JP2017526367A - 癌の処置のための方法および組成物 - Google Patents
癌の処置のための方法および組成物 Download PDFInfo
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Abstract
Description
本願は、35 U.S.C.§119(e)の下で、2014年8月29日に出願された米国仮出願第62/043,803号の恩典を主張し、その内容は全体として参照により本明細書に組み入れられる。
本発明は、国防総省から授与された助成金第W81XWH-09-1-0058号の下で政府の財政支援を受けてなされたものである。米国政府は、本発明に関して一定の権利を保有する。
本願は、ASCII形式で電子的に提出され、全体として参照により本明細書に組み入れられる配列表を含んでいる。2015年8月28日に作成されたこのASCIIコピーは、701039-082401-PCT_SL.txtと命名され、8,984バイトのサイズである。
本明細書に記載される技術は、EpCAM結合分子および阻害性核酸を含むキメラ分子、ならびに癌、例えば上皮癌の処置のためにそのような組成物を使用する方法に関する。
RNA干渉(RNAi)は、肝臓での遺伝子発現を減少させることにおける治療的使用のために検討されてきた。しかし、肝臓は、RNAi分子でトランスフェクトすることが容易な点で特有である。他の組織における低分子RNAの送達および結果として生じる遺伝子ノックダウンは、非効率的で、かつ最終的に無効であり続けている。特に、送達妨害は、癌を処置するためにRNAiを利用することの大きな障害である。
本明細書に記載されるように、本発明者らは、新規なアプタマー-siRNAキメラ分子(AsiC)を開発した。これらのAsiCは、癌細胞マーカーを標的としてsiRNAを癌細胞に特異的に方向付け、送達効力および治療有効性を増加させる一方で、副作用の潜在能を減少させる。
本発明者らは、癌の処置におけるAsiC(アプタマー-siRNAキメラ分子)の驚くべき効力を実証した。本明細書に記載されるAsiCは、キメラ分子を癌細胞に特異的に標的指向化するアプタマーを利用し、siRNAの標的とされる遺伝子の効果的で的を射た抑制をもたらす。
が含まれる。
を有するRFGFである。疎水性MTSを含むRFGFアナログ
は、ターゲティング部分でもあることができる。ペプチド部分は、細胞膜を通過してペプチド、オリゴヌクレオチド、およびタンパク質を含む大型極性分子を運搬することができる「送達」ペプチドであることができる。例えば、HIV Tatタンパク質
およびショウジョウバエ(Drosophila)アンテナペディアタンパク質
由来の配列は、送達ペプチドとして機能できることが見出されている。ペプチドまたはペプチド模倣体は、ファージディスプレイライブラリー、または1ビーズ-1化合物(one-bead-one-compound)(OBOC)コンビナトリアルライブラリーから同定されたペプチドのように、DNAのランダム配列によってコードされることができる(Lam et al., Nature, 354:82-84, 1991)。好ましくは、組み入れられたモノマーユニットを経由してdsRNA作用物質に繋留されるペプチドまたはペプチド模倣体は、アルギニン-グリシン-アスパラギン酸(RGD)-ペプチドのような細胞ターゲティングペプチド、またはRGD模倣体である。ペプチド部分は、約5アミノ酸長〜約40アミノ酸長の範囲であることができる。ペプチド部分は、例えば安定性を増加させる、または立体配座特性を支配するために、構造修飾を有することができる。下記の任意の構造修飾を利用することができる。
1.癌マーカー結合アプタマードメインおよび阻害性核酸ドメインを含む、キメラ分子。
2.癌マーカーが、EpCAMまたはEphA2である、項1記載の分子。
3.アプタマー-siRNAキメラ(AsiC)である、項1〜2のいずれか一項記載の分子。
4.阻害性核酸が、癌細胞においてアップレギュレートされる遺伝子産物と特異的に結合する、項1〜3のいずれか一項記載の分子。
5.阻害性核酸が、
Plk1;MCL1;EphA2;PsmA2;MSI1;BMI1;XBP1;PRPF8;PFPF38A;RBM22;USP39;RAN;NUP205;およびNDC80
からなる群より選択される遺伝子の発現を阻害する、項1〜4のいずれか一項記載の分子。
6.癌マーカーが、EpCAMであり、阻害性核酸ドメインが、Plk1の発現を阻害する、項1〜5のいずれか一項記載の分子。
7.癌マーカー結合アプタマードメインが、SEQ ID NO:33の配列を含む、項1〜6のいずれか一項記載の分子。
8.癌マーカー結合アプタマードメインが、本質的にSEQ ID NO:33の配列からなる、項1〜6のいずれか一項記載の分子。
9.阻害性核酸ドメインが、SEQ ID NO:2の配列を含む、項1〜8のいずれか一項記載の分子。
10.阻害性核酸ドメインが、本質的にSEQ ID NO:2の配列からなる、項1〜8のいずれか一項記載の分子。
11.SEQ ID NO:1〜3のうちの1つの配列を含む、項1〜10のいずれか一項記載の分子。
12.本質的にSEQ ID NO:1〜3のうちの1つの配列からなる、項1〜11のいずれか一項記載の分子。
13.その3'末端が、dTdTを含む、項1〜12のいずれか一項記載の分子。
14.少なくとも1つの2'-Fピリミジンを含む、項1〜13のいずれか一項記載の分子。
15.項1〜14のいずれか一項記載の分子および薬学的に許容される担体を含む、薬学的組成物。
16.項1〜14のいずれか一項記載の少なくとも2種類のキメラ分子を含む組成物であって、該キメラ分子が、異なるアプタマードメインまたは阻害性核酸ドメインを有する、項15記載の組成物。
17.異なるアプタマーまたは阻害性核酸ドメインが、異なる標的を認識する、項16記載の組成物。
18.異なるアプタマーまたは阻害性核酸ドメインが、配列を有し、かつ同じ標的を認識する、項16記載の組成物。
19.項1〜18のいずれか一項記載の分子または組成物を投与する工程を含む、癌を処置する方法。
20.癌が、上皮癌または乳癌である、項19記載の方法。
21.乳癌が、トリプルネガティブ乳癌である、項20記載の方法。
22.投与が、皮下である、項19〜21のいずれか一項記載の方法。
23.対象に、追加的な癌処置がさらに施される、項19〜22のいずれか一項記載の方法。
24.癌処置が、パクリタキセルである、項23記載の方法。
肝臓外の細胞における遺伝子をノックダウンするインビボsiRNA送達のための有効な治療戦略は、癌の処置にRNA干渉を利用するために必要である。EpCAMは、一般的な上皮癌およびそれらの癌源細胞(T-IC、癌幹細胞としても公知)に高度に発現される腫瘍関連抗原である。アプタマー-siRNAキメラ(AsiC、siRNAセンス鎖に連結し、かつsiRNAアンチセンス鎖にアニーリングさせたEpCAMアプタマー)は、インビトロEpCAM+癌細胞およびヒト癌生検組織において選択的に取り込まれ、遺伝子発現をノックダウンすることが、本明細書において実証されている。PLK1 EpCAM-AsiCは、ヌードマウスにおいて、EpCAM-間葉系基底B型トリプルネガティブ乳癌(TNBC)ではなく、EpCAM+管腔型および基底A型TNBC細胞株による、コロニーおよびマンモスフィア形成(インビトロT-ICアッセイ)ならびに発がんイニシエーションを阻害する。皮下投与されたEpCAM-AsiCはEpCAM+ Her2+およびTNBC腫瘍に集中し、それらの成長を抑制する。したがって、EpCAM-AsiCは、上皮癌を処置するための魅力的なアプローチを提供する。
RNA干渉(RNAi)は、病原遺伝子をノックダウンすることによって疾患を処置する機会を提供する1。最近の初期臨床試験から、脂質ナノ粒子に封入したまたはGalNAcにコンジュゲートしたsiRNAを使用して肝臓における一握りの遺伝子標的の強い(75〜95%)、持続性の(数週間または最大数ヶ月持続する)、安全なノックダウンが示された2-5。身体の主要濾過器官である肝臓は粒子を捕捉するので、トランスフェクトが比較的容易である。しかし、大部分の疾患を処置するためにRNAiを利用する大きな障害、すなわち肝臓以外の細胞における低分子RNAの効率的な送達および遺伝子ノックダウンは、まだ解決されていない。特に、送達妨害は、癌の処置にRNAiを利用するための大きな障害である6。
最初に、乳癌細胞株におけるEpCAMの発現を調査した。Cancer Cell Line Encyclopedia40での遺伝子発現データに基づくと、EpCAM mRNAは、基底A型TNBCおよび管腔型乳癌細胞株において高発現されるが、基底B型(間葉系)TNBCではあまり発現されない(図1A)。フローサイトメトリーによって評価した表面EpCAM染色は、hTERTで不死化させた正常上皮(BPE)41、線維芽細胞または間葉系TNBCよりも、試験したすべての管腔型および基底細胞様細胞株の方が2〜3log明るかった(図1B)。したがって、EpCAMは、正常細胞または間葉系腫瘍と比較して上皮性乳癌細胞株において高発現される。
12nMの親和性でヒトEpCAMと結合するヌクレオチド(nt)19個のアプタマー19をSELEXにより同定した42,43。該アプタマーは、マウスEpCAMには結合しない(データは示さず)。いくつかのリンカーによりアプタマーの3'末端にsiRNAのセンス鎖またはアンチセンス鎖のいずれかを連結した一握りのEpCAM-AsiCを設計し、インビボ安定性を高め、類似配列を有する部分的相補遺伝子のオフターゲットノックダウンを回避し、自然免疫受容体刺激を制限するために2'-フルオロピリミジン置換および3'-dTdTオーバーハングを有するように合成した。RNA送達、遺伝子ノックダウンおよび抗腫瘍効果を試験するために、siRNAを組み入れて、eGFP(有用なマーカー遺伝子として);すべての被験細胞株に発現される内因性遺伝子であり、そのノックダウンが致死的でない、AKT1;および有糸分裂に必要なキナーゼであって、そのノックダウンが致死的である、PLK1を、ノックダウンした(図9)。遺伝子ノックダウンの用量反応試験で最も性能が良好であったAsiCは、U-U-Uリンカーを介して19ntのEpCAMアプタマーをsiRNAのセンス(不活性)鎖に結合させたものであった(図1C)。EpCAM-AsiCは、化学合成した約42〜44nt長の鎖(19ntのアプタマー+リンカー+20〜22ntのsiRNAセンス鎖)を20〜22ntのアンチセンスsiRNA鎖にアニーリングすることによって産生した。2'-フルオロピリミジンを用いて工業的に合成されたので{Jackson, 2003 #11353; Scacheri, 2004 #11912; Jackson, 2006 #13758; Wheeler, 2011 #17906}、これらはRNアーゼ耐性であり、ヒト血清中で非常に安定であり(T1/2≫36時間、図7)、担腫瘍マウスにインビボ注射したときに自然免疫を誘発しない(図7)。
EpCAM-AsiCが乳癌において抗腫瘍剤として使用できるかどうかを調査するために、本発明者らは、CellTiterGloアッセイによって、有糸分裂に必要なキナーゼであるPLK1に対するAsiCが、5つの基底A型TNBC、2つの管腔型細胞株、および3つの基底B型TNBCを含む10種類の乳癌細胞株の生存に及ぼす効果を検討した。eGFPに対する対照AsiCではなく、PLK1を標的とするEpCAM-AsiCは、基底A型および管腔型細胞株における細胞増殖を減少させたが、基底B型細胞を阻害しなかった(図2A)。PLK1 siRNAの脂質トランスフェクションは、すべての細胞株の成長を抑制した。この抗増殖効果は、EpCAMの発現と強く相関した(図2B)。ノックダウン後の生存EpCAM+細胞の減少は、アネキシンV-ヨウ化プロピジウム染色およびカスパーゼ活性化によって評価されたアポトーシス誘導が原因であった(データは示さず)。EpCAMアプタマーの連結がEpCAM-AsiCの抗増殖効果に寄与したかどうかを判定するために、本発明者らは、PLK1 EpCAM-AsiCで処理した細胞の生存を、アプタマーのみで処理した細胞と比較した(図2C)。アプタマー自体は、任意の乳癌細胞株の生存に再現性のある効果を有さなかった。これは、可能性があることには、アプタマーがモノマー性作用物質としてEpCAM受容体と架橋せず、EpCAMシグナル伝達を改変しないからである。このように、PLK1 EpCAM-AsiCは、EpCAM+乳癌細胞に対するその特異的抗腫瘍効果を遺伝子ノックダウンにより行使する。
次に、EpCAM-AsiCが無傷組織内で正常乳房サンプルと比較してヒト乳房腫瘍中に集中するかどうかを調査した。乳癌患者3人からの正常組織生検および乳房腫瘍生検のペアを、一辺約3mmの立方体に切断し、ペトリ皿に入れた。腫瘍サンプル細胞はすべてEpCAMbrightであり、正常組織細胞はEpCAMdimであった(図3A)。蛍光標識Alexa647-siRNA(正常組織または腫瘍のどちらによっても取り込まれると予想されない)、Alexa647-コレステロールコンジュゲート型siRNA(chol-siRNA、両方によって取り込まれると予想される)、またはCy3-EpCAM-AsiCを培地に添加し、組織を24時間インキュベートした後、回収した。肉眼により視覚化できたAsiCのCy3シグナルは、腫瘍標本のみに集中し、正常組織からは検出されなかった(図3B)。RNAの取り込みを定量するために、組織標本の洗浄済み単細胞懸濁液にフローサイトメトリー分析を行った(代表的な腫瘍-正常組織のペア(図3C)、3つのEpCAMbright乳房腫瘍-正常組織サンプルのペアからの3つ組の生検の平均±SD(図3D))。EpCAM-AsiCは、正常組織ではなく腫瘍によって有意に取り込まれたが、一方、どちらも非コンジュゲート型siRNAを取り込まず、両方がchol-siRNAをある程度取り込んだ。したがって、EpCAM-AsiCは、正常組織と比較して無傷組織内でEpCAMbright腫瘍に選択的に送達される。
EpCAMがT-ICおよび転移開始細胞(M-IC)を特徴づけることから、標的にEpCAMを選択した20,22,26,27,31。EpCAM-AsiCがT-ICを阻害するかどうかを検討するために、本発明者らは、モック処理、パクリタキセル処理またはeGFPもしくはPLK1に対するEpCAM-AsiC処理後に、コロニーおよびマンモスフィア形成(T-IC機能的代替アッセイ)を比較した。PLK1 EpCAM-AsiCは、EpCAM+基底A型TNBCおよび管腔型細胞株のコロニーおよびマンモスフィア形成をパクリタキセルよりも強く阻害したが、EpCAM-基底B型TNBCに対して不活性であった(図4A〜C)。eGFP AsiCが効果を有さなかったので、T-IC阻害は特異的であった。eGFP AsiCではなく、PLK1 EpCAM-AsiCとのインキュベーションはまた、基底A型および管腔型乳癌細胞株に特異的に、T-ICの表現型を有する細胞の比率、すなわちCD44+CD24low/-およびALDH+細胞数も減少させた(データは示さず)。発がんイニシエーションにおよぼすEpCAM-AsiCの効果を評価するために、ルシフェラーゼを安定的に発現しているEpCAM+ MB468細胞を培地またはPLK1 EpCAM-AsiCでまたはeGFP EpCAM-AsiCで一晩処理し、次に等しい数の生存細胞をヌードマウスにsc移植した。PLK1 EpCAM-AsiCは、インビボ腫瘍細胞発光によって判断される腫瘍形成を完全にブロックした(データは示さず)。対照的に、基底B型MB436細胞の類似の処理は発がんイニシエーションに効果を有さなかった(データは示さず)。したがって、PLK1 EpCAM-AsiCは、EpCAM+乳癌に選択的にインビトロT-ICアッセイおよび発がんイニシエーションを阻害する。
臨床的に有用であるために、EpCAM-AsiCは、播種性腫瘍細胞によって取り込まれる必要がある。マウスの尾静脈への蛍光EpCAM-AsiCの静脈内注射は、ヌードマウスの側腹部に植え込んだ皮下腫瘍内の顕著なAsiC蓄積に繋がらなかったが(データは示さず)、それはおそらく、そのサイズ(約25kDa)が腎臓濾過の閾値未満であり、それらが急速に排泄されるからである。ポリエチレングリコールとの連結は、前立腺癌のマウス異種移植モデルにおけるPSMA-AsiCの循環半減期、腫瘍蓄積および抗腫瘍治療効果を大きく高めた11。しかし、この修飾を回避できるかを調べるために、本発明者らは、マウス7匹の頸背部(scruff of the neck)へのAlexa750標識eGFP EpCAM-AsiCのsc注射が、各側腹部にsc植え込みした遠隔EpCAM+ MB468 TNBCおよびEpCAM- MB231 TNBCでの蓄積に繋がったかどうかをライブ動物落射蛍光イメージングによって調査した(図5A、5B)。注射当日内は、EpCAM-AsiCは、EpCAM+腫瘍のみに集中し、そこで少なくとも4日間存続した。EpCAM-AsiCは、2日目に注射部位周囲で検出されたが、4日目にはEpCAM+腫瘍内だけに見出された。
sc注射したEpCAM-AsiCが遠隔EpCAM+腫瘍に集中したので、本発明者らは、次に、PLK1 EpCAM-AsiCのsc注射がEpCAM+ TNBC異種移植腫瘍の成長を選択的に阻害することができるかどうかを調べた。EpCAM+ MB468-luc細胞をマトリゲルに入れてヌードマウスの片方の側腹部に植え込み、EpCAM- MB231-luc-mCherry細胞を反対側の側腹部に植え込んだ。両方の腫瘍のルシフェラーゼシグナルがバックグラウンドを超えてはっきりと検出された後、マウス5〜6匹の群をモック処置するか、またはPLK1もしくはeGFPを標的とする5mg/kg EpCAM-AsiCを3日毎に2週間sc注射した。腫瘍の成長を発光によって経過観察した。PLK1ターゲティングAsiCを受け入れたマウスにおいてのみ、すべてのEpCAM+腫瘍は急速に完全に退縮した(図6A、6B)。eGFPターゲティングAsiCで処置したマウスにおけるEpCAM+ 腫瘍およびすべてのEpCAM- 腫瘍は、成長し続けた。この実験を繰り返し、PLK1 AsiCの注射後に類似の結果が得られた。また、EpCAMアプタマーだけまたはPLK1 siRNAで処置した追加的な群の対照マウスにおいて、および担Her2+ MCF10A-CA1aマウスに投与した場合に、腫瘍は成長し続け、有意な変化を有さなかった(データは示さず)(図34)。このように、sc注射したPLK1 EpCAM-AsiCは、基底A型TNBCおよびEpCAM+ヒト異種移植片に対して特異的抗腫瘍活性を示す。
標的指向化された療法は、これまでのところ発癌キナーゼに対する腫瘍特異的抗体または阻害剤を使用することに依存してきた。これまで誰も、非コンジュゲート型AsiCが強力な抗腫瘍効果を有することができることも、AsiCがsc投与できることも示していない。現在、TNBCまたはT-ICに対する標的指向化された療法はない。TNBCに対する標的指向化された療法を開発することおよびT-ICを消失させる方法を開発することは、癌研究のまだ実現されていない重要な目標である。
細胞培養。ヒトBPEおよびBPLER細胞をWIT培地(Stemgent)中で成長させた。MB468にルシフェラーゼレポーターを形質導入した。すべての他のヒト細胞株をATCCから入手し、特に示さない限り、すべて10%FBS、1mM L-グルタミンおよびペニシリン/ストレプトマイシン(Gibco)を補充したMEM(MCF7、BT474)、マッコイ5A(SKBR3)、RPMI1640(HCC1806、HCC1143、HCC1937、HCC1954、HCC1187、MB468、T47D)またはDMEM(MB231、BT549、MB436)中で成長させた。4T1マウス乳癌細胞を10%FBS DMEM中で成長させた。インビボイメージングのために、ホタルルシフェラーゼを安定発現しているMB468細胞(MB468-luc)を使用し、pLV-Fluc-mCherry-Puroレンチウイルス(Columbia University, Andrew Kungにより提供)を感染させた後にホタルルシフェラーゼおよびmCherryを安定発現しているMB231細胞(MB231-luc-mCherry)を選択した。MB231細胞をピューロマイシンで選択した。
細胞表面タンパク質への高親和性結合について選択されたアプタマーと呼ばれる構造化RNAがsiRNAと共有結合したものから構成されるキメラRNAを使用する、標的指向化されたsiRNA送達(アプタマー-siRNAキメラ(AsiC))の開発が、本明細書に記載されている。これらのAsiCは、アプタマーが認識する受容体を発現している細胞によって取り込まれ、細胞内でプロセシングされて、活性siRNAを放出する。これは、特異的細胞表面受容体を標的とすることによって異なる細胞を標的とするように修飾することができ、かつ、任意の遺伝子または遺伝子の組み合わせをノックダウンするように設計することができる、柔軟性のあるプラットフォームである。
遺伝子発現を調節するための遍在性メカニズムは、RNA干渉と呼ばれる。それは、低分子相補的配列を有する低分子RNAを使用して、遺伝情報からタンパク質への翻訳をブロックする。この内因性プロセスを利用することは、病原遺伝子の発現をノックダウンすることによって、疾患を処置する刺激的な可能性を提供する。主な障壁は、RNA干渉機構が位置する細胞内に低分子RNAを送達することである。昨年、予備臨床試験によって、肝臓における異常な遺伝子発現によって起こる少数の疾患に顕著な毒性なしに非常に有望な結果が示された。しかし、血中の粒子を捕捉する器官である肝臓への送達の方が、転移腫瘍細胞に薬物を送達するよりも達成が容易である。最も攻撃的な種類の乳癌であるトリプルネガティブ乳癌(TNBC)のターゲティングに特に優れた、上皮癌細胞中にRNAをターゲティングするための戦略が、本明細書に記載されている。そのうえ、この戦略は、癌幹細胞と呼ばれる、大部分の乳癌における最も悪性の亜集団も標的とする。これらの細胞は、化学療法薬に耐性であり、腫瘍の再発および転移を担うと考えられる。現在の癌研究の重要な目標は、癌細胞および正常に分裂している細胞(血液形成細胞および腸管の内面を覆う細胞)の両方に対して毒性である細胞傷害性化学療法薬を、腫瘍に対して、特に腫瘍中の癌幹細胞に対して選択的活性を有する作用物質に置換することである。
EpCAMおよびEphA2を認識し、正常上皮細胞と比較して基底A型TNBCに選択的にインターナライズされる種間反応性アプタマー
正常上皮細胞と比較した乳癌細胞株におけるTNBCターゲティングAsiCの選択的取り込み、遺伝子サイレンシングおよびインビトロ細胞傷害効果の検証、それらがトランスフェクトする乳癌細胞株のサブタイプの判定、ならびにそれらが乳房T-Icをトランスフェクトし、消失させる潜在能の評価
インビボ全身送達および腫瘍濃度の評価、PKおよびPDの定義ならびにTNBCターゲティングAsiCの最大耐用量、ならびにPLK1をノックダウンする、最適化されたTNBCターゲティングAsiCの抗腫瘍効果の評価ならびにマウスにおける原発性および転移性癌のヒトTNBC細胞株モデルでの基底細胞様TNBCの依存遺伝子。
次に、一方にMB468またはHCC1187などのアプタマーリガンド+基底A型TNBC株の乳房脂肪体異種移植片を、比較として他方に基底B型MB231のようなリガンド-乳癌細胞株を担持するヌードマウス(これらのモデルでの本発明者らの経験に基づき再現性のある統計を得るために1群マウス約5〜8匹)を使用して、最も性能の良好な少数のAsiCをインビボ評価することができる。インビボイメージングのために、本発明者らは、ルシフェラーゼ-およびmCherry-発現レンチウイルスの感染により安定な発光/蛍光細胞株をすでに作製していた。
RNA干渉(RNAi)は、病原性遺伝子をノックダウンすることによって疾患を処置する絶好の機会を提供する。最近の初期臨床試験から、有望で持続性の遺伝子ノックダウンおよび/または肝臓での異常な遺伝子発現によって起こる一握りの疾患での臨床的利益が示された。癌の処置にRNAiを利用する主な障壁は、播種性癌細胞への低分子RNAの送達である。それらの中の大部分の上皮癌細胞および癌源細胞(T-IC)は、最初に記載された腫瘍抗原であるEpCAMを高度に発現する。本発明者らが試験したすべての上皮性乳癌細胞株は、EpCAMについて明るく染色され、一方で不死化正常乳房上皮細胞および線維芽細胞は染色されない。上皮癌細胞におけるインビトロでの標的指向化された遺伝子ノックダウンは、EpCAMへの高親和性結合について選択されたアプタマーと呼ばれる構造化RNAをsiRNAと共有結合させたものから構成されるキメラRNAを使用して達成することができる。これらのEpCAMアプタマー-siRNAキメラ(AsiC)は、EpCAM+細胞によって取り込まれ、正常上皮細胞ではなく上皮性乳癌細胞に選択的に遺伝子ノックダウンを引き起こす。そのうえ、EpCAM-AsiCを用いたPLK1のノックダウンは、上皮性乳癌株のコロニーおよびマンモスフィア形成、発がんイニシエーション潜在能のインビトロアッセイ、および発がんイニシエーションを抑制する。
本明細書において、以下について実証される:(1)EpCAMアプタマーは、単独ではEpCAM+乳房腫瘍細胞株の細胞成長または生存率に影響しない(示さず);(2)正常乳房生検をEpCAM+ TNBCヒト乳房腫瘍組織とインビトロで混合すると、蛍光EpCAM-AsiCは腫瘍のみに集中する(図14);(3)間葉系TNBCではなく、EpCAM+管腔型および基底A型TNBC細胞をPLK1 EpCAM-AsiCで処理すると、癌源細胞(T-IC、コロニーおよびマンモスフィア形成)ならびにインビボ発がんイニシエーション(図15A〜15Cおよび16)のインビトロアッセイがブロックされる;(4)いずれかの側腹部にEpCAM+ TNBCおよびEpCAM- TNBCを担持するマウスのEpCAM+腫瘍中に皮下(sc)注射されたEpCAM-AsiCの集中は、注射部位から離れて位置した(図17A〜18B);ならびに(5)最も重要なことには、PLK1 EpCAM-AsiCの皮下(sc)注射は、触知可能な基底A型TNBC異種移植片の完全退縮を導いた(図18A〜18B)。加えて、(6)新しいsiRNAスクリーニングは、EpCAM-AsiCのノックダウンについて基底A型TNBCの新規な共通遺伝的依存性を同定した(図19)。
(1)EpCAM結合性。EpCAMアプタマーは12nMの親和性を有する。この親和性がEpCAM-AsiCにおいて保存されることを検証することができる。AsiCがアプタマーよりも低い親和性を有するならば、本発明者らは、組み換えEpCAMを用いるバイオレイヤー干渉法(OctetRED System, ICCB-Longwood Core)を使用して、アプタマーとAsiCとの親和性を比較することができる。AsiCがより低い結合親和性を有するならば、AsiCは適正にフォールディングしない場合がある。所望の立体配座へのフォールディングを高めるために、本発明者らは、アプタマーとAsiCセンス鎖との間のリンカーの種類および長さを変えてみることができる(すなわち、本発明者らは、より多くの3Cリンカーまたはトリエチレングリコールスペーサーもしくはヘキサエチレングリコールスペーサーを組み入れることができる)。
材料および方法
細胞培養
ヒトBPEおよびBPLER細胞をWIT培地(Stemgent)中で成長させた。MB468にルシフェラーゼレポーターを形質導入した。すべての他のヒト細胞株をATCCから入手し、特に表示しない限りすべて10%FBS、1mM L-グルタミンおよびペニシリン/ストレプトマイシン(Gibco)を補充したMEM(MCF7、BT474)、マッコイ5A(SKBR3)、RPMI1640(HCC1806、HCC1143、HCC1937、HCC1954、HCC1187、MB468、T47D)またはDMEM(MB231、BT549、MB436)中で成長させた。4T1マウス乳癌細胞を10%FBS DMEM中で成長させた。インビボイメージングのために、ホタルルシフェラーゼを安定発現しているMB468細胞(MB468-luc)を使用し、ホタルルシフェラーゼおよびmCherryを安定発現しているMB231細胞(MB231-luc-mCherry)は、pLV-Fluc-mCherry-Puroレンチウイルスに感染させた後に選択した。ピューロマイシンを用いてMB231細胞を選択した。
EpCAM-AsiCは基底A型乳癌細胞を特異的に標的とする
試験管内進化法(SELEX)によってヒトEpCAMとの結合についてEpCAMアプタマーを選択した。最適化したアプタマーは、わずか19ヌクレオチド(nt)長であり、ヒトEpCAMと12nMの親和性で結合する(Shigdar S. et. al. RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule affinity Cancer Sci. 2011 May;102(5):991-8)。それはマウスEpCAMとは結合しない(図22)。長さが約60nt以下のRNAは安価に効率的に化学合成できるので、その短い長さは、AsiC薬にとって理想的である。本発明者らが設計したEpCAM-AsiCは、42〜44ntのより長い鎖(19ntのアプタマー+3ntのリンカー+20〜22ntのsiRNAのセンス(不活性)鎖)が20〜22ntのアンチセンス(活性)siRNA鎖にアニーリングしたものからなる(図21A)。両方の鎖は、血清および他の体液中での増強した安定性(T1/2≫3日)を付与し、かつ自然免疫RNAセンサーの刺激を防止する2'-フルオロピリミジン置換を有するように工業的に合成される。本発明者らは、まず、フローサイトメトリーによってヒト乳房細胞株のパネルにおけるEpCAMの細胞表面レベルを評価した(表2、図23)。EpCAMは、基底B型癌細胞株ではなく、試験されたすべての基底A型および管腔型癌細胞株によって高発現された。正常ヒト上皮細胞(BPE)のEpCAM染色は、バックグラウンドに近く、一方でその形質転換派生株BPLERは、明るいEpCAM染色を有した(図21B)。試験した一握りの設計のいくつか(センス鎖およびアンチセンス鎖が交換されたもの、ならびに数種類のリンカー)は、EpCAM-ではなく、EpCAM+ 細胞株における遺伝子発現をノックダウンしたが、用量反応実験において最もうまく機能した設計を図21Aに示す。EpCAM-AsiCがEpCAM+ 細胞株によって特異的に取り込まれるかどうかを試験するために、本発明者らは、AsiCのアンチセンス鎖の3'末端をAlexa647で標識した。BPLER基底A型TNBC細胞株はEpCAMを過剰発現し、一方で対照上皮乳房細胞株BPEは過剰発現しない(図21B)。BPLER細胞およびBPE細胞の両方を、GFPを標的とするAlexa647-EpCAM-AsiCで処理し、BPLERだけがAsiCの取り込みを示した(図21C)。本発明者らは、さらに、EpCAM+ MDA-MB-468細胞およびBPE対照をCy3標識EpCAM-アプタマー(19ntのアプタマーの5'末端をCy3で標識した)で処理することによってEpCAM-AsiCの選択的取り込みを検証した。22および43時間後に、本発明者らは、EpCAM+細胞における選択的なAsiC取り込みをはっきりと認識した(データは示さず)。EpCAM AsiCが遺伝子ノックダウンを選択的にトリガーする能力を理解するために、本発明者らは、GFPを安定的に過剰発現するBPLER細胞株およびBPE細胞株を選んだ。細胞をGFPを標的とするEpCAM-AsiCで処理するか、または陽性対照としてのGFP-siRNAでトランスフェクトした(図21D)。GFP-siRNAを用いたトランスフェクションはBPEおよびBPLERにおいて遺伝子発現を等しくノックダウンしたものの、EpCAM-AsiCはいかなる脂質もなしにBPLERでの発現を選択的にノックダウンし;ノックダウンは均質であり、脂質トランスフェクションで達成されたノックダウンに匹敵した。
EpCAM-AsiCが基底A型および管腔型乳癌細胞を特異的に標的とし、増殖を阻害することができるかどうかを理解するために、本発明者らは、PLK1を標的とするEpCAM-AsiCを設計した。PLK1は、G2/M移行をトリガーすることが公知である。基底A型、B型および管腔型細胞株を代表する10種類の乳癌細胞を用いて、PLK1を標的とするEpCAM-AsiCが細胞増殖に及ぼす効果を試験した。PLK1を標的とするEpCAM-AsiCは、基底A型および管腔型細胞株の両方での細胞増殖を減少させ、一方で基底B型細胞に効果を有さなかった(図27A)。EpCAM発現レベルと細胞生存率との間に相関関係が見られた(図27B)。EpCAM-AsiCが混合細胞集団におけるEpCAM+ 細胞を特異的に標的とするかを理解するために、HCC1937(EpCAM+GFP-)細胞をBPE(EpCAM-GFP+)細胞と共に共培養し、PLK1を標的とするEpCAM-AsiCで処理するかまたは未処理とした。未処理の共培養物は、類似の比の細胞(41%BPEおよび59%HCC1937)を示した。PLK1を標的とするEpCAM-AsiCによる処理後に、EpCAM+細胞の比は17%に減少し、EpCAM- 細胞は83%に増加し、これは、EpCAM-AsiCがEpCAM+ 細胞における増殖を特異的に抑制することを示している。他の基底A型細胞株(MB468およびHCC1143)で共培養を繰り返し、類似の結果が得られた。BPE細胞を基底B型細胞(MB231)との共培養で成長させたとき、BPE細胞とMB231細胞との比は、EpCAM-AsiC処理にかかわらず同じままであった(未処理共培養物において66%BPEおよび33%MB231、ならびにEpCAM-AsiC処理後に61%BPEおよび38%MB231)(図27C、27D)。
本発明者らは、EpCAM-AsiCがインビトロでEpCAM+ 細胞を特異的に標的とできることを示すことができた。この能力がインビボで保持されるかどうかを理解するために、本発明者らは、まず、マウスおよびヒト血清中でのEpCAM-AsiCの経時的安定性を試験した。本発明者らは、EpCAM-AsiCがマウスおよびヒト血清の両方で少なくとも36時間安定であることが分かった(図30A〜30B)。本発明者らは、ヌードマウスの相反する側腹部にMB468-luc細胞およびMB231-luc-mCherry細胞の両方を注射した。5日後、IVIS Spectraイメージングシステムを使用して腫瘍がはっきりと視認可能になった時に、本発明者らは、マウスに0.5mg/kgのGFP標的指向化Alexa750標識EpCAM-AsiCを皮下(s.c.)注射した(頚部領域に、腫瘍細胞の注射部位から可能な限り遠く)。注射直後にマウスをイメージングし、24、48時間および5日後にもイメージングしてAsiCの局在を追跡した。GFPを標的とするAlexa750標識EpCAM-AsiCは、MB231-luc-mCherry(EpCAM-)腫瘍ではなくMB468-luc腫瘍(EpCAM+)にはっきりと局在した(図31A)。マウス7匹の分析は、MB468(EpCAM+)腫瘍におけるAlexa750の有意な増加を示している(図31B)。5日目に腫瘍を取り出し、視覚化してGFPを標的とするAlexa750標識EpCAM-AsiCが実際に腫瘍に進入したことを検証した。増加したレベルのAlexa750は、mCherryレベルと負の相関関係にあった(データは示さず)。
トリプルネガティブ乳癌は、あらゆる乳癌サブタイプの最悪の予後を有し、標的指向化されたTNBC治療はない。TNBCは、癌幹細胞としても公知の癌源細胞(T-IC)に関連する表現型を有する。T-ICは、化学療法に耐性であり、腫瘍の再発および転移を担うと考えられる。
Claims (24)
- 癌マーカー結合アプタマードメインおよび阻害性核酸ドメインを含む、キメラ分子。
- 癌マーカーが、EpCAMまたはEphA2である、請求項1記載の分子。
- アプタマー-siRNAキメラ(AsiC)である、請求項1〜2のいずれか一項記載の分子。
- 阻害性核酸が、癌細胞においてアップレギュレートされる遺伝子産物と特異的に結合する、請求項1〜3のいずれか一項記載の分子。
- 阻害性核酸が、
Plk1;MCL1;EphA2;PsmA2;MSI1;BMI1;XBP1;PRPF8;PFPF38A;RBM22;USP39;RAN;NUP205;およびNDC80
からなる群より選択される遺伝子の発現を阻害する、請求項1〜4のいずれか一項記載の分子。 - 癌マーカーが、EpCAMであり、阻害性核酸ドメインが、Plk1の発現を阻害する、請求項1〜5のいずれか一項記載の分子。
- 癌マーカー結合アプタマードメインが、SEQ ID NO:33の配列を含む、請求項1〜6のいずれか一項記載の分子。
- 癌マーカー結合アプタマードメインが、本質的にSEQ ID NO:33の配列からなる、請求項1〜6のいずれか一項記載の分子。
- 阻害性核酸ドメインが、SEQ ID NO:2の配列を含む、請求項1〜8のいずれか一項記載の分子。
- 阻害性核酸ドメインが、本質的にSEQ ID NO:2の配列からなる、請求項1〜8のいずれか一項記載の分子。
- SEQ ID NO:1〜3のうちの1つの配列を含む、請求項1〜10のいずれか一項記載の分子。
- 本質的にSEQ ID NO:1〜3のうちの1つの配列からなる、請求項1〜11のいずれか一項記載の分子。
- その3'末端が、dTdTを含む、請求項1〜12のいずれか一項記載の分子。
- 少なくとも1つの2'-Fピリミジンを含む、請求項1〜13のいずれか一項記載の分子。
- 請求項1〜14のいずれか一項記載の分子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1〜14のいずれか一項記載の少なくとも2種類のキメラ分子を含む組成物であって、該キメラ分子が、異なるアプタマードメインまたは阻害性核酸ドメインを有する、請求項15記載の組成物。
- 異なるアプタマーまたは阻害性核酸ドメインが、異なる標的を認識する、請求項16記載の組成物。
- 異なるアプタマーまたは阻害性核酸ドメインが、配列を有し、かつ同じ標的を認識する、請求項16記載の組成物。
- 請求項1〜18のいずれか一項記載の分子または組成物を投与する工程を含む、癌を処置する方法。
- 癌が、上皮癌または乳癌である、請求項19記載の方法。
- 乳癌が、トリプルネガティブ乳癌である、請求項20記載の方法。
- 投与が、皮下である、請求項19〜21のいずれか一項記載の方法。
- 対象に、追加的な癌処置がさらに施される、請求項19〜22のいずれか一項記載の方法。
- 癌処置が、パクリタキセルである、請求項23記載の方法。
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US10385343B2 (en) | 2019-08-20 |
EP4043567C0 (en) | 2024-05-08 |
CN107106704A (zh) | 2017-08-29 |
EP3185910A4 (en) | 2018-01-10 |
US11180762B2 (en) | 2021-11-23 |
EP3185910A1 (en) | 2017-07-05 |
CA2959386A1 (en) | 2016-03-03 |
EP4043567B1 (en) | 2024-05-08 |
US20170275629A1 (en) | 2017-09-28 |
WO2016033472A1 (en) | 2016-03-03 |
US20190309297A1 (en) | 2019-10-10 |
CA2959386C (en) | 2024-06-04 |
AU2015308721A1 (en) | 2017-03-16 |
AU2015308721B2 (en) | 2021-04-01 |
KR20170070022A (ko) | 2017-06-21 |
EP4043567A1 (en) | 2022-08-17 |
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