JP5208734B2 - ステロイドに対する応答性を調節する方法 - Google Patents
ステロイドに対する応答性を調節する方法 Download PDFInfo
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- JP5208734B2 JP5208734B2 JP2008519236A JP2008519236A JP5208734B2 JP 5208734 B2 JP5208734 B2 JP 5208734B2 JP 2008519236 A JP2008519236 A JP 2008519236A JP 2008519236 A JP2008519236 A JP 2008519236A JP 5208734 B2 JP5208734 B2 JP 5208734B2
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Description
添付の特許請求の範囲は、本明細書にその全文が取り込まれている。
図1は、ELISpotによって分析した5名(n=5)の異なる健常ドナーからのPBMCにおける、DIMS0150促進48時間に対応するIL−10産生細胞の数を示すグラフである。PBMCは、IL−10陽性スポットの検出前に、培地(基礎培地)中で、又は濃度を増加したCpG含有DIMS0150若しくはそのGpC対照IDX0526(0.1、1、5、10、25、100、150又は200μM)と、又はCpG−ODNのIDX0910(0.1又は10μM)及びIDX0900(3μM)と、48時間インキュベートした。柱状グラフの各柱は、5名の異なる血液ドナーからの平均した結果を表す。試料は、各実験/血液ドナーについて3回実施及び分析した。IDX0900は、3人の個人(n=3)について試験したものであることに注意すること。
5’−Xm−TTCGT−Yn−3’ (配列番号18)(ここで、XはA、T、C又はG、YはA、T、C又はG、m=0〜7、n=0〜7であり、少なくとも1つのCGジヌクレオチドはメチル化されていない)
を有するオリゴヌクレオチドの有効量が、前記患者に投与される。オリゴヌクレオチドは、又、以下の式:
5’−Xm−GTTCGTC−Yn−3’(配列番号17)(ここで、m=0〜6及びn=0〜6)
5’−Xm−AGTTCGTCC−Yn−3’(配列番号16)(ここで、m=0〜5及びn=0〜5)
5’−Xm−CAGTTCGTCCA−Yn−3’(配列番号15)(ここで、m=0〜4及びn=0〜4)
5’−Xm−ACAGTTCGTCCAT−Yn−3’(配列番号14)(ここで、m=0〜3及び n=0〜3)
5’−Xm−AACAGTTCGTCCATG−Yn−3’(配列番号13)(ここで、m=0〜2及びn=0〜2)
又は
5’−Xm−GAACAGTTCGTCCATGG−Yn−3’(配列番号12)(ここで、m=0〜1及びn=0〜1)
も有することができる。
5’−GGAACAGTTCGTCCATGGC−3’ (配列番号1)
を有する。
5’−Xm−TTCGT−Yn−3’(配列番号18)
(ここで、XはA、T、C又はG、YはA、T、C又はG、m=0〜7、n=0〜7であり、少なくとも1つのCGジヌクレオチドはメチル化されていない)
を有するオリゴヌクレオチドの使用に関する。
オリゴデオキシヌクレオチド(ODN)
本発明において、多くのODNが、ヒト末梢血単球(PBMC)又はマウス脾細胞を用いた促進実験に使用された。使用されたODNを表1に列挙する。オリゴヌクレオチドのいくつかにおいて、ジヌクレオチドモチーフを「逆転」させ、対照として機能させた。
Aveciaにより合成されたDIMS0150及びIDX0250を除き、全てのODNはBiomers. net, Germanyによって合成され、供給された。
細胞の調製
血液試料は、健常ボランティアから得た。PBMCをFicoll-Paque Plus(Pharmacia Biotech, Uppsala, Sweden)を使用して密度勾配遠心分離法により単離し、生理食塩リン酸バッファー(PBS)で3回洗浄し、10%熱不活性化ウシ胎仔血清(FCS)(Life Technologies)、100U/mlのペニシリン、100μg/mlのストレプトマイシン(Life Technologies)、2mMのL−グルタミン(Sigma)、ゲンタマイシン(Sigma)及び5mMのHEPES(Gibco, Life Technologies)を含有するRPMI1640(Sigma)に再懸濁した。細胞は0.4%トリパンブルー溶液(Sigma Aldrich)を使用して計数した。
各実験用に、脾臓をC57BL/6マウスから摘出した(マウスは、MTC animal unit,
Karolinska Institutetから入手し、ナイロン細胞濾過器を使用して滅菌条件下に単個細胞浮遊液を調製した(細胞濾過器100μM、BD Falcon)。次いで、細胞を完全RPMI1640(5%の熱不活性化FCS、2mMのL−グルタミン、100U/mlのペニシリン及び100μg/mlのストレプトマイシンを含有するRPMI1640)中、1,200rpm、7〜10分間で1回洗浄した。上清を静かにデカントし、細胞を赤血球細胞溶解バッファー(Sigma)(1ml)に再懸濁し、室温で、最大2分間インキュベートした。別の完全培地(5ml)を、既に記載したようにして遠心する前に加えた。上清を静かにデカントした後、細胞ペレットを完全培地に再懸濁し、細胞数を0.4%トリパンブルー溶液で測定した。
ELISpot
既に記載したように、プレコートしたPVDF系の、ELISpot(MABTech AB, Sweden)用膜プレートにPBMCを播種した。細胞を加える前に、PDVFプレートを、それぞれIFN−α、IFN−γ又はIL−10(ELISpotキットに含まれる;IFN−α、IFN−γ又はIL−10は、MABTech AB, Swedenから入手)に対する特異的被覆抗体で一夜、+4℃で被覆した。PBMCを完全RPMIcに500,000細胞/ウエルで播種した。播種後に直接、細胞をそれぞれのオリゴヌクレオチド(ODN)で処理した。最終ODN濃度が、100μl/ウエルの総容積中、0.1、1、5、10、25、50、100、150及び200μMになるように、各ODNを特定のウエルに加えた。試料は、3通り作成した。処理後、細胞を5%炭酸ガス、37℃、加湿インキュベーターで、インキュベートした。IFN−αを、24、48及び72時間に、それぞれ2、10及び3ドナーにつき分析した。IFN−γは、2、7及び5ドナーについて、それぞれ24、48及び72時間に分析した。IL−10は5及び4ドナーにつき、24、48及び72時間に分析した。サイトカイン産生細胞の検出及び計数は、生産者のマニュアルに従って実施した。ELISpotリーダーソフトウエアは、Center for Molecular Medicine, CMM, Karolinska Hospital, Solna, SwedenにあるAID2.3.3であった。
既に記載したようにして調製したPBMCを、PRMIc中500,000細胞/ウエルで、96ウエルフラット底面細胞培養プレートに播種した。播種後に直接、細胞をそれぞれのODNで処理した。最終ODN濃度を100μl/ウエルの総容積中、0.1、1、5、10、25、50、100、200及び300μMとなるように、特定のウエルに各ODNを加えた。試料は2重に調製した。処理後、細胞を5%炭酸ガスで、37℃、48時間、加湿インキュベーターでインキュベートした。上清を集め、製造者のプロトコールに従って−20℃で貯蔵した後、特定のQuantikine ELISAを使用して、サイトカインレベルを決定した(ヒトPBMC実験には、以下のELISAキットを使用した:ヒトIL−10及びヒトIFN−α。マウス脾細胞実験用には、ネズミIL−10及びネズミIFN−α、R&D Systems, Abingdon, UK、を使用した)。
DIMS0150で促進したPBMCのサイトカイン産生の評価
CpG含有ODN、DIMS0150の免疫促進活性を、ヒトPBMCで評価した。仮説は、異なった濃度のDIMS0150で、異なった時間インキュベートしたPBMCは、CpGに依存する様式でサイトカイン産生を促進するであろう、というものであった。そのため、CpG-DNAに応答してPBMCによって産生されることが知られている3つのサイトカイン、即ち、IFN−α、IL−10及びIFN−γを選択した。実際、別々の健常なドナー由来のPBMCは、ELISpotによって分析されたように、DIMS0150に応答して、全て時間に依存して(データは示していない)及び投与量に依存して、サイトカイン産生を示した。試験した3つのサイトカインの中では、IL−10が、DIMS0150で促進48時間後、最も応答したサイトカインであった(図1)。IL−10に対照的に、DIMS0150は、試験した全ての濃度及び時間点において、PBMCにおいてIFN−α及びIFN−γを誘導するのが、IFN−γの72時間(図2参照)及びIFN−αの48時間(図3を参照)に代表されるように、より弱かった。DIMS0150のCpG逆転型であるIDX0526も、又、潜在的なサイトカイン産生のCpG依存性を評価するために、全ての実験に含めた。IDX0526で処理したPBMCは、DIMS0150での促進と比較して、試験した3つの全てのサイトカインの産生はないか、又は、減少を示した(図1、2及び3を参照)。
DIMS0150に応答したPBMCのサイトカイン産生の定量
ELISpotにより観察された陽性細胞からのサイトカイン産生量を定量するため、ELISA分析を実施した。PBMCをDIMS0150の濃度を増加してインキュベートし、上清を、IL−10、IFN−α及びIFN−γのレベルにつき分析した。ELISpotのデータによって得られたこれらの結果に一致して、0.1μMと200μMの間(又はIFN−α及びIFN−γについては300μM)の濃度を用いて、インキュベーション48時間後に、全てのサイトカインのCpG依存性用量応答が得られた(図4A、B及びCを参照)。ELISpotとELISAは異なったパラメーター(即ち、特定のサイトカインを分泌する細胞数に対して、分泌されたサイトカイン量)を測定するので、ELISA測定は、注目するサイトカインを分泌する細胞数にかかわらず、特定の濃度で産生される実際の量に関する補足的情報として考慮すべきである。それ故、用量応答パターンは、これらの異なった技術から得られたものを比較する場合相異が表れるであろう。定量ELISAにより分析されたDIMS0150に対応する個々の相異について、ELISpotと比較して、広範に調べた(1〜3ドナー)。
PBMCにおける異なるCpG−ODNとのDIMS0150の比較
DIMS0150促進の用量応答を、公知のヒト及びネズミCpG−ODNのIDX0910及びIDX0920とそれぞれ比較した。加えて、このODN配列も、又、CpGジヌクレオチドを含有しており、CpG−DNAとして作用するであろうから、IDX0250も、又、この実験に組入れた。IDX0250のCpG側面塩基は、DIMS0150と少し異なっており、このことは、促進に際して、PBMCでのサイトカイン応答のレベルに影響するであろう。この研究において、PBMCは、CpG−ODNで48時間処理され、表面に浮かぶ前のそれら個々の逆転GpC対照を、IL−10及びIFN−γDIMS0150についての定量ELISAアッセイを用いて2重に分析し、IDX0250は100μMで同様のIL−10応答を引き起こしたが(図5)、しかし最低濃度(0.1μMから1μM)では、これらODNはPBMCのIL−10産生を促進しなかった。相対的に、PBMCとIDX0910又はIDX0920とのインキュベーションでは、使用した低濃度で最高のIL−10産生に達した。上清のIFN−γ分析では、IL−10と比較して、このサイトカインは低分泌となった(図6)。GpCの逆転対照又はIDX0304のいずれも、IFN−γを誘導しなかったが、PBMCにおいて幾分かのレベルでIL−10分泌が、2つの対照GpC−ODN、IDx0915及びIDX0925、で観察された。このことは、これらODNに完全なホスホロチオエート骨格が存在するからであろう。
マウス脾細胞におけるDIMS0150と異なるCpG−ODNとの比較
ヒト及びマウスは、異なるCpG−ODNに応答する。DIMS0150の免疫促進効果を、マウス脾細胞系で、PBMCにおいて実施されたCpG−ODNと同じセットと比較した(図6参照)。脾細胞をCpG−ODN及びそれらの個々の逆転陰性GpC対照と、上清をIFN−γ及びIL−10について分析する48時間前に、定量的ELISAアッセイを使って2重に処理した。脾細胞をDIMS0150と処理した場合、使用した最高濃度で強いIFN−γ応答がもたらされた。しかし、このアッセイで、IDX0250はDIMS0150よりもより強力であって、このことは、CpGの周囲の配列が応答のレベルにインパクトを有することを示唆した(図7)。最も顕著なIFN−γレベルは、使用した低濃度でCpG−ODN、IDX0920で促進した細胞からの上清で見出された。最後に、IL−10のレベル(図8)について上清を分析すると、IFN−γを測定した場合に観察されたのと類似のパターンが示された。GpCは逆転ODN対照のいずれもIFN−γを誘導しなかったが、しかしIDX0920は、ネズミの系でIL−10のいくらかのレベルを誘導した。
TLR9の阻害
健常者ボランティアからのPBMCを、標準的手順を使って調製した。細胞を、5%FCS(Gibco)を含有するPRMIcでウエル当たり5×106細胞の密度で96ウエル培養プレートに播いた。公知のTLR9阻害剤であるクロロキン(CQ)及びConcavalin A(ConA)はSigmaから購入し、5mg/mlの原液として調製し貯蔵した。免疫促進オリゴヌクレオチド、配列番号11(IDX−0912b)、配列番号9(IDX−0920)及び配列番号1(DIMS0150)を前もって決定した至適作用濃度で培地に加えた。細胞を細胞インキュベーター(37℃、5%CO2)で、0、1、10又は50μg/mlCQで40分間予備インキュベートした。次いで、IS−ODNを、培養培地に加えた。
切断試験
末梢血細胞濃縮(軟膜)をKarolinska University Hospital Blood Bankからの健常血ドナーから得た。末梢血単核細胞(PBMC)をFicoll-Paque(Amersham Biosciences AB, Uppsala, Sweden)で、勾配遠心分離により分離した。リン酸バッファー生理食塩水(PBS、pH7.4、Ca2+及びMg2+不含)で3回洗浄後、細胞数及び生存率をトリパンブルー排除法で定量した。細胞を、完全培地、RPMIc(25mg/mlのゲンタマイシン、2mMのL−グルタミン、100U/mlのペニシリン、100mg/mlストレプトマイシン(Gibco BRL, Life Technologies Ltd)、5mMのHEPES及び熱不活化ウシ胎仔血清(FCS、Hyclone, Logan,UT, USA)を補充したRPMI1640培地)で、10×106細胞/mlに希釈した。単離したPBMCを、異なるオリゴジヌクレオチド(ODN)(表1)の存在下、最終濃度10又は100μMで、48ウエル培養プレート(400μl培地/ウエル、2×106細胞)にて培養した。RPMIcのみを陰性対照とした。細胞を48時間、37℃で、空気中6%CO2、加湿条件下でインキュベートした。細胞上清を集め、製造者のプロトコールに従って、FACSCaliburフローサイトメーターを用いたcytometric bead array (CBA)(Becton Dickinson)を利用し、次いでCellQuestソフトウエア(Becton Dickinson)を用いて解析して、サイトカインの存在を分析した。低検出限界は、各サイトカインにつき、20pg/mlであった。図10A及び10Bは、オリゴヌクレオチドの各末端からヌクレオチドを除去して配列を切断することによって、配列番号1の長さを減少しても、IL−10促進に関して活性はまだ保持されていることを示唆している。例えば、IDX−0031b、原配列番号1を切断した13量体(13 mer)は、なお濃度100μMでIL−10を誘導することができた。10μMの低濃度で、原配列番号1から切断した15量体(15 mer)バージョン(IDX−0027b1)まで活性が見られた。
研究コンセプトの予備試験
研究コンセプトの予備試験については、付録Iに全てを記載する。
試験目標
第1目標:
潰瘍性大腸炎及びクローン病患者における、配列番号1と表示されるDNAを基礎とするオリゴヌクレオチドの使用に関する安全性の問題を評価すること。
第2目標:
内視鏡的及び臨床的寛解/改善率、組織学的改善及び臨床検査パラメーターにおける変化によって定量された、臨床的有効性を探究する。
試験は、プラセボ対照、二重盲検単回投与であり、コルチコステロイドに非応答性か、又はコルチコステロイド依存性の患者で、同時にステロイド療法を受けている患者を考慮する。
第1周での臨床応答
i)配列番号1 5/7(71%)の応答者
ii)プラセボ 1/4(25%)の応答者
全体として、この予備試験は、単回直腸投与後の両投与群において、良好な有効性を示唆した。多分もっと驚くべきことは、全ての応答した患者が試験薬を受けてから1週間以内に応答したように、応答の速さであった。興味あることは、配列番号1を受けた7患者中2名は、今日同様に寛解状態にあり、ステロイドなしであることである。更に、重篤な有害事象は記録されなかった。
臨床第II相試験
試験目標
第1目標:
軽度から中等度の活性の潰瘍性大腸炎(UC)の患者における臨床的寛解を導く抗炎症療法として、オリゴヌクレオチド配列番号1の4投与水準(0.3mg、3mg、30mg及び100mg)の各作用能力を、プラセボと比較しながら評価すること。
第2目標
プラセボと比較しながら、配列番号1のオリゴヌクレオチドの単回直腸投与の忍容性を評価すること、及び配列番号1のオリゴヌクレオチドの有効性及び安全性を4投与水準で更に評価すること、及び直腸投与後の配列番号1のオリゴヌクレオチドの薬物動態を評価すること。
Bauer M, Redecke V, Ellwart JW, Scherer B, Kremer JP, Wagner H, Lipford GB.
Bacterial CpG-DNA triggers activation and maturation of human CD11c-, CD123+ dendritic cells. J Immunol. 2001 Apr 15;166(8):5000-7.
Bennet JD and Brinkman M (1989) Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet 1:164.
Borody TJ, Warren EF, Leis S, Surace R, Ashman O. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003 Jul;37(1):42-7.
Chikanza IC and Kozaci DL. Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives. Rheumatology 2004 43:1337-1345.
Cowdery JS, Chace JH, Yi AK, Krieg AM.Bacterial DNA induces NK cells to produce IFN-gamma in vivo and increases the toxicity of lipopolysaccharides. J Immunol 1996 Jun 15;156(12):4570-5.
Eiseman B, Silen W, Bascom GS et al (1958) Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 44:854-859.
Eui-Young So, Hyun-Hee Park and Choong-Eun Lee. IFN-gamma and IFN-alpha post transcriptionally down regulate the IL-4 induced IL-4 receptor gene expression. J of Immunology, 2000 165:5472-5479.
Gill PS, Harrington W Jr, Kaplan MH, Ribeiro RC, Bennett JM, Liebman HA, Bernstein-Singer M, Espina BM, Cabral L, Allen S, et al (1995) Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 332:1744-8.
Hacker H, Mischak H, Miethke T, Liptay S, Schmid R, Sparwasser T, Heeg K, Lipford GB, Wagner H. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 1998 Nov 2;17(21):6230-40.
Hamid QA, Wenzel SE, Hauk PJ, Tsicopoulos A, Wallaert B, Lafitte JJ, Chrousos GP, Szefler SJ, Leung DY Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1600-4.
Hartmann G, Krieg AM.Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol 2000 Jan 15;164(2):944-53.
Hartmann G, Weiner GJ, Krieg AM. CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9305-10.
Hawrylowicz CM, O'Garra A (2005) Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol. 5:271-83.
Hawrylowicz CM, Richards D, Loke TK, Corrigan C, Lee T (2002) A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol. 109:369-70.
Iho S, Yamamoto T, Takahashi T, Yamamoto S.Oligodeoxynucleotides containing palindrome sequences with internal 5'-CpG-3' act directly on human NK and activated T cells to induce IFN-gamma production in vitro. J Immunol 1999 Oct 1;163(7):3642-52.
Jakob T, Walker PS, Krieg AM, Udey MC, Vogel JC Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA. J Immunol 1998 Sep 15;161(6):3042-9.
Kline JN. .Effects of CpG DNA on Th1/Th2 balance in asthma. Curr Top Microbiol
Immunol. 2000;247:211-25.
Klinman DM, Barnhart KM, Conover J. CpG motifs as immune adjuvants. Vaccine. 1999 Jan;17(1):19-25.
Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA,
Klinman DM. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995 Apr 6; 374(6522):546-9.
Krieg AM, Matson S, Fisher E.Oligodeoxynucleotide modifications determine the magnitude of B cell stimulation by CpG motifs. Antisense Nucleic Acid Drug Dev 1996 Summer;6(2):133-9.
Krieg. Applied Oligonucleotide Technology. C.A. Stein and A. M. Krieg (Eds.), John Wiley and Sons, Inc., New York, Ny, 1998, pp. 431-448.
Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R, Giese T, Engelmann H, Endres S, Krieg AM, Hartmann G. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol. 2001 Oct;31(10):3026-37.
Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL, Quezado M, Neurath MF, Salfeld J, Veldman GM, Schwertschlag U, Strober W; Anti-IL-12 Crohn's Disease Study Group.Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med. 2004 Nov 11;351(20):2069-79.
Musch E, Andus T, Malek M. Induction and maintenance of clinical remission by interferon-beta in patients with steroid-refractory active ulcerative colitis-an open long-term pilot trial. Aliment Pharmacol Ther. 2002 Jul;16(7):1233-9.
Naseer T, Minshall EM, Leung DY, Laberge S, Ernst P, Martin RJ, Hamid Q.Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am J Respir Crit Care Med. 1997 Mar;155(3):845-51.
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W.Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995 Nov 1;182(5):1281-90.
Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, Haussinger D. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996 May 30;334(22):1422-7.
Pisetsky DS. The immunologic properties of DNA. J Immunol. 1996 Jan 15;156(2):421-3.
Richards DF, Fernandez M, Caulfield J, Hawrylowicz CM (2005) Glucocorticoids drive human CD8(+) T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production. Eur J Immunol. 30:2344-54.
Smeltz RB, Chen J, Ehrhardt R, Shevach EM. Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression. J Immunol. 2002 Jun 15;168(12):6165-72.
Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol. 2000 May;105(5):943-50.
Sparwasser T, Koch ES, Vabulas RM, Heeg K, Lipford GB, Ellwart JW, Wagner H.Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol 1998 Jun;28(6):2045-54.
Stacey KJ, Sweet MJ, Hume DA. Macrophages ingest and are activated by bacterial DNA. J Immunol 1996 Sep 1;157(5):2116-22.
Stelmach I, Jerzynska J, Kuna P (2002) A randomized, double-blind trial of the
effect of glucocorticoid, antileukotriene and beta-agonist treatment on IL-10 serum levels in children with asthma. Clin Exp Allergy. 32:264-9.
Sumer N, Palabiyikoglu M (1995) Induction of remission by interferon-alpha in patients with chronic active ulcerative colitis. Eur J Gastroenterol Hepatol. 7:
597-602.
Taniguchi T and Takaoka A (2001) A weak signal for strong responses: interferons-alpha/beta revisited. Nat Rev Mol Cell Biol 2:378-386.
Tighe H, Takabayashi K, Schwartz D, Marsden R, Beck L, Corbeil J, Richman DD, Eiden JJ Jr, Spiegelberg HL, Raz E. Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur J Immunol. 2000 Jul;30(7):1939-47.
Tokunaga T, Yano O, Kuramoto E, Kimura Y, Yamamoto T, Kataoka T, Yamamoto S. Synthetic oligonucleotides with particular base sequences from the cDNA encoding proteins of Mycobacterium bovis BCG induce interferons and activate natural killer cells. Microbiol Immunol. 1992;36(1):55-66.
Tomitai K, Lim S, Hanazawa T, Usmani O, Stirling R, Chung KF, Barnes PJ, Adcock IM (2002) Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma. Clin Immunol. 102:258-66.
Tormey VJ, Leonard C, Faul J, Bernard S, Burke CM, Poulter LW (1998) Deregulations of monocyte differentiation in asthmatic subjects is reversed by IL-10. Clin Exp Allergy. 28:992-8.
Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O'Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006 Jan;116(1):146-55. Epub 2005 Dec 8.
Yamamoto S, Yamamoto T, Kataoka T, Kuramoto E, Yano O, Tokunaga T.Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN-mediated [correction of INF] natural killer activity. J Immunol. 1992 Jun 15;148(12):4072-6.
Zhao Q, Temsamani J, Iadarola PL, Jiang Z, Agrawal S Effect of different chemically modified oligodeoxynucleotides on immune stimulation. Biochem Pharmacol 1996 Jan 26;51(2):173-82.
Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, O'Grady J, Reichen J, Diago M, Lin A, Hoffman J, Brunda MJ. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000 Dec 7;343(23):1666-72.
Zimmermann S, Egeter O, Hausmann S, Lipford GB, Rocken M, Wagner H, Heeg K.CpG
oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J Immunol. 1998 Apr 15;160(8):3627-30.
Claims (21)
- 抗炎症治療に非応答性又は不十分な若しくは不適切な応答性の炎症状態に苦しむステロイド難治性の患者において、ステロイドの効果を増強するための薬剤を製造するための、下記配列:
5'−X m −AGTTCGTCC−Y n −3'(配列番号16)
(ここで、XはA、T、C又はG、YはA、T、C又はG、m=0〜5、n=0〜5であり、少なくとも1つのCGジヌクレオチドはメチル化されておらず、そしてオリゴヌクレオチドの長さは8〜100核酸塩基である)
を有するオリゴヌクレオチドの使用。 - オリゴヌクレオチドが、
5'−Xm−CAGTTCGTCCA−Yn−3'(配列番号15)
(ここで、m=0〜4、及びn=0〜4である)
である、請求項1に記載の使用。 - オリゴヌクレオチドが、
5'−Xm−ACAGTTCGTCCAT−Yn−3'(配列番号14)
(ここで、m=0〜3、及びn=0〜3である)
である、請求項1又は2に記載の使用。 - オリゴヌクレオチドが、
5'−Xm−AACAGTTCGTCCATG−Yn−3'(配列番号13)
(ここで、m=0〜2、及びn=0〜2である)
である、請求項1〜3のいずれか1項に記載の使用。 - オリゴヌクレオチドが、
5'−Xm−GAACAGTTCGTCCATGG−Yn−3'(配列番号12)
(ここで、m=0〜1、及びn=0〜1である)
である、請求項1〜4のいずれか1項に記載の使用。 - オリゴヌクレオチドの長さが8〜40核酸塩基である、請求項1に記載の使用。
- 患者がステロイド治療中である、請求項1〜6のいずれか1項に記載の使用。
- 患者が非ステロイド性抗炎症薬で治療中である、請求項1〜7のいずれか1項に記載の使用。
- 炎症状態が、潰瘍性大腸炎(UC)、クローン病(CD)、関節リウマチ、乾癬、肺気腫、喘息及び慢性閉塞性肺疾患(COPD)から成る群から選択される、請求項1〜8のいずれか1項に記載の使用。
- オリゴヌクレオチドが、骨格修飾を有する少なくとも1つのヌクレオチドを含み、そして修飾がオリゴヌクレオチドの全長に沿った任意の位置における1つ又はそれ以上のヌクレオチドで生じる、請求項1〜9のいずれか1項に記載の使用。
- 修飾が、ホスホロチオエート及びホスホロジチオエート修飾からなる群から選択されるリン酸骨格修飾である、請求項10に記載の使用。
- オリゴヌクレオチドが、メチルホスホネート、N3'→P5'−ホスホルアミデート、モルホリノ、ペプチド核酸(PNA)、架橋型核酸(LNA)、アラビノシル核酸(ANA)、フルオロアラビノシル核酸(FANA)及びメトキシエチル核酸(MOE)から成る群から選択される、DNA又はDNAの類縁体若しくは模倣体から成るオリゴヌクレオチドである、請求項1〜11のいずれか1項に記載の使用。
- オリゴヌクレオチドがステロイドと併用して投与される、請求項1〜12のいずれか1項に記載の使用。
- オリゴヌクレオチドがステロイドと同時に、又は逐次に投与される請求項13に記載の使用。
- オリゴヌクレオチドがステロイドと数ヶ月まで離れた一時的間隔で投与される請求項7に記載の使用。
- オリゴヌクレオチドが単回投与される請求項1〜15のいずれか1項に記載の使用。
- オリゴヌクレオチドが単回を超えて投与される請求項1〜15のいずれか1項に記載の使用。
- 患者に対するオリゴヌクレオチドの投与量が0.01μg〜100mg/kg体重である請求項1〜17のいずれか1項に記載の使用。
- 患者に対するオリゴヌクレオチドの投与量が0.1μg〜10mg/kg体重である請求項18に記載の使用。
- 患者に対するオリゴヌクレオチドの投与量が1μg〜5mg/kg体重である請求項19に記載の使用。
- オリゴヌクレオチドが吸入投与、眼投与、鼻腔内投与、非経口投与、経口投与、皮膚内投与又は直腸投与される請求項1〜20のいずれか1項に記載の使用。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012193192A (ja) * | 2005-07-01 | 2012-10-11 | Index Pharmaceuticals Ab | ステロイドに対する応答性を調節する方法 |
JP2012232988A (ja) * | 2005-07-01 | 2012-11-29 | Index Pharmaceuticals Ab | 免疫促進方法 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2625969A1 (en) * | 2005-10-28 | 2007-05-03 | Index Pharmaceuticals Ab | Composition and method for the prevention, treatment and/or alleviation of an inflammatory disease |
DK2656850T3 (en) | 2007-10-05 | 2016-11-28 | Index Pharmaceuticals Ab | Oligonucleotides for the treatment or alleviation of EDEMA |
CN105641700B (zh) | 2007-10-26 | 2021-01-01 | 莱顿教学医院 | 对抗肌肉病症的方式和方法 |
USRE48468E1 (en) | 2007-10-26 | 2021-03-16 | Biomarin Technologies B.V. | Means and methods for counteracting muscle disorders |
EP2119783A1 (en) | 2008-05-14 | 2009-11-18 | Prosensa Technologies B.V. | Method for efficient exon (44) skipping in Duchenne Muscular Dystrophy and associated means |
AU2009260907A1 (en) * | 2008-06-18 | 2009-12-23 | Index Pharmaceuticals Ab | Combination therapies against cancer |
AU2009311753B2 (en) | 2008-11-04 | 2015-01-15 | Index Pharmaceuticals Ab | Compounds and methods for the treatment of inflammatory diseases of the CNS |
WO2012084991A1 (en) * | 2010-12-21 | 2012-06-28 | Index Pharmaceuticals Ab | Biologically active oligonucleotides capable of modulating the immune system ii |
EP2596806A1 (en) | 2011-11-25 | 2013-05-29 | Index Pharmaceuticals AB | Method for prevention of colectomy |
CN112251436A (zh) | 2012-01-27 | 2021-01-22 | 比奥马林技术公司 | 治疗杜兴型肌营养不良症和贝克型肌营养不良症的具有改善特性的rna调节性寡核苷酸 |
JP2019535839A (ja) | 2016-11-29 | 2019-12-12 | ピュアテック ヘルス エルエルシー | 治療剤の送達のためのエクソソーム |
GB201707501D0 (en) * | 2017-05-10 | 2017-06-21 | Index Pharmaceuticals Ab | New therapy 2 |
GB201707503D0 (en) * | 2017-05-10 | 2017-06-21 | Index Pharmaceuticals Ab | New Therapy 3 |
Family Cites Families (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5149797A (en) * | 1990-02-15 | 1992-09-22 | The Worcester Foundation For Experimental Biology | Method of site-specific alteration of rna and production of encoded polypeptides |
EP0468520A3 (en) | 1990-07-27 | 1992-07-01 | Mitsui Toatsu Chemicals, Inc. | Immunostimulatory remedies containing palindromic dna sequences |
TW244371B (ja) * | 1992-07-23 | 1995-04-01 | Tri Clover Inc | |
US6346614B1 (en) * | 1992-07-23 | 2002-02-12 | Hybridon, Inc. | Hybrid oligonucleotide phosphorothioates |
US5652355A (en) * | 1992-07-23 | 1997-07-29 | Worcester Foundation For Experimental Biology | Hybrid oligonucleotide phosphorothioates |
CA2105595A1 (en) * | 1992-09-23 | 1994-03-24 | Ramaswamy Narayanan | Antisense polynucleotides |
US5849719A (en) | 1993-08-26 | 1998-12-15 | The Regents Of The University Of California | Method for treating allergic lung disease |
ATE420171T1 (de) | 1994-07-15 | 2009-01-15 | Univ Iowa Res Found | Immunomodulatorische oligonukleotide |
US6429199B1 (en) * | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
US6239116B1 (en) * | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US20030078223A1 (en) * | 1996-01-30 | 2003-04-24 | Eyal Raz | Compositions and methods for modulating an immune response |
ATE437943T1 (de) | 1996-01-30 | 2009-08-15 | Univ California | Expressionsvektoren, die eine antigen-spezifische immunantwort induzieren, und methoden für ihre verwendung. |
SE9602300D0 (sv) | 1996-06-11 | 1996-06-11 | Karolinska Innovations Ab | New composition and methods |
EP0930893B1 (en) | 1996-10-11 | 2005-04-13 | The Regents of The University of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
US6214806B1 (en) * | 1997-02-28 | 2001-04-10 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CPC dinucleotide in the treatment of LPS-associated disorders |
US6406705B1 (en) * | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
PT1005368E (pt) | 1997-03-10 | 2009-11-19 | Coley Pharm Gmbh | Utilização de ácidos nucleicos contendo dinucleótidos cpg não metilados em combinação com alúmen como adjuvante |
US6426334B1 (en) * | 1997-04-30 | 2002-07-30 | Hybridon, Inc. | Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal |
CA2301575C (en) | 1997-05-20 | 2003-12-23 | Ottawa Civic Hospital Loeb Research Institute | Vectors and methods for immunization or therapeutic protocols |
US6589940B1 (en) * | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US6133246A (en) * | 1997-08-13 | 2000-10-17 | Isis Pharmaceuticals Inc. | Antisense oligonucleotide compositions and methods for the modulation of JNK proteins |
DE69935507T2 (de) * | 1998-04-03 | 2007-12-06 | University Of Iowa Research Foundation | Verfahren und produkte zur stimulierung des immunsystems mittels immunotherapeutischer oligonukleotide und zytokine |
EP1077708A1 (en) | 1998-05-06 | 2001-02-28 | University Of Iowa Research Foundation | Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides |
CA2328406A1 (en) | 1998-05-14 | 1999-11-18 | Hermann Wagner | Methods for regulating hematopoiesis using cpg-oligonucleotides |
SI1077722T1 (sl) | 1998-05-22 | 2007-02-28 | Ottawa Health Research Inst | Metode in produkti za induciranje sluznicne imunosti |
US6562798B1 (en) | 1998-06-05 | 2003-05-13 | Dynavax Technologies Corp. | Immunostimulatory oligonucleotides with modified bases and methods of use thereof |
JP4663047B2 (ja) * | 1998-07-13 | 2011-03-30 | 株式会社半導体エネルギー研究所 | レーザー照射装置及び半導体装置の作製方法 |
AU764532B2 (en) | 1998-07-27 | 2003-08-21 | University Of Iowa Research Foundation, The | Stereoisomers of CpG oligonucleotides and related methods |
DK1221955T3 (da) | 1999-09-25 | 2006-01-30 | Univ Iowa Res Found | Immunstimulerende nukleinsyre |
US6949520B1 (en) * | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
EP1688147A1 (en) | 1999-09-27 | 2006-08-09 | Coley Pharmaceutical Group, Inc. | Methods Related to Immunostimulatory Nucleic Acid-Induced Interferon |
CA2386019C (en) | 1999-09-27 | 2011-06-21 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
US7223398B1 (en) * | 1999-11-15 | 2007-05-29 | Dynavax Technologies Corporation | Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof |
US7585847B2 (en) | 2000-02-03 | 2009-09-08 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for the treatment of asthma and allergy |
US20020156033A1 (en) * | 2000-03-03 | 2002-10-24 | Bratzler Robert L. | Immunostimulatory nucleic acids and cancer medicament combination therapy for the treatment of cancer |
US20040131628A1 (en) * | 2000-03-08 | 2004-07-08 | Bratzler Robert L. | Nucleic acids for the treatment of disorders associated with microorganisms |
US20020107212A1 (en) | 2000-03-10 | 2002-08-08 | Nest Gary Van | Methods of reducing papillomavirus infection using immunomodulatory polynucleotide sequences |
US6649341B1 (en) * | 2000-04-19 | 2003-11-18 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Human glucocorticoid receptor 1A promoter and splice variants |
PT1296714E (pt) | 2000-06-22 | 2009-10-15 | Coley Pharm Gmbh | Combinação de cpg e anticorpos dirigidos contra cd19, cd20, cd22 ou cd40 para o tratamento ou prevenção do cancro |
US20020198165A1 (en) * | 2000-08-01 | 2002-12-26 | Bratzler Robert L. | Nucleic acids for the prevention and treatment of gastric ulcers |
JP2005500806A (ja) * | 2000-09-15 | 2005-01-13 | コーリー ファーマシューティカル ゲーエムベーハー | CpGに基づく免疫アゴニスト/免疫アンタゴニストの高スループットスクリーニングのためのプロセス |
US6294382B1 (en) * | 2000-11-27 | 2001-09-25 | Isis Pharmaceuticals, Inc. | Antisense modulation of SRC-1 expression |
WO2002053141A2 (en) | 2000-12-14 | 2002-07-11 | Coley Pharmaceutical Group, Inc. | Inhibition of angiogenesis by nucleic acids |
JP2002257827A (ja) * | 2001-03-01 | 2002-09-11 | Jenokkusu Soyaku Kenkyusho:Kk | ステロイド応答性の検査方法 |
US20030050268A1 (en) * | 2001-03-29 | 2003-03-13 | Krieg Arthur M. | Immunostimulatory nucleic acid for treatment of non-allergic inflammatory diseases |
US20070021360A1 (en) | 2001-04-24 | 2007-01-25 | Nyce Jonathan W | Compositions, formulations and kit with anti-sense oligonucleotide and anti-inflammatory steroid and/or obiquinone for treatment of respiratory and lung disesase |
JP4397571B2 (ja) * | 2001-09-25 | 2010-01-13 | 株式会社半導体エネルギー研究所 | レーザ照射方法およびレーザ照射装置、並びに半導体装置の作製方法 |
WO2003031573A2 (en) * | 2001-10-05 | 2003-04-17 | Coley Pharmaceutical Gmbh | Toll-like receptor 3 signaling agonists and antagonists |
CN100438908C (zh) * | 2001-10-06 | 2008-12-03 | 梅瑞尔有限公司 | CpG制剂及相关方法 |
US7105048B2 (en) * | 2001-11-30 | 2006-09-12 | Semiconductor Energy Laboratory Co., Ltd. | Laser irradiation apparatus |
JP3949564B2 (ja) * | 2001-11-30 | 2007-07-25 | 株式会社半導体エネルギー研究所 | レーザ照射装置及び半導体装置の作製方法 |
EP1474432A1 (en) * | 2002-02-04 | 2004-11-10 | Biomira Inc. | Immunostimulatory, covalently lipidated oligonucleotides |
AU2003230806B2 (en) * | 2002-04-04 | 2009-05-07 | Zoetis Belgium S.A. | Immunostimulatory G,U-containing oligoribonucleotides |
US6977775B2 (en) * | 2002-05-17 | 2005-12-20 | Sharp Kabushiki Kaisha | Method and apparatus for crystallizing semiconductor with laser beams |
JP4474108B2 (ja) * | 2002-09-02 | 2010-06-02 | 株式会社 日立ディスプレイズ | 表示装置とその製造方法および製造装置 |
US20060257851A1 (en) * | 2002-11-26 | 2006-11-16 | Itzhak Bentwich | Bioinformatically detectable group of novel viral regulatory genes and uses thereof |
WO2004058179A2 (en) | 2002-12-23 | 2004-07-15 | Dynavax Technologies Corporation | Immunostimulatory sequence oligonucleotides and methods of using the same |
CA2508985A1 (en) | 2002-12-23 | 2004-07-15 | Dynavax Technologies Corporation | Branched immunomodulatory compounds and methods of using the same |
US7851453B2 (en) * | 2003-01-16 | 2010-12-14 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides |
US7517520B2 (en) * | 2003-03-26 | 2009-04-14 | Cytos Biotechnology Ag | Packaging of immunostimulatory oligonucleotides into virus-like particles: method of preparation and use |
AU2004226605A1 (en) * | 2003-04-02 | 2004-10-14 | Coley Pharmaceutical Group, Ltd. | Immunostimulatory nucleic acid oil-in-water formulations for topical application |
US7569554B2 (en) | 2003-05-16 | 2009-08-04 | Idera Pharmaceuticals, Inc. | Synergistic treatment of cancer using immunomers in conjunction with therapeutic agents |
US20050175630A1 (en) * | 2003-12-23 | 2005-08-11 | Eyal Raz | Immunogenic compositions and methods of use thereof |
US20050158325A1 (en) * | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Immunomodulatory combinations |
SE0400399D0 (sv) | 2004-02-20 | 2004-02-20 | Index Pharmaceuticals Ab | Methods and compositions for the treatment or prevention of secondary ischemic injury |
AU2005216075B2 (en) | 2004-02-20 | 2011-03-10 | Idera Pharmaceuticals, Inc. | Potent mucosal immune response induced by modified immunomodulatory oligonucleotides |
WO2005080567A1 (de) | 2004-02-20 | 2005-09-01 | Mologen Ag | Substituiertes, nicht-kodierendes nukleinsäuremolekül zur therapeutischen und prophylaktischen immunstimulation in menschen und höheren tieren |
BRPI0512110A (pt) | 2004-06-15 | 2007-10-23 | Idera Pharmaceutical Inc | multìmeros de oligonucleotìdeos imunoestimulatórios |
JP5072197B2 (ja) * | 2004-06-18 | 2012-11-14 | 株式会社半導体エネルギー研究所 | レーザ照射装置およびレーザ照射方法 |
WO2006015560A1 (de) | 2004-08-09 | 2006-02-16 | Mologen Ag | Immunmodulierendes mittel in verbindung mit chemotherapeutischen massnahmen |
PL1794174T3 (pl) | 2004-09-01 | 2012-11-30 | Dynavax Tech Corp | Sposoby i kompozycje do hamowania wrodzonych odpowiedzi immunologicznych i autoodporności |
AU2006235284A1 (en) * | 2005-04-08 | 2006-10-19 | Coley Pharmaceutical Group, Inc. | Methods for treating infectious disease exacerbated asthma |
SI2269622T1 (sl) * | 2005-07-01 | 2014-05-30 | Index Pharmaceuticals Ab | CpG OLIGONUKLEOTIDI, KI SE UPORABLJAJO ZA IZBOLJĹ ANJE STEROIDNE AKTIVNOSTI PRI STEROIDNO ODVISNIH BOLNIKIH |
PT2179737E (pt) * | 2005-07-01 | 2013-12-05 | Index Pharmaceuticals Ab | Método para modular a capacidade de resposta aos esteróides |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2012193192A (ja) * | 2005-07-01 | 2012-10-11 | Index Pharmaceuticals Ab | ステロイドに対する応答性を調節する方法 |
JP2012232988A (ja) * | 2005-07-01 | 2012-11-29 | Index Pharmaceuticals Ab | 免疫促進方法 |
Also Published As
Publication number | Publication date |
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EP1904077B1 (en) | 2009-08-12 |
EP2179737A3 (en) | 2010-08-25 |
WO2007004979A1 (en) | 2007-01-11 |
PL2179737T3 (pl) | 2014-01-31 |
EP1904077A1 (en) | 2008-04-02 |
US20080318885A1 (en) | 2008-12-25 |
ES2330884T3 (es) | 2009-12-16 |
DK2179737T3 (da) | 2013-11-11 |
US8569257B2 (en) | 2013-10-29 |
JP5886699B2 (ja) | 2016-03-16 |
PT2179737E (pt) | 2013-12-05 |
EP2179737B1 (en) | 2013-08-14 |
JP2008544984A (ja) | 2008-12-11 |
DE602006008473D1 (de) | 2009-09-24 |
JP2012193192A (ja) | 2012-10-11 |
SI2179737T1 (sl) | 2014-02-28 |
US20120172420A1 (en) | 2012-07-05 |
US8148341B2 (en) | 2012-04-03 |
ATE439135T1 (de) | 2009-08-15 |
ES2435531T3 (es) | 2013-12-20 |
EP2179737A2 (en) | 2010-04-28 |
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