上記ポリペプチドはC末端アミドを含む。
からなるペプチドに関し、ここで、X01およびX02はα-ヘリックス安定化残基(例えば、Ac5c、Ac3c、Deg、またはAib)であり、X03はAib、Gln、Deg、またはAsnであり、X04はMetまたはNleであり、X05はHarまたはLeuであり、X06はα-ヘリックス安定化残基(例えば、Aib)、Ala、またはGlyであり、X08はα-ヘリックス安定化残基(例えば、Aib)またはLysであり、およびX07はα-ヘリックス安定化残基(例えば、Aib)、TrpまたはHisであり、X08はArgまたはGluでありかつX09はTyrまたはMetであり;ここで上記ペプチドはP1RのJドメインに選択的に結合する。
に及ぶ。本発明はさらに、上記のペプチドの薬学的に許容される塩およびそれらのペプチドのN-またはC-誘導体を含む。本発明の態様は、上記に列挙されたポリペプチドのいずれかに及び、ここで上記ポリペプチドはC末端アミドを含む。
定義
単数形(「a」「an」「the」)などは、他に示されない限り、複数形を含んでもよい。また、単数形への言及は複数形を含む。それゆえに、例えば、ペプチドは複数のペプチドもまた含む。
α-アミノイソ酪酸(Aib)は、短いN末端PTHペプチドアナログに導入された。様々な極性溶媒または非極性溶媒の中で実施されたPTH(1-34)アナログの多数のNMR研究は、一般的に、2つのドメインの二次構造:ほぼSer-17からVal-31までに拡がる安定なC末端ヘリックス、およびSer-3からLys-13まで変動的に拡がるより短くかつより安定でないアミノ末端ヘリックスを示した。これらの2つのドメインはベンドまたはターン領域によって接続されている。
最近のPTH(1-34)の結晶学的研究は、Ser-3からHis-32までに拡がり、かつ中央部分にわずかな15°のベンドのみを含む連続的なα-ヘリックスを示した。しかし、NMRデータは、N末端ヘリックスが比較的弱いことを示す。ヘリックス安定化修飾(Aib残基の導入など)は、P1Rレセプターへの結合親和性に関して顕著な利点を提供し、PTH(1-34)と比較し得る結合親和性を有する短いペプチド(≦14アミノ酸)を生じる。
本発明の化合物またはその誘導体は、P1Rのアンタゴニストまたは逆アゴニストとして作用するそれらの能力に部分的に起因して複数の用途を有する。本発明のペプチドの複数の用途には、とりわけ、PTHもしくはPTHrPの活性および/または産生の増加によって症状が現れる哺乳動物の様々な状態の予防および治療、診断用プローブ、診断用プローブとしての使用のための抗体を調製するための抗原、ならびに分子量マーカーとしてさえの用途が含まれる。PTHポリペプチドにおいて1つまたは複数のアミノ酸を特異的に置換可能であることは、特定の分子量のポリペプチドの構築を可能にする。
ホルモン作用の発現の決定的な段階は、標的細胞の原形質膜表面上のレセプターとホルモンの相互作用である。ホルモン-レセプター相互作用の形成は、様々な生物学的応答を誘発するために細胞への細胞外シグナルの伝達を可能にする。
高カルシウム血症のある型は、PTHおよびPTHrPおよびPTH-1およびPTH-2レセプターの間の相互作用に関連する。高カルシウム血症は、血清カルシウムレベルの異常な上昇が存在する状態である;これはしばしば、他の疾患(副甲状機能亢進症、骨粗鬆症、***、肺、および前立腺の癌腫、頭頸部および食道の類表皮癌、多発性骨髄腫、ならびに副腎腫を含む)に伴う。
以下のプロトコールおよび実験の詳細は、以下に続く実施例において言及される。
ペプチドは、自動化ペプチドシンセサイザー(モデル430A PE, Applied Biosystems, Foster City, CA、またはモデル396 MBS Advanced Chem Tect, Louisville, KY)上で、FMOC主鎖保護基ケミストリー、カップリング反応のためにHBTU/HOBt/DIEA (1:1:2 モル比)、およびTFA媒介切断/側鎖-脱保護(MGH Biopolymer Synthesis Facility, Boston, MA)を使用して調製する。すべてのペプチドをC18含有カートリッジ上での吸着により脱塩し、HPLCによってさらに精製する。乾燥ペプチド粉末を10mM 酢酸中で再構成し、-80℃で保存する。各ペプチドの純度、同一性、およびストック濃度は、分析用HPLC、マトリックス支援レーザー脱離/イオン化(MALDI)質量スペクトル分析、およびアミノ酸分析によって保証する。放射性標識を、125I-Na(2,200 Ci/mmol、NEN)およびクロラミン-Tを使用して実施する;得られる放射性リガンドをHPLCによって精製する。
細胞株HKRK-B28(Shimizu, et al., Biochem. 41:13224-33 (2002))を、フクロネズミ/ラットハイブリッドP1RをコードするプラスミドDNAを用いる安定なトランスフェクションによって、ブタ腎臓細胞株LLC-PK1から誘導した。これは細胞あたり〜280,000レセプターを発現する。HKRK-B7細胞株を、ヒトP1RをコードするDNAを用いる安定なトランスフェクションによって、LLC-PK1細胞株から誘導した。HKRK-B7細胞は、細胞あたり約950,000ヒトP1Rを発現する(Takasu, H., et al., J. Bone Miner. Res. 14:11-20 (1999))。これらの細胞を、COS-7細胞およびSaOS-2-BlO細胞と同様に、T-75フラスコ(75mm2)中の、ウシ胎仔血清(10%)、ペニシリンG(20単位/ml)、硫酸ストレプトマイシン(20μg/ml)およびアンホテリシンB(0.05μg/ml)を補充したダルベッコ改変イーグル培地(DMEM)中で、5% CO2を含む加湿大気中で、27℃で培養した。EGTA/トリプシンのストック溶液および抗生物質はGIBCOからである;ウシ胎仔血清はHyclone Laboratories(Logan, UT)からである。COS-7を24ウェルプレート中で継代培養し、野生型ヒトP1Rまたは残基(24-181)が欠失している短縮型ヒトP1RをコードするプラスミドDNA(200ng/ウェル)でトランスフェクトする(Shimizu, M., et al., J. Biol. Chem. 275:21836-21843 (2000))。これを塩化セシウム/臭化エチジウム密度勾配遠心分離、および製造業者の推奨する手順に従って、FuGENE 6トランスフェクション試薬(Roche Indianapolis IN)によって精製する。24ウェルプレート中のすべての細胞を新鮮な培地で処理し、アッセイの12〜24時間前に33℃に移す。
ペプチドアナログによる細胞の刺激を、24ウェルプレート中で実施する。細胞を0.5 mLの結合緩衝液(50 mM Tris-HCI、100 mM NaCl、5 mM KCl、2 mM CaCl2、5% 熱不活化ウシ血清、0.5% ウシ胎仔血清、HClでpH 7.5に調整)ですすぎ、200μLのcAMPアッセイ緩衝液(2 mM 3-イソブチル-1-メチルキサンチン、1 mg/mLウシ血清アルブミン、35mM Hepes-NaOH, pH 7.4を含むダルベッコ改変イーグル培地)および様々な量のペプチドアナログを含む100μLの結合緩衝液で処理する(最終容量=300μL)。培地を、室温での30〜60分間のインキュベーションの後に除去し、細胞をドライアイス上で凍結し、0.5 mLの50 mM HClで溶解し、再度凍結する(-80℃)。希釈した溶解物のcAMP含量をラジオイムノアッセイによって測定する。EC50応答値を、非線形回帰を使用して計算する(以下を参照されたい)。
結合反応を、24ウェルプレート中で、HKRK-B28細胞、HKRK-B7細胞、またはCOS-7細胞を用いて実施する。細胞を0.5mLの結合緩衝液ですすぎ、次いで、様々な量の未標識競合リガンドを含む100μLの結合緩衝液、および125I-[M]PTH(1-21)、125I-[Aib1,3,Nle8,Gln10,Har11,Ala12,Trp14,Tyr15]PTH(1-15)NH2、または125I-[Aib1,3,M]PTH(1-21)を含む約100,000cpmの100μLの結合緩衝液で連続的に処理する(約26fmol;最終容量=300μL)。インキュベーションは4℃で4〜6時間であり、この時間にほぼ平衡状態が達成された。次いで、細胞を氷上に配置し、結合媒体を除去し、単層を0.5mLの冷結合緩衝液で3回すすぐ。次に、細胞を0.5mLの5N NaOHで溶解し、放射能を計数する。各トレーサーについておよび各実験において、非特異的結合を、1μMの濃度の同じ非標識ペプチドの存在下で結合する放射能として測定し、全体で〜1%の放射能が各トレーサーに加えられた。最大の特異的結合(B0)は、非特異的結合について補正された、競合リガンドの非存在下において結合した全体の放射能である。非線形回帰を使用して、結合IC50値を計算する(以下を参照されたい)。26fmolの125I-[Aib1,3,M]PTH(1-21)を用いる研究から誘導された相同の競合結合データのスキャッチャード変換が、単一のクラスの結合部位ならびにヨード化されたリガンドおよびヨード化されていないリガンドの等しい親和性を仮定して、見かけの平衡解離定数(kDapps)およびリガンド結合部位の総数(Bmax)の見積もりのために利用される。
上記のようにP1R-WTでトランスフェクトされたCOS-7細胞を、0.1%ウシ血清アルブミンおよび[3H]ミオ-イノシトール(NEN, Boston, MA)(2μCi/mL)を含み、血清を含まない、イノシトールを含まないDMEMで、アッセイの16時間前に処理する。アッセイの時点で、細胞を、LiCl(30mM)を含む結合緩衝液ですすぎ、PTHアナログを含むかまたは含まない同じ緩衝液で処理する。次いで、細胞を、37℃で40分間インキュベートし、その後、緩衝液を除去し、0.5mLの氷冷5%トリクロロ酢酸溶液に置き換える。氷上で3時間後、溶解物を収集し、エチルエーテルで2回抽出する。次いで、溶解物をイオン交換カラムに適用し(0.5mLレジンベッド)、以前に記載されたように全イノシトールリン酸を溶出させ(Berridge, M. J., et al.,Biochem. J. 212:473-482 (1983))、液体シンチレーションカクテル中で計数する。
PTH誘導体の結合アッセイをHKRK-B28細胞において実施した。親のペプチドの誘導体、
を、示されるように1位、2位、および/または3位で置換した。結合アッセイ(15℃で4時間)を、125I-[Aib1,3,Nle8,Gln10,Har11,Ala12,Trp14,Tyr15]PTH(1-15)NH2を用いて実施した。結果は、親のペプチドが、試験された誘導体の最高の親和性で結合したことを示す(図2および3(A))。
Claims (36)
- 以下からなる群より選択されるペプチドであって、
(a)
(b)アミノ酸1〜9、1〜10、1〜11、1〜12、または1〜13を含むそのフラグメント;
(c)その薬学的に許容される塩;および
(d)そのN-またはC-誘導体;
ここで、
X01およびX03はそれぞれα-ヘリックス安定化残基であり、
X02はTrp、Bpa、Arg、またはValであり、
X04はMetまたはNleであり、
X05はGln、Deg、またはAsnであり、
X06はHarまたはLeuであり、
X07はα-ヘリックス安定化残基、AlaまたはGlyであり、
X08はα-ヘリックス安定化残基、Trp、Tyr、またはHisであり、および
ここで、該ペプチドはP1RのJドメインに選択的に結合する、ペプチド。 - α-ヘリックス安定化残基が、Ac5c、Ac3c、Deg、Aib、またはAc5c、Ac3c、Deg、もしくはAibのデサミノ型からなる群より選択される、請求項1記載のペプチド。
- 以下からなる群より選択されるペプチドであって、
(a)
(b)アミノ酸1〜20、1〜19、1〜18、1〜17、1〜16、もしくは1〜15を含むそのフラグメント;
(c)その薬学的に許容される塩;または
(d)そのN-もしくはC-誘導体;
ここで、
X01およびX02はα-ヘリックス安定化残基であり、
X02はAib、Gln、Deg、またはAsnであり、
X03はMetまたはNleであり、
X04はHarまたはLeuであり、
X05はα-ヘリックス安定化残基、AlaまたはGlyであり、
X06はα-ヘリックス安定化残基(例えば、Aib)、またはLysであり、
X07はα-ヘリックス安定化残基、Trp、またはHisであり、
X08はArgまたはGluでありかつX09はTyrまたはMetであり;および
ここで該ペプチドはP1RのJドメインに選択的に結合する、ペプチド。 - 標識される、請求項1または15記載のペプチド。
- 蛍光標識で標識される、請求項17記載のペプチド。
- 化学発光標識で標識される、請求項17記載のペプチド。
- 生物発光標識で標識される、請求項17記載のペプチド。
- 放射活性標識で標識される、請求項17記載のペプチド。
- 125Iで標識される、請求項21記載のペプチド。
- 99mTcで標識される、請求項21記載のペプチド。
- PTHレセプターを請求項17記載の標識されたペプチドおよび候補レセプターリガンドと接触させる工程、ならびにレセプターに結合した標識を測定する工程を含む、PTHレセプターリガンドを同定するための競合結合アッセイ。
- PTHレセプターまたはそのフラグメントもしくは誘導体を、請求項17記載の標識されたペプチドおよび候補レセプターリガンドと接触させる工程、ならびにレセプターに結合した標識を測定する工程を含む、PTHレセプターリガンドを分析するための競合結合アッセイ。
- 請求項1または15記載のペプチド、および薬学的に許容される担体を含む薬学的組成物。
- 請求項1または15記載のペプチドの阻害有効量をその必要がある対象に投与する工程を含む、PTHもしくはPTHrPの活性または産生の増加によって特徴付けられる哺乳動物の状態を治療するための方法。
- 請求項1または15記載のペプチドおよび薬学的に許容される担体を含む組成物の阻害有効量をその必要がある対象に投与する工程を含む、PTHもしくはPTHrPの活性または産生の増加によって特徴付けられる哺乳動物の状態を治療するための方法。
- 治療される状態が高カルシウム血症である、請求項26または27記載の方法。
- 治療される状態が悪性高カルシウム血症である、請求項28記載の方法。
- 骨質量を増加させるためのペプチドの有効量が約0.01μg/kg/日〜約1.0μg/kg/日である、請求項26または27記載の方法。
- 投与の方法が非経口的である、請求項26または27記載の方法。
- 投与の方法が皮下的である、請求項26または27記載の方法。
- 投与の方法が経鼻吸入法である、請求項26または27記載の方法。
- ペプチドが固相合成によって合成される、請求項1または15記載のペプチドを作製する方法。
- ペプチドがFMOCによって保護される、請求項1または15記載のペプチドを作製する方法。
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PCT/US2004/022830 WO2005009358A2 (en) | 2003-07-17 | 2004-07-16 | Conformationally constrained parathyroid hormone (pth) analogs |
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Families Citing this family (15)
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EP1123401A1 (en) * | 1998-10-22 | 2001-08-16 | The General Hospital Corporation | BIOACTIVE PEPTIDES AND PEPTIDE DERIVATIVES OF PARATHYROID HORMONE (PTH) AND PARATHYROID HORMONE-RELATED PEPTIDE (PTHrP) |
JP4486258B2 (ja) | 1998-11-25 | 2010-06-23 | ザ・ジェネラル・ホスピタル・コーポレイション | ヒト副甲状腺ホルモンの改変、調製および使用 |
DK1141237T3 (da) | 1998-12-31 | 2006-02-13 | Gen Hospital Corp | PTH-receptor og screeningsassay der anvender denne |
AU7734800A (en) * | 1999-09-29 | 2001-04-30 | General Hospital Corporation, The | Polypeptide derivatives of parathyroid hormone (pth) |
CA2454275C (en) | 2001-07-23 | 2012-10-23 | The General Hospital Corporation | Conformationally constrained parathyroid hormone (pth) analogs |
WO2004093902A1 (en) * | 2003-03-19 | 2004-11-04 | The General Hospital Corporation | CONFORMATIONALLY CONSTRAINED PARATHYROID HORMONES WITH α-HELIX STABILIZERS |
JP2009545320A (ja) * | 2006-08-04 | 2009-12-24 | ザ ジェネラル ホスピタル コーポレイション | 副甲状腺ホルモン(pth)のポリペプチド誘導体 |
EP1961765A1 (en) * | 2006-12-08 | 2008-08-27 | Zealand Pharma A/S | Truncated PTH peptides with a cyclic conformation |
KR101661730B1 (ko) | 2007-08-01 | 2016-10-04 | 더 제너럴 하스피탈 코포레이션 | G―단백질 결합 수용체를 이용한 스크리닝 방법 및 관련 조성물 |
KR101451470B1 (ko) | 2009-04-24 | 2014-10-15 | 카딜라 핼쓰캐어 리미티드 | 부갑상선호르몬(pth) 수용체 작용물질로서의 단쇄 펩티드 |
WO2011143406A2 (en) | 2010-05-13 | 2011-11-17 | The General Hospital Corporation | Parathyroid hormone analogs and uses thereof |
WO2012120532A2 (en) | 2011-02-02 | 2012-09-13 | Cadila Healthcare Limited | Cyclic short chain peptides |
CA2903306A1 (en) | 2013-03-15 | 2014-09-18 | Fundacio Institut De Recerca Biomedica (Irb Barcelona) | Method for the diagnosis, prognosis and treatment of metastatic cancer |
JP7148493B2 (ja) | 2016-08-01 | 2022-10-05 | ゾーマ (ユーエス) リミテッド ライアビリティ カンパニー | 副甲状腺ホルモン受容体1(pth1r)抗体およびその使用 |
JP2021516222A (ja) | 2018-03-16 | 2021-07-01 | ザ ジェネラル ホスピタル コーポレイション | 副甲状腺ホルモンポリペプチドコンジュゲートおよびその使用方法 |
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WO2003009804A2 (en) * | 2001-07-23 | 2003-02-06 | The General Hospital Corporation | Conformationally constrained parathyroid hormone (pth) analogs |
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JP4871128B2 (ja) | 2012-02-08 |
EP1653985A4 (en) | 2009-08-05 |
EP1653985A2 (en) | 2006-05-10 |
WO2005009358A2 (en) | 2005-02-03 |
US20070203071A1 (en) | 2007-08-30 |
US7910544B2 (en) | 2011-03-22 |
WO2005009358A3 (en) | 2005-06-23 |
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