JP2017533728A - トランスフェリン受容体(tfr)に対するrnaアプタマー - Google Patents
トランスフェリン受容体(tfr)に対するrnaアプタマー Download PDFInfo
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Abstract
Description
[0001] 本出願は、2014年10月15日に出願された米国仮出願第62/064,310号の利益を主張し、その内容は、全ての目的に関して参照によりそのまま本明細書に援用される。
[0002] 2015年10月14日に作成されたファイル48440−551001WO_ST25.TXT(1,067バイト、機械形式IBM−PC、MS−Windowsオペレーティングシステム)中に記載されている配列リストが、参照により本明細書に援用される。
[0006] 一側面において、SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して少なくとも80%の配列同一性を有するRNA配列を含むリボ核酸化合物が、提供され、そのRNA配列は、少なくとも50ヌクレオチド長である。
[0009] 別の側面において、(その態様を含めて)本明細書で提供されるリボ核酸化合物および療法剤を含む医薬配合物が、提供される。
[0024] 本発明の様々な態様および側面が、本明細書において示され、記載されているが、当業者には、そのような態様および側面は、例としてのみ提供されていることは、明らかであろう。数多くのバリエーション、変更、および置換が、ここで、本発明から逸脱することなく当業者に思い浮かぶであろう。本明細書で記載される本発明の態様に対する様々な代替案が、本発明の実施において用いられることができることは、理解されるべきである。
(a)カルボキシル基ならびにN−ヒドロキシスクシンイミドエステル類、N−ヒドロキシベンゾトリアゾールエステル類、酸ハロゲン化物、アシルイミダゾール類、チオエステル類、p−ニトロフェニルエステル類、アルキル、アルケニル、アルキニルおよび芳香族エステル類を含むがそれらに限定されないその様々な誘導体;
(b)エステル類、エーテル類、アルデヒド類等に変換されることができるヒドロキシル基;
(c)ハロアルキル基であって、そのハライドが後で求核基、例えばアミン、カルボキシレートアニオン、チオールアニオン、カルボアニオン、またはアルコキシドイオンにより置換されることができ、それにより結果としてハロゲン原子の位置において新しい基の共有結合をもたらすハロアルキル基;
(d)ディールス・アルダー反応に参加することができる求ジエン基、例えばマレイミド基;
(e)例えばイミン類、ヒドラゾン類、セミカルバゾン類またはオキシム類のようなカルボニル誘導体の形成による、またはグリニャール付加もしくはアルキルリチウム付加のような機序によるその後の誘導体化が可能であるようなアルデヒドまたはケトン基;
(f)例えばスルホンアミド類を形成するようなその後のアミン類との反応のためのハロゲン化スルホニル基;
(g)ジスルフィドへと変換される、ハロゲン化アシル類と反応する、または金属、例えば金に結合することができるチオール基;
(h)例えばアシル化、アルキル化または酸化されることができるアミンまたはスルフヒドリル基;
(i)例えば環化付加、アシル化、マイケル付加等を受けることができるアルケン類;
(j)例えばアミン類およびヒドロキシル化合物と反応することができるエポキシド類;
(k)ホスホラミダイト類および核酸合成において有用な他の標準的な官能基;
(l)金属シリコン酸化物結合;
(m)例えばリン酸ジエステル結合を形成するための反応性リン基(例えばホスフィン類)への金属結合;ならびに
(n)スルホン類、例えばビニルスルホン。
[0079] 本明細書で提供されるリボ核酸化合物は、その態様を含め、特に、細胞上のトランスフェリン受容体(TfR)に結合して細胞中に内部移行することができる。TfRは、多種多様な異なる癌細胞(例えば乳癌、膵臓癌、肝臓癌、前立腺癌)の内部で発現されており、その表面上に存在する。従って、本明細書で提供されるリボ核酸化合物は、その態様を含め、療法分子または診断分子をTfR発現癌細胞中に送達するために用いられることができる。療法分子または診断分子は、(その態様を含めて)本明細書で提供されるリボ核酸化合物の部分を形成することができる。療法分子または診断分子が(その態様を含めて)本明細書で提供されるリボ核酸化合物の部分を(例えば共有結合により)形成する場合、その療法分子または診断分子は、“化合物部分”(例えば療法部分、イメージング部分)と呼ばれる。あるいは、療法分子または診断分子は、(その態様を含めて)本明細書で提供されるリボ核酸化合物の一部を形成しているのではなく、本明細書で提供されるリボ核酸化合物の前記の細胞上のTfRへの結合の際にTfR発現細胞により独立して内部移行させられる可能性がある。療法分子または診断分子が本明細書で提供されるリボ核酸化合物の一部を形成しない場合、その分子は、“化合物”と呼ばれる。(その態様を含めて)本明細書で提供されるリボ核酸化合物は、標的化された癌薬物送達および分子イメージングのための高度に特異的かつ効率的な手段を提供する。
[0081] 一側面において、SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して少なくとも80%の配列同一性を有するRNA配列を含むリボ核酸化合物が、提供され、そのRNA配列は、少なくとも40ヌクレオチド長である。別の側面において、SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して少なくとも80%の配列同一性を有するRNA配列を含むリボ核酸化合物が、提供され、そのRNA配列は、少なくとも50ヌクレオチド長である。RNA配列がSEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して少なくとも80%(80%より大きい)の配列同一性を有する場合、そのRNA配列は、SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%または100%の配列同一性を有し得る。複数の態様において、RNA配列は、SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3の配列にハイブリダイズする核酸に対して少なくとも80%(80%より大きい)の配列同一性を有する。RNA配列が少なくとも50(50ヌクレオチド以上)ヌクレオチド長である場合、そのRNA配列は、少なくとも50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190または200ヌクレオチド長である。複数の態様において、RNA配列は、少なくとも50ヌクレオチド長である。RNA配列が少なくとも40(40ヌクレオチド以上)ヌクレオチド長である場合、そのRNA配列は、少なくとも40、41、42、43、44、45、45、47、48、49、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190または200ヌクレオチド長である。従って、複数の態様において、RNA配列は、約43ヌクレオチド長である。
[0094] 本明細書で提供されるリボ核酸化合物の医薬組成物は、療法上有効量で、すなわちその意図される目的を達成するために有効な量で含有される療法的部分を有する組成物を含むことができる。本明細書で提供されるリボ核酸化合物の医薬組成物は、有効量で、すなわちその意図される目的を達成するために有効な量で含有されるイメージング部分を有する組成物を含むことができる。個々の適用に関して有効な実際の量は、特に、処置されている、試験されている、検出されている、または診断されている病気に依存するであろう。疾患を処置するための方法において投与される場合、そのような組成物は、所望の結果、例えば標的分子の活性の変調、および/または疾患症状の進行の低減、排除、もしくは減速を達成するために有効な量の有効成分を含有するであろう。本明細書で提供される療法的部分の療法上有効量の決定は、特に本明細書における詳述される開示を考慮すれば、十分に当業者の能力の範囲内である。疾患を診断または検出するための方法において投与される場合、そのような組成物は、所望の結果、例えば対象中の標的分子、細胞、または腫瘍の非存在または存在の検出を達成するために有効な量の本明細書で記載されるイメージング部分を含有するであろう。本明細書で提供されるイメージング部分の検出可能な量の決定は、特に本明細書における詳述される開示を考慮すれば、十分に当業者の能力の範囲内である。
[0100] 上記のように、(その態様を含めて)本明細書で提供されるリボ核酸化合物は、化合物部分または化合物(例えば療法剤またはイメージング剤)を細胞中に送達するために用いられることができる。化合物部分(例えば療法的部分またはイメージング部分)が細胞中に送達される場合、化合物部分は、(その態様を含めて)本明細書で提供されるリボ核酸化合物(RNA配列)に共有結合していることができる。リボ核酸化合物(RNA配列)の細胞上のTfRへの結合の際、化合物部分は、リボ核酸化合物(RNA配列)に共有結合したまま細胞により内部移行させられる。従って、一側面において、化合物部分を細胞中に送達する方法が、提供される。その方法は、以下の工程を含む:(i)細胞を(その態様を含めて)本明細書で提供されるリボ核酸化合物と接触させ、そして(ii)リボ核酸化合物を細胞上のTfRに結合させ、細胞中に通過させ、それにより化合物部分を細胞中に送達する。
[0102] 本明細書で用いられる際、“処置”または“処置すること”または“緩和すること”または“改善すること”は、本明細書において互換的に用いられている。これらの用語は、療法的利益および/または予防的利益を含むがそれらに限定されない有益な結果または所望の結果を得るためのアプローチを指す。療法的利益により、処置されている基礎となる障害の根絶または改善が意味される。また、療法的利益は、患者がなお基礎となる障害で苦しんでいる可能性があるにもかかわらず向上が患者において観察されるような、基礎となる障害と関係する生理学的症状の1以上の根絶または改善により達成される。予防的利益に関して、組成物は、特定の疾患を発現するリスクのある患者に、または疾患の生理学的症状の1以上を報告している患者に、たとえこの疾患の診断がなされたことがない可能性があっても、投与されることができる。処置は、疾患を予防すること、すなわち、疾患の誘導前の保護的組成物の投与により疾患の臨床症状が発現しないようにすること;疾患を抑制すること、すなわち、誘導事象後であるが疾患の臨床的出現または再発の前の保護組成物の投与により疾患の臨床症状が発現しないようにすること;疾患を阻害すること、すなわち、臨床症状の発現を、それらの最初の出現後の保護的組成物の投与により止めること;疾患の再発を予防すること、および/または疾患を軽減すること、すなわち、臨床症状の後退を、それらの最初の出現後の保護的組成物の投与により引き起こすことを含む。例えば、本明細書における特定の方法は、癌(例えば前立腺癌、腎臓癌、転移癌、黒色腫、性腺摘除抵抗性前立腺癌、乳癌、トリプルネガティブ乳癌、膠芽腫、卵巣癌、肺癌、扁平上皮癌(例えば頭、首、または食道)、結腸直腸癌、白血病、急性骨髄性白血病、リンパ腫、B細胞リンパ腫、または多発性骨髄腫)を処置する。例えば、本明細書における特定の方法は、癌を、癌の発生、成長、転移、もしくは進行を低下させる、もしくは低減する、もしくは予防することにより処置するか;または癌を、癌の症状を減少させることにより処置する。癌(例えば前立腺癌、腎臓癌、転移癌、黒色腫、性腺摘除抵抗性前立腺癌、乳癌、トリプルネガティブ乳癌、膠芽腫、卵巣癌、肺癌、扁平上皮癌(例えば頭、首、または食道)、結腸直腸癌、白血病、急性骨髄性白血病、リンパ腫、B細胞リンパ腫、または多発性骨髄腫)の症状は、既知であると考えられ、または当業者により決定されることができる。
[0108] 本明細書で提供される核酸組成物は、化合物および化合物部分のTfRを発現する細胞への送達のために用いられることもできる。上記のように、送達される化合物および化合物部分は、細胞の検出のために有用なイメージング剤であることができる。従って、一側面において、細胞を検出する方法が、提供される。その方法は、以下の工程を含む:(i)細胞を(その態様を含めて)本明細書で提供されるリボ核酸化合物と接触させ、ここで、そのリボ核酸化合物は、さらにイメージング部分を含み、(ii)リボ核酸化合物を細胞上のトランスフェリン受容体に結合させ、そして細胞中に通過させ、(iii)イメージング部分が検出され、それにより細胞を検出する。
[0112] TfRの細胞外ドメインは、Sino Biological lncから購入された(11020−H07H)。SELEXサイクルは、基本的にTuerk and Gold_ENREF_1(Tuerk, C, Methods Mol Biol., 67, 219-230 (1997))により記載されたように実施された。インビトロ選択は、本質的に下記のように実施された。2’F−RNAアプタマーが、ランダム化された配列から選択された。配列5’−GGGAGACAAGAATAAACGCTCAA−N40−TTCGACAGGAGGCTCACAACAGGC−3’[N40は、それぞれの位置におけるA、G、C、およびUの等モルでの組み込みにより形成された40ヌクレオチド(nt)配列を表す]のRNAオリゴヌクレオチドのランダムライブラリーが、合成DNA鋳型のNTP(2’F UTP、2’F CTP、GTP、ATP、Epicentre Biotechnologies、ウィスコンシン州マディソン)およびT7 RNAポリメラーゼを用いたインビトロ転写により構築された。ヌクレアーゼ耐性を増大させるために、2’F−RNAが用いられた。アガロースビーズに非特異的に結合するRNAを除去するため、1.44uMのRNAライブラリーが、100ulの結合緩衝液(30mM トリス−HCl、150mM NaCl、1.5mM MgC12、2mM ジチオスレイトール、および1% BSA)中で20ulのNi−NTAアガロースビーズと共に室温で30分間振盪しながらプレインキュベートされ、遠心分離により沈殿させられ、廃棄された。その予め澄ませた上清が、新しいチューブに移され、333nMのhisタグ化TfRと共に室温で30分間インキュベートされた。TfRに結合したRNAが回収され、RT−PCRおよびインビトロ転写により増幅され、続く選択ラウンドにおいて用いられた。その後のラウンドにおいて、カプシド濃度が、よりストリンジェントな条件に関して3ラウンドごとに2倍低減された。12ラウンドのSELEXの後、結果として得られたcDNAが増幅された。増幅されたDNAは、クローン化され、個々のクローンが、DNA配列決定により同定された。アプタマーの構造は、http://www.bioinfo.rpi.edu/applications/mfold/において入手可能なMFOLD(Zuker, M., Nucleic Acids Res., 31, 3406-3415 (2003))を用いて、塩補正アルゴリズムおよび25℃に関する温度補正を用いて予測された。
[0114] BIAcore T100(GE Healthcare、ウプサラ、スウェーデン)が、表面プラズモン共鳴(SPR)技法により結合パラメーターを測定するために用いられた。簡潔には、アプタマー鋳型が、5’鋳型プライマーおよびdT16タグ付け3’鋳型プライマーを用いるPCRにより増幅され、39−末端においてdT16でタグ付けされた。次いで、これらのDNA鋳型が、ポリ(A)テールRNAへと転写された。5’−ビオチン化dT16オリゴマーが、フローセル1および2のストレプトアビジンセンサーチップ(GE Healthcare)の表面に結合させられた。ポリ(A)テールRNAは、フローセル2においてdT16オリゴマーへの相補的ハイブリダイゼーションにより約100RUになるように固定された。100〜6nMの異なる濃度のTfR溶液が、センサーチップのフローセル1および2に注入された。データは、フローセル1のデータをフローセル2のデータから減算することにより得られ、それにより、RNAおよびタンパク質の間の正味の相互作用を示した。センサーチップを再生するため、結合した物質は、50mM NaOHを注入することにより完全に除去された。速度定数が、BIAevaluation 3.0ソフトウェア(GE Healthcare)を用いることにより推定された。
[0116] 癌細胞における選択されたRNAアプタマーの内部移行を試験するため、細胞が、35mmガラス底ディッシュ(MatTek、米国マサチューセッツ州アッシュランド)において、培地中で1×105細胞で蒔かれ、24時間増殖させられた。RNAが、Cy3 Silencer siRNA標識キット(Ambion、米国テキサス州)を製造業者の説明書に従って用いてCy3で標識された。100nMのCy3標識RNAが、細胞に添加され、1時間インキュベートされた。インキュベーション後、細胞は、生細胞核染色のために5ug/mlのHoechst 33342(Molecular Probes米国カリフォルニア州)を用いて染色された。画像は、Zeiss LSM 510 Meta Inverted 2光子共焦点顕微鏡システムを用いて、C−Apo 40x/1.2NA水浸対物レンズを用いて撮られた。
[0118] 2’F RNAのライブラリーが、ヌクレアーゼ耐性を増大させ、アプタマーの折り畳みを増進するために用いられた。完全な細胞に結合する2’F RNAアプタマーを単離するため、定められた配列により隣接される40nt長のランダム配列を含有するおおよそ440の異なる2’F RNA分子のライブラリーが、SELEXによりスクリーニングされた。12サイクルの選択後、高度に富化されたアプタマーのプールが、クローニングされた。TR14およびTR18の配列は、下記の通りであり、それらの間に単一のヌクレオチドの違いがあった。MFoldによる予想される構造は、図1であった。
[0120] TR14の結合を確かめ、その親和性を測定するため、SPRが利用された。測定された解離定数(KD)は、31.7pMであった(図2)。
[0122] 療法薬の送達に関する細胞内部移行を検証するため、様々な癌細胞が、蛍光標識されたTR14 RNA(100nM)と共にインキュベートされた。図3〜5において示されているように、TR14は、肝臓癌、膵臓癌、前立腺癌および乳癌において内部移行した。
[0126] SEQ ID NO:1(TR14):
[0129] 態様1.SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して少なくとも80%の配列同一性を有するRNA配列を含むリボ核酸化合物であって、前記のRNA配列が、少なくとも40ヌクレオチド長であるリボ核酸化合物。
[0131] 態様3.態様1のリボ核酸化合物であって、前記のRNA配列が、約50ヌクレオチド長であるリボ核酸化合物。
[0133] 態様5.態様4のリボ核酸化合物であって、前記の化合物部分が、前記のRNA配列に共有結合した療法的部分またはイメージング部分であるリボ核酸化合物。
[0135] 態様7.態様5のリボ核酸化合物であって、前記の療法的部分が、活性化核酸部分またはアンチセンス核酸部分であるリボ核酸化合物。
[0137] 態様9.態様5のリボ核酸化合物であって、前記の療法的部分が、siRNA部分またはsaRNA部分であるリボ核酸化合物。
[0139] 態様11.態様5のリボ核酸化合物であって、前記の療法的部分が、C/EBPアルファsaRNA部分であるリボ核酸化合物。
[0141] 態様13.態様1または3〜1212の1態様のリボ核酸化合物であって、前記のRNA配列が、87ヌクレオチド長であるリボ核酸化合物。
[0144] 態様16.態様1、2、13または14の1態様のリボ核酸化合物および療法剤を含む医薬配合物。
[0146] 態様18.化合物部分を細胞中に送達する方法であって、該方法が、以下の工程:(i)細胞を態様4〜14の1態様のリボ核酸化合物と接触させ、そして(ii)前記のリボ核酸化合物を前記の細胞上のトランスフェリン受容体に結合させ、前記の細胞中に通過させ、それにより前記の化合物部分を前記の細胞中に送達する;を含む方法。
[0149] 態様21.癌を処置する方法であって、該方法が、それを必要とする対象に有効量の態様1〜11、13または14の1態様のリボ核酸化合物を投与することを含み、前記のリボ核酸化合物が、さらに抗癌療法的部分を含む方法。
Claims (24)
- SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3に対して少なくとも80%の配列同一性を有するRNA配列を含むリボ核酸化合物であって、前記のRNA配列が、少なくとも40ヌクレオチド長であるリボ核酸化合物。
- 請求項1に記載のリボ核酸化合物であって、前記のRNA配列が、約43ヌクレオチド長であるリボ核酸化合物。
- 請求項1に記載のリボ核酸化合物であって、前記のRNA配列が、少なくとも50ヌクレオチド長であるリボ核酸化合物。
- 請求項1〜3の1項に記載のリボ核酸化合物であって、さらに、前記のRNA配列に共有結合した化合物部分を含むリボ核酸化合物。
- 請求項4に記載のリボ核酸化合物であって、前記の化合物部分が、前記のRNA配列に共有結合した療法的部分またはイメージング部分であるリボ核酸化合物。
- 請求項5に記載のリボ核酸化合物であって、前記の療法的部分が、核酸部分、ペプチド部分または小分子薬物部分であるリボ核酸化合物。
- 請求項5に記載のリボ核酸化合物であって、前記の療法的部分が、活性化核酸部分またはアンチセンス核酸部分であるリボ核酸化合物。
- 請求項5に記載のリボ核酸化合物であって、前記の療法的部分が、miRNA部分、mRNA部分、siRNA部分またはsaRNA部分であるリボ核酸化合物。
- 請求項5に記載のリボ核酸化合物であって、前記の療法的部分が、siRNA部分またはsaRNA部分であるリボ核酸化合物。
- 請求項5〜9の1項に記載のリボ核酸化合物であって、前記の療法的部分が、抗癌剤部分であるリボ核酸化合物。
- 請求項5に記載のリボ核酸化合物であって、前記の療法的部分が、C/EBPアルファsaRNA部分であるリボ核酸化合物。
- 請求項5に記載のリボ核酸化合物であって、前記のイメージング剤部分が、生物発光分子、光活性分子、金属またはナノ粒子であるリボ核酸化合物。
- 請求項1または3〜12の1項に記載のリボ核酸化合物であって、前記のRNA配列が、87ヌクレオチド長であるリボ核酸化合物。
- 請求項1〜13の1項に記載のリボ核酸化合物であって、前記のRNA配列が、SEQ ID NO:1、SEQ ID NO:2またはSEQ ID NO:3であるリボ核酸化合物。
- 請求項1〜14の1項に記載のリボ核酸化合物および薬学的に許容可能な賦形剤を含む医薬配合物。
- 請求項1〜3、13または14の1項に記載のリボ核酸化合物および療法剤を含む医薬配合物。
- 請求項16に記載の医薬配合物であって、前記の療法剤が、抗癌剤である医薬配合物。
- 化合物部分を細胞中に送達する方法であって、該方法が、以下の工程:
(i)細胞を請求項4〜14の1項に記載のリボ核酸化合物と接触させ;そして
(ii)前記のリボ核酸化合物を前記の細胞上のトランスフェリン受容体に結合させ、前記の細胞中に通過させ、それにより前記の化合物部分を前記の細胞中に送達する;
を含む方法。 - 化合物を細胞中に送達する方法であって、該方法が、以下の工程:
(i)細胞を化合物および態様1〜3、13または14の1項に記載のリボ核酸化合物と接触させ;そして
(ii)前記のリボ核酸化合物を前記の細胞上のトランスフェリン受容体に結合させ、前記の化合物を前記の細胞中に通過させ、それにより前記の化合物を前記の細胞中に送達する;
を含む方法。 - 請求項19に記載の方法であって、前記の化合物が、療法剤またはイメージング剤である方法。
- 癌を処置する方法であって、該方法が、それを必要とする対象に有効量の請求項1〜11、13または14の1項に記載のリボ核酸化合物を投与することを含み、前記のリボ核酸化合物が、さらに抗癌療法的部分を含む方法。
- 癌を処置する方法であって、該方法が、それを必要とする対象に有効量の抗癌剤および請求項1〜3、13または14の1項に記載のリボ核酸化合物を投与することを含む方法。
- 細胞を検出する方法であって、該方法が、以下の工程:
(i)細胞を請求項1〜5または12〜14の1項に記載のリボ核酸化合物と接触させ、ここで、前記のリボ核酸化合物は、さらに、イメージング部分を含み;
(ii)前記のリボ核酸化合物を前記の細胞上のトランスフェリン受容体に結合させ、前記の細胞中に通過させ、そして
(iii)前記のイメージング部分を検出し、それにより前記の細胞を検出する;
を含む方法。 - 細胞を検出する方法であって、該方法が、以下の工程:
(i)細胞をイメージング剤および請求項1〜3、13または14の1項に記載のリボ核酸化合物と接触させ;
(ii)前記のリボ核酸化合物を前記の細胞上のトランスフェリン受容体および前記のイメージング剤に結合させて前記の細胞中に通過させ;そして
(iii)前記のイメージング剤を検出し、それにより前記の細胞を検出する;
を含む方法。
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