JP6545248B2 - Stat5阻害剤およびその使用 - Google Patents
Stat5阻害剤およびその使用 Download PDFInfo
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- JP6545248B2 JP6545248B2 JP2017500445A JP2017500445A JP6545248B2 JP 6545248 B2 JP6545248 B2 JP 6545248B2 JP 2017500445 A JP2017500445 A JP 2017500445A JP 2017500445 A JP2017500445 A JP 2017500445A JP 6545248 B2 JP6545248 B2 JP 6545248B2
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Description
a.本明細書中の上記のものなどのアプタマーを対象から前もって採取した前記試料と接触させ、
b.前記試料に結合した前記アプタマーの量を決定すること
を含む方法も有する。
本発明において、次の用語は次の意味を有する。
配列番号1:5’−TATCCGCAACCCACCTAGCGCCCTACCTCGTGGGAATCCAAACCCAACCAGTCCACCCAC−3’
配列番号2:5’−GTGTCTGTTCACTCGTCGATACACAGCATACTCAACCCAGGCCCCTGACTGCTAATCCCC−3’
配列番号57:5’−GTGTCTGTTCACTCGTCGATACACAACATACTCAACCCAGGCCCCTGACTGCTAATCCCC−3’。
配列番号3:5’−ATACCAGCTTATTCAATTTATCCGCAACCCACCTAGCGCCCTACCTCGTGGGAATCCAAACCCAACCAGTCCACCCACAGATAGTAAGTGCAATCT−3’.
配列番号4:5’−ATACCAGCTTATTCAATTGTGTCTGTTCACTCGTCGATACACAGCATACTCAACCCAGGCCCCTGACTGCTAATCCCCAGATAGTAAGTGCAATCT−3’.
配列番号58:5’−ATACCAGCTTATTCAATTGTGTCTGTTCACTCGTCGATACACAACATACTCAACCCAGGCCCCTGACTGCTAATCCCCAGATAGTAAGTGCAATCT−3’。
5’−GTGGGAATCCAAACCCAACCAGTCCACCCAC−3’(配列番号11);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACA−3’(配列番号12);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACT−3’(配列番号13);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACC−3’(配列番号14);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACG−3’(配列番号15);
5’−AGTGGGAATCCAAACCCAACCAGTCCACCCAC−3’(配列番号16);
5’−TGTGGGAATCCAAACCCAACCAGTCCACCCAC−3’(配列番号17);
5’−CGTGGGAATCCAAACCCAACCAGTCCACCCAC−3’(配列番号18);
5’−GGTGGGAATCCAAACCCAACCAGTCCACCCAC−3’(配列番号19);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACAT−3’(配列番号20);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACAC−3’(配列番号21);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACAG−3’(配列番号22);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACAA−3’(配列番号23);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACACA−3’(配列番号24);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACACT−3’(配列番号25);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACACG−3’(配列番号26);
5’−GTGGGAATCCAAACCCAACCAGTCCACCCACACC−3’(配列番号27);
5’−GTGGGAATCCTAACCCAACCAGTCCACCCAC−3’(配列番号28);
5’−GTGGGAATCCAAACCCAACCAGTCCAGCCAC−3’(配列番号29);
5’−GTGGGAATCCAAATCCCAACCAGTCCACCCAC−3’(配列番号30);
5’−GTGGGAATCCAAACCCAACCGAGTCCACCCAC−3’(配列番号31)。
5’−TTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号32);
5’−TTGTGTCTGTTCACTCGTCGATACACAGA−3’(配列番号33);
5’−TTGTGTCTGTTCACTCGTCGATACACAGT−3’(配列番号34);
5’−TTGTGTCTGTTCACTCGTCGATACACAGC−3’(配列番号35);
5’−TTGTGTCTGTTCACTCGTCGATACACAGG−3’(配列番号36);
5’−ATTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号37);
5’−CTTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号38);
5’−GTTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号39);
5’−TTTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号40);
5’−AATTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号41);
5’−TATTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号42);
5’−CATTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号43);
5’−GATTGTGTCTGTTCACTCGTCGATACACAG−3’(配列番号44);
5’−TTGTGTCTGTTCACTCGTCGATACACAGAA−3’(配列番号45);
5’−TTGTGTCTGTTCACTCGTCGATACACAGAT−3’(配列番号46);
5’−TTGTGTCTGTTCACTCGTCGATACACAGAC−3’(配列番号47);
5’−TTGTGTCTGTTCACTCGTCGATACACAGAG−3’(配列番号48);
5’−TTGTGTCTGTTCACTCGTCGATACACAGTA−3’(配列番号49);
5’−TTGTGTCTGTTCACTCGTCGATACACAGTT−3’(配列番号50);
5’−TTGTGTCTGTTCACTCGTCGATACACAGTC−3’(配列番号51);
5’−TTGTGTCTGTTCACTCGTCGATACACAGTG−3’(配列番号52);
5’−TTGTGTCTGTACACTCGTCGATACACAG−3’(配列番号53);
5’−TTGTGTCTGTTCACTCCTCGATACACAG−3’(配列番号54);
5’−TTGTGTCTGTTCAACTCGTCGATACACAG−3’(配列番号55);
5’−TTGTGTCTGTTCACTCGTCGGATACACAG−3’(配列番号56)。
5’−TTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号59);
5’−TTGTGTCTGTTCACTCGTCGATACACAAA−3’(配列番号60);
5’−TTGTGTCTGTTCACTCGTCGATACACAAT−3’(配列番号61);
5’−TTGTGTCTGTTCACTCGTCGATACACAAC−3’(配列番号62);
5’−TTGTGTCTGTTCACTCGTCGATACACAAG−3’(配列番号63);
5’−ATTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号64);
5’−CTTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号65);
5’−GTTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号66);
5’−TTTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号67);
5’−AATTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号68);
5’−TATTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号69);
5’−CATTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号70);
5’−GATTGTGTCTGTTCACTCGTCGATACACAA−3’(配列番号71);
5’−TTGTGTCTGTTCACTCGTCGATACACAAAA−3’(配列番号72);
5’−TTGTGTCTGTTCACTCGTCGATACACAAAT−3’(配列番号73);
5’−TTGTGTCTGTTCACTCGTCGATACACAAAC−3’(配列番号74);
5’−TTGTGTCTGTTCACTCGTCGATACACAAAG−3’(配列番号75);
5’−TTGTGTCTGTTCACTCGTCGATACACAATA−3’(配列番号76);
5’−TTGTGTCTGTTCACTCGTCGATACACAATT−3’(配列番号77);
5’−TTGTGTCTGTTCACTCGTCGATACACAATC−3’(配列番号78);
5’−TTGTGTCTGTTCACTCGTCGATACACAATG−3’(配列番号79);
5’−TTGTGTCTGTACACTCGTCGATACACAA−3’(配列番号80);
5’−TTGTGTCTGTTCACTCCTCGATACACAA−3’(配列番号81);
5’−TTGTGTCTGTTCAACTCGTCGATACACAA−3’(配列番号82);
5’−TTGTGTCTGTTCACTCGTCGGATACACAA−3’(配列番号83)。
a.少なくとも1つの本発明によるアプタマーを予め採取した対象からの細胞の試料と接触させ;
b.この試料に結合したアプタマーの量を決定すること
を含む方法である。
a.少なくとも1つの本発明によるアプタマーを予め採取した対象からの細胞の試料と接触させ;
b.この試料に結合したアプタマーの量を決定し;
c.この量を参照対照と比較すること;
を含み、試料に連結したこのアプタマーの検出の増加は、本発明の疾患を明らかにすることに対応する。
材料および方法
STAT5組み換えタンパク質を作製するための方法:
消化
QiaPrep Spin Mini−Prepキット(Qiagen)を用いて24時間細菌予備培養物を使用して、pTAT/HAプラスミドの抽出を行う。
遺伝子stat5Bと同じ条件でベクターpRSETBをKpnIおよびEcoRIによって消化する。
E.コリ(E.coli)細胞を予めコンピテントにし、pRSETB/stat5Bプラスミド構築によって形質転換する。
pRSETB/STAT5Bにより形質転換した細胞の10μLのグリセロール原液を10mLのLB/アンピシリン培地(5g NaCl、5gの酵母抽出物、10gのトリプトン;100μg/mLのアンピシリン)に添加する。撹拌しながら(180rpm−INFORS HT)細胞を37℃で12時間培養する。
標準範囲の濃度のウシ血清アルブミン(BSA)を調製する(0;25;50;75;100;150;200;300および500μg/mL)。BCA試薬は、ビシンコニン酸の溶液Aおよび4%硫酸銅である溶液Bから構成される(A/B:50/1)。10μLの一連のおよび各試料を96ウェルプレートで2つ組で分注する。BCA試薬を200μL/ウェルの割合で添加する。このプレートを37℃で30分間温置し、次いで560nmでの吸収を測定する。色の強度はタンパク質の質量濃度と比例する。
Stoltenburgら(2005 Anal Bioanal Chem.383(1):83−91)から始まったオリゴヌクレオチドのランダムバンクを次の形態で合成した(Eurogentec):
5’ATACCAGCTTATTCAATT N60 AGATAGTAAGTGCAATCT3’(式中、Nは無作為にA、T、GまたはCである。)(配列番号84)。
2mgのビーズを150から200μgのSTAT5Bタンパク質と温置すること(周囲温度で1時間)によって、ダイナビーズ(登録商標)His−Tag Isolation & Pulldown(Dynal)ビーズ上で精製STAT5Bタンパク質を捕捉する。オリゴヌクレオチドバンクを3nmol(ラウンド1)または200pmol(nでラウンド2)の割合で添加する。結合/洗浄緩衝液を最大で700μL、ビーズに添加し、これを4℃で撹拌しながら一晩温置する。
次のプライマー、一方の(センス)蛍光性、他方の(アンチセンス)荷電プライマーを用いて、PCRによってアプタマーを増幅する:
センス5’−フルオ−ATACCAGCTTATTCAATT−3’(配列番号9);
アンチセンス5’−ポリ−dA20−AGATTGCACTTACTATCT−3’(配列番号10)。
適応発現系で保持された配列をクローニングすることによって、選択したアプタマーの分析を行う。発現ベクターpGEMT(登録商標)の介在によってクローニングを行う。標準的プライマーT7を用いて配列決定を行う。
活性化STAT5細胞タンパク質の抽出
STAT5の2つの活性化細胞供給源を使用した:
−STAT5B1*6と呼ばれるSTAT5Bの発癌形態により形質転換されたBa/F3前リンパ球性マウス株;
−慢性骨髄性白血病に罹患した患者(染色体Phあり)を使用して樹立されたKU−812骨髄ヒト株。
結合/洗浄緩衝液(5X:Tris pH7.5 50mM;NaCl 50mM;EDTA 5mM;PMSF 2.5mM;グリセロール25%;NP40−テルギトール(Tergitol)(登録商標)0.5%)中、氷上で2時間にわたり細胞質および核抽出物の200μgのタンパク質とともに200pmolのビオチン化アプタマーを温置する。次いで混合物を4℃で撹拌しながら100μLのストレプトアビジンビーズ(Dynal)と30分間接触させる。全体を洗浄緩衝液で3時間洗浄する。次いでタンパク質を40μLの溶出緩衝液(Tris 0.5M 250mM pH6.8;グリセロール25%、SDS8%、β−メルカプトエタノール20%;H2O10mLまで)を添加することにより、および90℃で5分間加熱することによって溶出する。
SDS−PAGEゲル上での電気泳動後、ウエスタンブロットによってタンパク質を分析する。
37℃、5%CO2湿潤雰囲気で温置することによって、RPMI培地、10%SVF、1%グルタミン、1%ペニシリン/ストレプトマイシン中の培養物中で白血病細胞株を維持する。500,000個の細胞においてアプタマーの遺伝子移入を行う。6μgのビオチン化アプタマーおよび12μLのJetPEI(−ポリプラス・トランスフェクション(商標))を個々に100μLのNaCl 150mM中で希釈する。2種類の溶液を混合し、処理しようとする細胞に注ぐ。細胞を24時間置温する。
予め遺伝子移入した白血病細胞での遺伝子一式の発現におけるアプタマーの効果を試験した。タンパク質を抽出し、ヒトアポトーシス抗体アレイキット(R&D Systems)を用いてウエスタンブロットにより分析する。
タネル技術(末端デオキシヌクレオチドトランスフェラーゼdUTPニック末端標識)は、低分子量(モノまたはオリゴヌクレオソーム)の2本鎖DNA断片だけでなく高分子量の1本鎖断片の、アポトーシス細胞における存在に基づく。これらは、アポトーシス過程中のDNAの断片化の結果である。タネル技術の原理は、自由3’OH末端でフルオレセインでマークされたヌクレオチドの付加を触媒する末端デオキシヌクレオチジルトランスフェラーゼ酵素を使用することによりこれらの断片の末端を標識することに存する。
消化、ライゲーション、細菌形質転換の段階によりサブクローニングされたベクターpTAT−HA/statB5ベクターを使用してSTAT5Bマウスタンパク質(配列番号8)を作製する。先行技術からSTAT5Aマウス組み換えタンパク質(配列番号7)に関してSTAT5B組み換えタンパク質のより良好な産生が示される場合、STAT5の特異的なアプタマーを作製するためにSTAT5Bを作製することを決定した。配列決定後、組み換えタンパク質を産生させる目的で、原核発現系にベクター構築物を導入した。殆どの組み換えタンパク質と同様に、STAT5Bタンパク質は、細胞質において凝集し、封入体を形成する傾向がある。したがって、変性緩衝液によってこれらの封入体を用いてタンパク質を抽出した。次いで、産生されたタンパク質と一体化された6−His標識によってNi−NTA樹脂上でタンパク質を精製する。この段階に続いて、装置および方法に記載のものなどの再生段階を行う。
本明細書中上記で作製したSTAT5B組み換えタンパク質の特異的な阻害剤を選択するために、実行されるストラテジーはアプタマーの選択に基づいた。アプタマーは、複雑な三次元構造に組み立てることができるDNAまたはRNAの合成オリゴヌクレオチドである。したがって、アプタマーの選択は、核酸バンクを用いて最も相補的な標的構造、言い換えると最も安定な相互作用を生成させるものを同定することに戻る。
Apta1:5’ATACCAGCTTATTCAATTTATCCGCAACCCACCTAGCGCCCTACCTCGTGGGAATCCAAACCCAACCAGTCCACCCACAGATAGTAAGTGCAATCT−3’(配列番号3);
Apta2:5’ATACCAGCTTATTCAATTGTGTCTGTTCACTCGTCGATACACAGCATACTCAACCCAGGCCCCTGACTGCTAATCCCCAGATAGTAAGTGCAATCT−3’(配列番号4);
Apta3:5’ATACCAGCTTATTCAATTGTGTCTGTTCACTCGTCGATACACAACATACTCAACCCAGGCCCCTGACTGCTAATCCCCAGATAGTAAGTGCAATCT−3’(配列番号58)。
Apta1により遺伝子移入したKU−812細胞の増殖を図7で示す。
KU−812細胞にApta2を遺伝子移入した。Apta2を遺伝子移入したKU−812細胞の増殖を図10で示す。Apta2は、KU−812細胞の増殖を低下させる。
用量依存性について試験するために、KU812細胞に異なる濃度のApta2:50nM、150nMおよび300nMを遺伝子移入した(図12)。次いで、時間の関数として細胞生存能を試験した。このために、遺伝子移入6時間、12時間および24時間に、これらの濃度のそれぞれに対して細胞計数を行った。
DAPIで核をマークし、次いで断片を自由3’OH末端でフルオレセインとカップリングされたdUTPでマークすることによって、遺伝子移入後のDNAの断片化の観察を行った。遺伝子移入の6時間、12時間および24時間後に、150nMのapta2およびApta ctrl(変性させた配列Apta2)により処理した細胞において、タネルを介した分析を行った((図13)。
Claims (9)
- STAT5Bに特異的に結合する核酸アプタマーであって、配列番号1、配列番号2もしくは配列番号57の配列、あるいは配列番号1、配列番号2もしくは配列番号57と少なくとも90%の配列同一性を有する変異体、を含むことを特徴とする核酸アプタマー。
- さらなる安定化基および/またはベクトル化のためのさらなる基をさらに含む、請求項1に記載の核酸アプタマー。
- 少なくとも1つの請求項1から2の何れかに記載のアプタマーと、医薬的に許容可能な賦形剤と、を含む医薬組成物。
- 少なくとも1つの請求項1から2の何れかに記載のアプタマーを含む、薬剤。
- 癌または白血病の処置において使用するための、請求項1から2の何れかに記載の核酸アプタマー、請求項3に記載の医薬組成物または請求項4に記載の薬剤。
- 抗癌剤、抗血管新生薬、抗転移薬、抗白血病薬、葉酸代謝拮抗薬、代謝拮抗薬、アルキル化剤、挿入剤、紡錘体に作用する物質、チロシンキナーゼ阻害剤、分化剤またはそれらの混合物から選択される別の活性物質と組み合わせて使用するための、請求項1から2の何れかに記載の核酸アプタマー、請求項3に記載の医薬組成物または請求項4に記載の薬剤。
- 癌または白血病の処置において使用するための、抗癌剤、抗血管新生薬、抗転移薬、抗白血病薬、葉酸代謝拮抗薬、代謝拮抗薬、アルキル化剤、挿入剤、紡錘体に作用する物質、チロシンキナーゼ阻害剤、分化剤またはそれらの混合物から選択される別の活性物質と組み合わせた、請求項1または2に記載の核酸アプタマー。
- 癌または白血病の処置において使用するための、抗癌剤、抗血管新生薬、抗転移薬、抗白血病薬、葉酸代謝拮抗薬、代謝拮抗薬、アルキル化剤、挿入剤、紡錘体に作用する物質、チロシンキナーゼ阻害剤、分化剤またはそれらの混合物から選択される別の活性物質と組み合わせた、請求項3に記載の医薬組成物または請求項4に記載の薬剤。
- 生体試料においてSTAT5Bを検出するための方法であって、
a.請求項1から2の何れかに記載のアプタマーを、対象から前もって採取された前記試料と接触させることと;
b.前記試料に結合した前記アプタマーの量を決定することと、
を含む方法。
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FR1452345A FR3018820B1 (fr) | 2014-03-20 | 2014-03-20 | Inhibiteurs de stat5 et utilisation de ceux-ci |
PCT/FR2015/050711 WO2015140479A1 (fr) | 2014-03-20 | 2015-03-20 | Inhibiteurs de stat5 et utilisation de ceux-ci |
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US20070010468A1 (en) * | 2003-04-23 | 2007-01-11 | Georgetown University | Methods and compositions for the inhibition of stat5 in prostate cancer cells |
JP5610459B2 (ja) * | 2008-02-06 | 2014-10-22 | 独立行政法人産業技術総合研究所 | 単純ヘルペスウイルスに対するアプタマー |
FR2931152B1 (fr) * | 2008-05-16 | 2010-07-30 | Centre Nat Rech Scient | Nouveau systeme de transfert d'acide nucleique |
EP2356234B1 (en) * | 2008-11-14 | 2017-08-16 | Autotelic LLC | Dosage of oligonucleotides suitable for the treatment of tumors |
JP5673992B2 (ja) * | 2009-10-30 | 2015-02-18 | 国立大学法人東京農工大学 | 血管内皮細胞増殖因子結合性アプタマー |
JP6038017B2 (ja) * | 2010-03-24 | 2016-12-07 | メデシス・ファルマ・ソシエテ・アノニムMedesis Pharma S.A. | 核酸を含む逆ミセル系及びその使用 |
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2014
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FR3018820A1 (fr) | 2015-09-25 |
FR3018820B1 (fr) | 2018-01-05 |
AU2015233244B2 (en) | 2020-11-12 |
EP3119889B1 (fr) | 2021-02-24 |
EP3119889A1 (fr) | 2017-01-25 |
US10072266B2 (en) | 2018-09-11 |
WO2015140479A1 (fr) | 2015-09-24 |
IL247872A0 (en) | 2016-11-30 |
JP2017510295A (ja) | 2017-04-13 |
AU2015233244A1 (en) | 2016-11-03 |
US20170137817A1 (en) | 2017-05-18 |
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