JP2016516416A - 修飾tgf−ベータ2オリゴヌクレオチド - Google Patents
修飾tgf−ベータ2オリゴヌクレオチド Download PDFInfo
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- JP2016516416A JP2016516416A JP2016504685A JP2016504685A JP2016516416A JP 2016516416 A JP2016516416 A JP 2016516416A JP 2016504685 A JP2016504685 A JP 2016504685A JP 2016504685 A JP2016504685 A JP 2016504685A JP 2016516416 A JP2016516416 A JP 2016516416A
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Abstract
Description
以下の実施例において、表1で挙げられたオリゴヌクレオチドの影響は、それぞれTGF−ベータ1および/またはTGF−ベータ2発現の減少および阻害の観点から試験されている。SEQ ID NO.21(T−LNA:CGGCATGTCTATTTTGTA、5’−末端および3’−末端の3xヌクレオチドはLNAである)およびSEQ ID NO.22(scr−LNA:CGTTTAGGCTATGTACTT、5’−末端および3’−末端の3xヌクレオチドはLNAのある)が対照オリゴヌクレオチドとして使用され、SEQ ID NO.22(陰性対照)はSEQ ID NO.21(陽性対照)のスクランブル形式である。細胞は、トランスフェクション剤(例えば、リポフェクタミン)の存在下、または任意のトランスフェクション剤の非存在下(ジムノティックトランスフェクションまたはアンアシステッドランスフェクションまたはジムノティックデリバリーとして規定される)のいずれかでトランスフェクションされる。ジムノティックデリバリーの場合のように、細胞へのオリゴヌクレオチドのエントリーが細胞とのオリゴヌクレオチドの相互作用にもっぱら依存する(どの製剤もエントリーを支持せず)。それ故、ジムノティックデリバリーは、インビボでの設定のより良い条件を反映していると考えられている。
ヒトPanc−1膵臓癌細胞(図3a)またはマウスRenCa腎細胞癌細胞(図3b)を、トランスフェクション剤(ジムノティックトランスフェクションまたはジムノティックデリバリー)の非存在下で、1.1μΜのASPH190、ASPH191、ASPH192、ASPH193、ASPH194、ASPH195、ASPH196、ASPH197、ASPH198、ASPH199、ASPH200、ASPH201、ASPH202、ASPH203、ASPH204、ASPH205、ASPH206、ASPH207、ASPH208、ASPH209、ASPH210、ASPH211、ASPH212、ASPH213、ASPH214、ASPH215、ASPH216、ASPH217、ASPH218、ASPH219、ASPH220、ASPH221、ASPH222、またはASPH223で処理した。TGF−ベータ1(黒カラム)、TGF−ベータ2(白カラム)およびTGF−ベータ3(ストライプカラム)mRNAの発現をトランスフェクションから72時間後に決定した。TGF−ベータ2mRNAの発現の有意な減少を図3aおよび図3bに示す。陰性対照は、SEQ ID NO.22のスクランブルLNA(scr LNA)である。
ヒトPanc−1膵臓癌細胞を、トランスフェクション剤(ジムノティックトランスフェクションまたはジムノティックデリバリー)の非存在下で、10μΜ、3.3μΜ、1.1μΜ、0.37μΜおよび0.12μΜのASPH47、M1−ASPH47、M2−ASPH47、M3−ASPH47、M4−ASPH47、M5−ASPH47、Μ6−ASPH47、M7−ASPH47、M8−ASPH47、M9−ASPH47、M10−ASPH47、M11−ASPH47、M12−ASPH47、M13−ASPH47、M14−ASPH47、またはM15−ASPH47で処理した。TGF−ベータ2mRNAの発現に対する修飾オリゴヌクレオチドの阻害効果を、処理開始から72時間後に測定した。TGF−ベータ2の値は、GAPDHに対して正規化し、TGF−ベータ2mRNAの50%の減少(=IC50値)をもたらすオリゴヌクレオチド濃度を算出した。ジムノティックトランスフェクション実験条件下で、オリゴヌクレオチドは細胞に入り、TGF−ベータ2mRNAの発現を強く阻害する。実験結果を表2に示す。
ヒトPanc−l膵臓癌細胞を、20、6.67、2.22、0.74、0.25、0.08または0.009μΜの修飾オリゴヌクレオチドASPH47でトランスフェクトし、結果を図4aに示す。陰性対照は、SEQ ID NO.22(図4b)のスクランブルオリゴヌクレオチド(scrLNA)である。細胞を、トランスフェクション剤(ジムノティックトランスフェクションまたはジムノティックデリバリー)の非存在下で、トランスフェクトした。オリゴヌクレオチドは、37℃でインキュベートされた細胞に3日間添加された。その後、培地を、培地を含有する新鮮なオリゴヌクレオチドと交換し、細胞を37℃でさらに4日間インキュベートした。細胞上清中のTGF−ベータ1およびTGF−ベータ2タンパク質レベルは、ELISAによって決定された。ASPH47は、用量依存的にTGF−ベータ2の発現を特異的に阻害し、TGF−ベータ1に対するターゲット阻害効果を示さない(図4a)。たとえ、ASPH47の濃度と比較して2倍の濃度(40、13.33、4.44、1.48、0.49、0.16、0.05、0.02μM)にしても、SEQ ID NO.22のscrLNAは、TGF−ベータ1またはTGF−ベータ2のいずれの発現に対しても全く阻害効果を示さない。図4aおよび図4b中に、TGF−ベータ1の結果を菱形で示し、TGF−ベータ2の結果を四角で示す。
Claims (8)
- オリゴヌクレオチドの、1以上のヌクレオチドが修飾され、修飾ヌクレオチドは、LNAおよび/若しくはENA、ポリアルキレンオキシド−、2’−フルオロ−、2’−O−メトキシ−、並びに/または2’O−メチル−修飾ヌクレオチドである、SEQ ID NO.1のTGF−ベータ2核酸配列の10から18のヌクレオチドからなるアンチセンスオリゴヌクレオチド。
- 前記修飾ヌクレオチドは、前記オリゴヌクレオチドの5’および/または3’末端に位置する、請求項1に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、
SEQ ID NO.2、SEQ ID NO.3、SEQ ID NO.4、SEQ ID NO.5、SEQ ID NO.6、SEQ ID NO.7、SEQ ID NO.8、SEQ ID NO.9、SEQ ID NO.10、SEQ ID NO.11、SEQ ID NO.12、SEQ ID NO.13、SEQ ID NO.14、SEQ ID NO.15、SEQ ID NO.16、SEQ ID NO.17、およびSEQ ID NO.18.からなる群から選択される配列を含む、または、からなる、請求項1または2に記載のアンチセンスオリゴヌクレオチド。 - 前記オリゴヌクレオチドは、AGTATTTGGTCTCC(ASPH190)、AAGTATTTGGTCTC(ASPH191)、AAGTATTTGGTCTCC(ASPH192)、CAAAGTATTTGGTCT(ASPH193)、AGTATTTGGTCTCC(ASPH194)、AGTATTTGGTCTCC(ASPH195)、AGTATTTGGTCTCC(ASPH196)、AGTATTTGGTCTCC(ASPH197)、AAGTATTTGGTCTC(ASPH198)、AGTATTTGGTCTCCA(ASPH199)、AGTATTTGGTCTCCA(ASPH200)、AGTATTTGGTCTCCA(ASPH201)、AGTATTTGGTCTCCA(ASPH202)、AGTATTTGGTCTCCA(ASPH203)、AGTATTTGGTCTCCA(ASPH204)、AGTATTTGGTCTCCA(ASPH205)、AAGTATTTGGTCTCC(ASPH206)、AAGTATTTGGTCTCC(ASPH207)、AAGTATTTGGTCTCC(ASPH208)、AAGTATTTGGTCTCC(ASPH209)、AAGTATTTGGTCTCC(ASPH210)、AAGTATTTGGTCTCC(ASPH211)、CAAAGTATTTGGTCTCC(ASPH212)、CAAAGTATTTGGTCTCC(ASPH213)、CAAAGTATTTGGTCTCC(ASPH214)、CAAAGTATTTGGTCTCC(ASPH215)、CAAAGTATTTGGTCTCC(ASPH216)、CAAAGTATTTGGTCTCC(ASPH217)、CAAAGTATTTGGTCTCC(ASPH218)、CAAAGTATTTGGTCTCC(ASPH219)、CAAAGTATTTGGTCTCC(ASPH220)、CAAAGTATTTGGTCTCC(ASPH221)、CAAAGTATTTGGTCTCC−TEG(ASPH222)、CAAAGTATTTGGTCTCC−TEG(ASPH223)、CAAAGTATTTGGTCTC(M1−ASPH47)、CAAAGTATTTGGTCT(M2−ASPH47)、CAAAGTATTTGGTC(M3−ASPH47)、AAAGTATTTGGTCTCC(M4−ASPH47)、AAAGTATTTGGTCTC(M5−ASPH47)、AAAGTATTTGGTCT(M6−ASPH47)、AAAGTATTTGGTC(M7−ASPH47)、AAGTATTTGGTCTCC(M8−ASPH47)、AAGTATTTGGTCTC(M9−ASPH47)、AAGTATTTGGTCT(M10−ASPH47)、AAGTATTTGGTC(M11−ASPH47)、AGTATTTGGTCTCC(M12−ASPH47)、AGTATTTGGTCTC(M13−ASPH47)、AGTATTTGGTCT(M14−ASPH47)、AGTATTTGGTC(M15−ASPH47)、およびCAAAGTATTTGGTCTCC(ASPH47)からなる群から選択される、請求項1または3に記載のアンチセンスオリゴヌクレオチド。
- 請求項1から4のいずれか1項に記載のアンチセンスオリゴヌクレオチドおよび選択的に薬学的に許容される担体を含む医薬組成物。
- 悪性および/若しくは良性腫瘍、免疫疾患、線維症、または眼の疾患を予防および/または治療する方法において使用される、請求項1から4のいずれか1項に記載のアンチセンスオリゴヌクレオチドまたは請求項5に記載の医薬組成物。
- 腫瘍は、固形腫瘍、血液生まれの腫瘍、白血病、腫瘍転移、血管腫、聴神経腫、神経線維腫、トラコーマ、化膿性肉芽腫、乾癬、星細胞腫、聴神経腫、芽細胞腫、ユーイング腫瘍、頭蓋咽頭腫、上衣腫、髄芽腫、神経膠腫、血管芽腫、ホジキンリンパ腫、髄芽腫、白血病、中皮腫、神経芽腫、神経線維腫、非ホジキンリンパ腫、松果体腫、網膜芽細胞腫、肉腫、セミノーマ、トラコーマ、ウィルムス腫瘍からなる群から選択される、または胆管癌、膀胱癌、脳腫瘍、乳癌、気管支癌、腎臓、子宮頸がん、絨毛癌、脈絡膜癌、嚢胞腺癌、胎生期癌、上皮癌、子宮頸癌、結腸癌、結腸直腸癌、子宮内膜癌の癌、胆嚢癌、胃癌、頭部癌、肝癌、肺癌、髄様癌、頸部癌、非小細胞気管支/肺癌、卵巣癌、膵臓癌、乳頭癌、乳頭状腺癌、前立腺癌、小腸癌、前立腺癌、直腸癌、腎細胞癌、皮膚癌、小細胞気管支/肺癌、扁平上皮癌、皮脂腺癌、睾丸癌、および子宮癌からなる群から選択される、請求項6に記載の使用のためアンチセンスオリゴヌクレオチドまたは医薬組成物。
- 前記眼の疾患は、緑内障、後嚢混濁、ドライアイ、例えば加齢黄斑変性症、糖尿病性黄斑エンドマのような黄斑変性症、白内障、増殖性硝子体網膜症、マルファンおよびロイエス−ディーツ症候群からなる群から選択される、請求項6に記載の使用のためのアンチセンスオリゴヌクレオチドまたは医薬組成物。
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EP1568383A3 (en) | 2004-02-27 | 2005-11-16 | Antisense Pharma GmbH | Use of an oligonucleotide or its active derivative for the preparation of a pharmaceutical composition for inhibiting the formation of metastases in cancer treatment |
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US20110119781A1 (en) * | 2008-07-15 | 2011-05-19 | Birgit Bramlage | Compositions and Methods for Inhibiting Expression of TGF-BETA Receptor Genes |
EP2453017A1 (en) | 2010-11-12 | 2012-05-16 | Antisense Pharma GmbH | Oligonucleotides for use in prophylaxis and/or treatment of TGF-beta1 and TGF-beta2, TGF-beta2 and TGF-beta3, TGF-beta1 and TGF-beta3, or TGF-beta1, TGF-beta2, and TGF-beta3 mRNA overexpressing diseases |
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JP2019534042A (ja) * | 2016-10-07 | 2019-11-28 | セカルナ・ファーマシューティカルズ・ゲーエムベーハー・ウント・コ・カーゲー | Cd39の発現を阻害する免疫抑制復帰オリゴヌクレオチド |
JP7146777B2 (ja) | 2016-10-07 | 2022-10-04 | セカルナ・ファーマシューティカルズ・ゲーエムベーハー・ウント・コ・カーゲー | Cd39の発現を阻害する免疫抑制復帰オリゴヌクレオチド |
US11959083B2 (en) | 2016-10-07 | 2024-04-16 | Secarna Pharmaceuticals Gmbh & Co. Kg | Immunosuppression-reverting oligonucleotides inhibiting the expression of CD39 |
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BR112015024729B1 (pt) | 2022-02-15 |
BR112015024729A2 (pt) | 2017-10-24 |
CN105308182B (zh) | 2018-09-25 |
EP2978844A1 (en) | 2016-02-03 |
PL2978844T3 (pl) | 2021-01-25 |
DK2978844T3 (da) | 2020-11-16 |
BR112015024729A8 (pt) | 2018-01-23 |
KR20150140703A (ko) | 2015-12-16 |
ES2830051T3 (es) | 2021-06-02 |
US20180087055A1 (en) | 2018-03-29 |
EP2978844B1 (en) | 2020-08-12 |
CA2908105A1 (en) | 2014-10-02 |
HK1221255A1 (zh) | 2017-05-26 |
CA2908105C (en) | 2021-07-27 |
US20160060632A1 (en) | 2016-03-03 |
WO2014154843A1 (en) | 2014-10-02 |
KR102108600B1 (ko) | 2020-05-08 |
EA201591595A1 (ru) | 2016-05-31 |
US9840707B2 (en) | 2017-12-12 |
JP6492054B2 (ja) | 2019-03-27 |
CN105308182A (zh) | 2016-02-03 |
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