JP6811718B2 - Tp53のヘミ接合性喪失を保有するがんを処置する方法 - Google Patents
Tp53のヘミ接合性喪失を保有するがんを処置する方法 Download PDFInfo
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- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4748—Details p53
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- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
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Description
本願は、2015年3月4日に提出された米国仮出願第62/128,480号に対する優先権の利益を主張する。この出願の内容全体は、ここに参考として援用される。
本発明は、National Institutes of Healthによって授与された助成金番号R01 CA136549およびU54 CA151668の下での政府支援を受けてなされた。政府は、本発明に一定の権利を有する。
本発明は、全般的には、薬およびがん生物学の分野に関する。より詳細には、本発明は、TP53のヘミ接合性喪失を保有するがんを処置する方法に関係する。
周知の腫瘍サプレッサー遺伝子であるTP53は、ヒト腫瘍の大部分において変異または欠失によって高頻度で不活性化されている(Petitgeanら、2007年;Vazquezら、2008年)。がん療法において、p53活性を回復するために多大な労力が払われてきた(Chene、2003年;Wadeら、2013年)。野生型p53を発現するアデノウイルスベクターを使用した遺伝子療法が、いくつかの治験において活性を示した一方、全ての腫瘍細胞への、ばらつきがあり不十分な遺伝子送達およびアデノウイルスに対する宿主抗体の存在は、その臨床使用を限定した(Laneら、2010年;HauptおよびHaupt、2004年)。p53活性をブーストする多数の小分子化合物も開発された。しかし、これらの物質は、野生型p53を保有するヒトがんにしか適用できない(Cheokら、2011年;Goldsteinら、2011年)。しかし、p53調節因子の複雑さおよびその不十分な薬物適用性(drugability)のため、有効なp53に基づく療法を臨床的がん処置へと橋渡しすることに成功していない。そのため、p53欠損がんを処置するための新たな戦略が必要とされる。
特定の実施形態において、例えば、以下が提供される:
(項目1)
がんを有する患者の処置における使用のための組成物であって、該がんの細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照発現レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を示し、該組成物が治療有効量のPOLR2A阻害剤を含む、組成物。
(項目2)
前記POLR2A阻害剤が、POLR2Aタンパク質の発現を阻害する核酸を含む、項目1に記載の組成物。
(項目3)
前記POLR2A阻害剤が、アマトキシンを含む、項目1に記載の組成物。
(項目4)
前記アマトキシンが、アルファ−アマニチンである、項目3に記載の組成物。
(項目5)
前記アマトキシンが、抗体にコンジュゲートされている、項目3に記載の組成物。
(項目6)
前記抗体が、抗EpCAM抗体である、項目5に記載の組成物。
(項目7)
前記抗体が、腫瘍関連抗原に特異的に結合する、項目5に記載の組成物。
(項目8)
前記POLR2A遺伝子産物が、mRNAである、項目1に記載の組成物。
(項目9)
前記mRNAの発現のレベルが、ノーザンブロッティング、逆転写定量的リアルタイムPCR(RT−qPCR)、ヌクレアーゼプロテクション、トランスクリプトーム解析、ハイブリダイゼーションアッセイ、チップに基づく発現プラットフォームまたはインベーダーRNAアッセイプラットフォームによって決定される、項目8に記載の組成物。
(項目10)
前記POLR2A遺伝子産物が、タンパク質である、項目1に記載の組成物。
(項目11)
前記タンパク質の発現のレベルが、質量分析、ウエスタンブロット、ELISA、免疫沈降、免疫組織化学的検査またはラジオイムノアッセイによって決定される、項目10に記載の組成物。
(項目12)
前記参照発現レベルが、非がん性細胞における発現レベルである、項目1に記載の組成物。
(項目13)
前記TP53遺伝子の前記ヘミ接合性喪失または前記POLR2A遺伝子の前記ヘミ接合性喪失が、ゲノムハイブリダイゼーション技法、PCR解析または制限断片解析によって決定される、項目1に記載の組成物。
(項目14)
前記がん細胞が、前記TP53遺伝子のヘミ接合性喪失を示す、項目1に記載の組成物。
(項目15)
前記がん細胞が、前記POLR2A遺伝子のヘミ接合性喪失を示す、項目1に記載の組成物。
(項目16)
前記患者が、参照発現レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を示すがん細胞を有する、項目1に記載の組成物。
(項目17)
前記がん細胞が、肺がん細胞、脳がん細胞、乳がん細胞、肝臓がん細胞、卵巣がん細胞
、結腸直腸がん細胞、前立腺がん細胞または膵臓がん細胞である、項目1に記載の組成物。
(項目18)
前記がん細胞が、転移性、再発性または多剤耐性である、項目1に記載の組成物。
(項目19)
少なくとも第2の抗がん療法薬をさらに含む、項目1に記載の組成物。
(項目20)
前記第2の抗がん療法薬が、化学療法剤である、項目19に記載の組成物。
(項目21)
前記化学療法剤が、5−フルオロウラシル、オキサリプラチンまたはSN−38である、項目20に記載の組成物。
(項目22)
前記患者が、ヒトである、項目1に記載の組成物。
(項目23)
前記患者が、非ヒト哺乳動物である、項目1に記載の組成物。
(項目24)
前記患者が、少なくとも1ラウンドの抗がん療法を以前に受けたことがある、項目1に記載の組成物。
(項目25)
(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照発現レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を示すがん細胞を有する患者を処置する方法であって、治療有効量のPOLR2A阻害剤をかかる患者に投与するステップを含む方法。
(項目26)
前記患者が、少なくとも再度処置される、項目25に記載の方法。
(項目27)
前記患者が、1週間〜6ヶ月間の期間にわたって処置される、項目26に記載の方法。
(項目28)
少なくとも第2の抗がん療法を前記被験体に投与するステップをさらに含む、項目25に記載の方法。
(項目29)
前記第2の抗がん療法が、外科的療法、化学療法、放射線療法、寒冷療法、ホルモン療法、毒素療法、免疫療法またはサイトカイン療法である、項目28に記載の方法。
(項目30)
前記化学療法が、5−フルオロウラシル、オキサリプラチンまたはSN−38である、項目29に記載の方法。
(項目31)
がんを有する患者を処置する方法であって、
(a)(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むがん細胞を有すると決定された患者を選択するステップと、
(b)治療有効量のPOLR2A阻害剤を該患者に投与するステップと
を含む方法。
(項目32)
POLR2A阻害剤による処置のための患者を選択するin vitro方法であって、該患者由来のがん細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むかどうかを決定するステップを含むin vitro方法。
(項目33)
患者を選択するステップが、前記がんの試料を得るステップと、該がんの細胞が、(i)前記TP53遺伝子のヘミ接合性喪失;(ii)前記POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むかどうかを決定するステップとを含む、項目32に記載の方法。
(項目34)
前記決定するステップに関する報告を提供するステップをさらに含む、項目33に記載の方法。
(項目35)
前記報告が、書面または電子の報告である、項目34に記載の方法。
(項目36)
前記報告が、前記患者、医療費支払者、医師、保険代理人または電子システムに提供される、項目34に記載の方法。
(項目37)
患者を選択するステップが、前記がんの細胞が、(i)前記TP53遺伝子のヘミ接合性喪失;(ii)前記POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むかどうかを決定する検査の結果を得るステップを含む、項目32に記載の方法。
(項目38)
前記がん細胞が、前記TP53遺伝子のヘミ接合性喪失を含むかどうかを決定するステップを含む、項目32に記載の方法。
(項目39)
前記がん細胞が、前記POLR2A遺伝子のヘミ接合性喪失を含むかどうかを決定するステップを含む、項目32に記載の方法。
(項目40)
前記がん細胞が、参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むかどうかを決定するステップを含む、項目32に記載の方法。
(項目41)
がん患者のための薬物療法を選択するin vitro方法であって、
(a)該がんの試料を得るステップと、
(b)該がんの細胞における(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少の存在を検出するステップと、
(c)該がんの細胞において(i)該TP53遺伝子のヘミ接合性喪失が検出される;(ii)該POLR2A遺伝子のヘミ接合性喪失が検出される;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少が検出される場合、POLR2A阻害剤を選択するステップと
を含むin vitro方法。
(項目42)
治療有効量のPOLR2A阻害剤を前記患者に投与するステップをさらに含む、項目41に記載の方法。
(項目43)
前記がんの細胞が、前記TP53遺伝子のヘミ接合性喪失を含む、項目41に記載の方法。
(項目44)
前記がんの細胞が、前記POLR2A遺伝子のヘミ接合性喪失を含む、項目41に記載の方法。
(項目45)
前記がんの細胞が、参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含む、項目41に記載の方法。
(項目46)
被験体におけるがんの処置における使用のためのPOLR2A阻害剤を含む組成物であって、該がんの細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むことが決定されている、組成物。
(項目47)
がんの処置のための医薬の製造におけるPOLR2A阻害剤の使用であって、該がんの細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むことが決定されている、使用。
本明細書に提示されている研究は、TP53のゲノム欠失が、隣接する必須遺伝子を高頻度で包含し、ヘミ接合性TP53欠失を有するがん細胞を、かかる遺伝子のさらなる抑制に対して脆弱にすることを実証する。POLR2Aは、多くの種類のヒトがんにおいて、TP53と実質的に共欠失されるかかる必須ハウスキーピング遺伝子として同定される。この遺伝子は、α−アマニチンによって特異的に阻害される、RNAポリメラーゼII複合体の最大かつ触媒性のサブユニットをコードする(Bensaude、2011年;Lindellら、1970年)。したがって、p53またはその調節因子の薬理学的介入の代わりに、POLR2A阻害に対する副次的な脆弱性の原理は、がん療法の最新の戦略を提供する。
少なくとも1個の細胞標的化剤にα−アマニチン分子(またはいずれかのアマトキシン)をコンジュゲートして、α−アマニチンの有用性を増強し、肝毒性を低下させることが望まれ得る。かかるコンジュゲートは、「免疫毒素」と呼ばれることがある。例えば、治療剤としてのα−アマニチンの有効性および有用性を増加させるために、これは、所望の細胞標的化部分にコンジュゲートまたは共有結合することができる。かかる部分は、がん細胞等の細胞型における外部受容体または結合部位に結合することにより、所望の前記細胞型を標的化するのに十分な選択性、特異性または親和性を有するいずれかの部分であり得る(米国特許出願公開第2009/0304666号)。かかる部分の例として、抗体またはその抗原結合性断片、抗体様タンパク質およびアプタマーが挙げられるがこれらに限定されない。抗原結合性抗体断片の例として、(i)VLドメイン、VHドメイン、CLドメインおよびCH1ドメインからなるFab断片;(ii)VHドメインおよびCH1ドメインからなる「Fd」断片;(iii)単一抗体のVLドメインおよびVHドメインからなる「Fv」断片;(iv)VHドメインからなる「dAb」断片;(v)単離されたCDR領域;(vi)2個の連結されたFab断片を含む二価断片であるF(ab’)2断片;(vii)VHドメインおよびVLドメインが、この2個のドメインが会合して結合ドメインを形成することを可能にするペプチドリンカーによって連結されている、単鎖Fv分子(「scFv」);(viii)二特異性単鎖Fv二量体(米国特許第5,091,513号を参照)ならびに(ix)遺伝子融合によって構築された多価または多特異性断片であるダイアボディ(diabody)(米国特許出願公開第2005/0214860号)が限定されることなく挙げられる。Fv、scFvまたはダイアボディ分子は、VHドメインおよびVLドメインを連結するジスルフィド架橋の取込みによって安定化させることができる。細胞標的化部分は、例えば、CD19、CD20、CD30、CD33、CD52、EpCAM、癌胎児性抗原、アルファフェトプロテイン、gpA33、ムチン、CA−125、MUC−1、CD56、EGFR、ERBB2、ERBB3、c−Met、IGF1R、EPHA3、TRAILR1、TRAILR2、RANKL、FAP、テネイシン、AKT、Her2/neu、Her3、上皮腫瘍抗原、メラノーマ関連抗原、変異したp53、変異したras、デクチン−1、gp100、MART−1/メランA、TRP−1(gp75)、チロシナーゼ、TAG−72、CAIX、PSMA、葉酸結合タンパク質、ガングリオシド(例えば、GD2、GD3、GM2)、MAGE−1、MAGE−3、BAGE、GAGE−1、GAGE−2、N−アセチルグルコサミニルトランスフェラーゼ−V、p15、β−カテニン、MUM−1、CDK4、HPV−E6、HPV−E7、ZFP161、ユビキリン(Ubiquilin)−1、HOX−B6、IFI27、YB−1、KIAA0136、オステオネクチン、F−ボックスのみのタンパク質21、ILF3、SSX−2、PSMA、NY−ESO−1、PRAME、メソセリン、VEGF、VEGFR、インテグリンアルファVベータ3、インテグリンアルファ5ベータ1またはPLK1等、いずれかの腫瘍関連抗原に特異的に結合することができる。
本実施形態のある特定の態様を使用して、TP53のヘミ接合性喪失およびそれに伴うPOLR2A喪失に関連する疾患または障害を防止または処置することができる。POLR2Aの機能をいずれか適した物質によって低下させて、TP53および/またはPOLR2Aのヘミ接合性喪失を有するがんを処置することができる。かかる例示的な物質は、いずれかのアマトキシン、α−アマニチンまたはいずれかのアマトキシンもしくはα−アマニチンにコンジュゲートされた細胞標的化部分であり得る。
ある特定の実施形態では、本発明の組成物および方法は、第2のまたは追加的な治療法と組み合わせた、α−アマニチンにコンジュゲートされた細胞標的化部分が関与する。かかる治療法は、TP53および/またはPOLR2Aのヘミ接合性喪失に関連するいずれかの疾患の処置において適用することができる。例えば、疾患は、がんであり得る。
A/B/AB/A/BB/B/AA/A/BA/B/BB/A/AA/B/B/BB/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/BA/B/B/AB/B/A/A
B/A/B/A B/A/A/B A/A/A/BB/A/A/AA/B/A/AA/A/B/A
多種多様な化学療法剤を、本発明に従って使用することができる。用語「化学療法」は、がんを処置するための薬物の使用を指す。「化学療法剤」は、がんの処置において投与される化合物または組成物を暗示するように使用される。これらの作用物質または薬物は、細胞内におけるその活性機序によって、例えば、これが細胞周期に影響を与えるか否かおよびいずれのステージでそれが為されるかによってカテゴリー化される。あるいは、作用物質は、DNAを直接架橋する、DNA内にインターカレートする、または核酸合成に影響を与えることにより染色体および有糸分裂異常を誘導するその能力に基づき特徴付けることができる。大部分の化学療法剤は、次のカテゴリーに該当する:アルキル化剤、代謝拮抗薬、抗腫瘍抗生物質、有糸分裂阻害剤およびニトロソウレア。
DNA損傷を生じる、広範に使用されてきた他の因子は、γ線、X線および/または腫瘍細胞への放射性同位元素の定方向送達として一般的に公知のものを含む。マイクロ波、陽子線照射(米国特許第5,760,395号および同第4,870,287号)およびUV照射等、他の形態のDNA損傷因子も企図される。これらの因子の全てが、DNA、DNAの前駆体、DNAの複製および修復、ならびに染色体のアセンブリおよび維持における広範囲の損傷に影響を与える可能性が最も高い。X線の線量範囲は、延長された期間にわたる(3〜4週間)50〜200レントゲンの一日線量から、2000〜6000レントゲンの単一線量に及ぶ。放射性同位元素の線量範囲は、広く変動し、同位元素の半減期、放射する放射線の強度および種類、ならびに新生物細胞による取込みに依存する。
がん処置の文脈において、免疫療法は、一般に、がん細胞を標的および破壊するための免疫エフェクター細胞および分子の使用に頼る。トラスツズマブ(Herceptin(商標))は、かかる例である。免疫エフェクターは、例えば、腫瘍細胞の表面におけるあるマーカーに特異的な抗体であり得る。抗体は単独で、治療法のエフェクターとして機能することができる、または他の細胞を動員して、細胞殺滅に実際に影響させることができる。抗体は、薬物または毒素(化学療法薬、放射性核種、リシン(ricin)A鎖、コレラ毒素、百日咳毒素等)にコンジュゲートし、単に標的化作用物質として機能することもできる。あるいは、エフェクターは、直接的または間接的のいずれかで、腫瘍細胞標的と相互作用する表面分子を有するリンパ球であり得る。様々なエフェクター細胞は、細胞傷害性T細胞およびNK細胞を含む。治療モダリティ、すなわち、直接的な細胞傷害活性およびErbB2の阻害または低下の組合せは、ErbB2過剰発現がんの処置における治療利益をもたらすであろう。
がんを有する人のおよそ60%が、予防的、診断的または進行度診断的、根治的および姑息的手術を含むある種の手術を受ける。根治的手術は、本発明の処置、化学療法、放射線療法、ホルモン療法、遺伝子療法、免疫療法および/または代替的治療法等、他の治療法と併せて使用することができるがん処置である。
本発明のある特定の態様と組み合わせて他の作用物質を使用して、処置の治療有効性を改善することができることが企図される。これらの追加的な作用物質は、免疫調節剤、細胞表面受容体およびGAP結合の上方調節に影響を与える作用物質、細胞分裂阻害および分化剤、細胞接着の阻害剤、アポトーシス誘導物質に対する過剰増殖細胞の感受性を増加させる作用物質、または他の生物学的作用物質を含む。免疫調節剤は、腫瘍壊死因子;インターフェロンアルファ、ベータおよびガンマ;IL−2および他のサイトカイン;F42Kおよび他のサイトカインアナログ;またはMIP−1、MIP−1ベータ、MCP−1、RANTESおよび他のケモカインを含む。Fas/Fasリガンド、DR4またはDR5/TRAIL(Apo−2リガンド)等、細胞表面受容体またはそのリガンドの上方調節が、過剰増殖性細胞における自己分泌または傍分泌効果の確立によって、本発明のアポトーシス誘導能力を強めるであろうことがさらに企図される。GAP結合の数を上昇させることによる細胞間シグナル伝達の増加は、隣接する過剰増殖細胞集団における抗過剰増殖効果を増加させるであろう。他の実施形態では、細胞分裂阻害または分化剤は、本発明のある特定の態様と組み合わせて使用して、処置の抗過剰増殖有効性を改善することができる。細胞接着の阻害剤は、本発明の有効性を改善することが企図される。細胞接着阻害剤の例は、接着斑キナーゼ(FAK)阻害剤およびロバスタチンである。抗体c225等、アポトーシスに対する過剰増殖細胞の感受性を増加させる他の作用物質は、本発明のある特定の態様と組み合わせて使用して、処置有効性を改善することができることがさらに企図される。
以下の実施例は、本発明の好ましい実施形態を実証するために含まれる。以下の実施例に開示されている技法は、本発明者により、本発明の実施においてよく機能することが発見された技法であり、したがって、それを実施するための好ましいモードを構成するとみなすことができることが当業者には理解されるべきである。しかし、当業者は、本開示に照らして、開示されている特定の実施形態に多くの変更を行うことができ、それでもなお、本発明の主旨および範囲から逸脱することなく同様または類似の結果が得られることを理解するべきである。
細胞培養、抗体およびウエスタンブロット解析。HCT116細胞株、SW480細胞株、SW837細胞株、HT29細胞株、DLD1細胞株およびHT29細胞株をアメリカ合衆国培養細胞系統保存機関(American Type Culture Collection)から入手し、製造業者によって指定された標準条件下で培養した。SNU283細胞株およびSNU1197細胞株を韓国細胞株バンク(Korean Cell Line Bank)から入手し、10%FBSおよび2mM L−グルタミンを補充したRMPI 1640培地中で培養した。異種移植されたヒト初代CRC(xhCRC)細胞の単離、培養および維持を以前に記載された通りに行った(Luら、2013年)。手短に説明すると、患者由来の異種移植片を無菌条件下で収集し、機械的に解離させ、続いてコラゲナーゼII中で37℃にて30分間インキュベーションを行った。この検体を無菌100μm漉し器で濾過した。低浸透圧性赤血球溶解バッファー(eBioscience)により赤血球を排除した。マウスMHCクラスI分子H−2K抗体を使用した負の選択と、続く磁気ビーズ精製キット(Miltenyi)の使用によって、異種移植したヒトCRC検体におけるマウス細胞を除去した。MACS磁気ビーズ分離キット(Miltenyi)を使用した負の選択によって、線維芽細胞を除去した。単離したばかりのxhCRC細胞を、コラーゲン−1でコーティングした培養プレート(BD Biosciences)で維持し、10%FBS、ビタミン(1×)、非必須アミノ酸(1×)、Pen−Strep(1×)、ピルビン酸ナトリウム(1×)およびL−グルタミン(1×)を補充したMEMにおいて培養した。全ての培地サプリメントは、Sigmaから購入した。
POLR2Aの発現は遺伝子コピー数と相関するが、TP53の発現は遺伝子コピー数と相関しない
腫瘍サプレッサー遺伝子のゲノム欠失は、がん発生に寄与しない可能性があるが細胞増殖および生存に必須な複数の隣接する遺伝子を包含することが多い(Negriniら、2010年)。かかるハウスキーピング遺伝子のこの部分的喪失は、がん細胞を、これらの遺伝子のさらなる阻害に対して高度に脆弱にすると仮定された(Nijhawanら、2012年)。TCGAの解析は、TP53遺伝子のヘミ接合性欠失が、多様なヒトがんにおいて高頻度で起こることを明らかにした(図1A)。POLR2Aは、細胞生存に必須な、TP53に近接した(ヒトゲノムにおいて約200キロベース離れて存在)ハウスキーピング遺伝子として同定された(図1B)。POLR2Aの随伴性欠失は、TP53のヘミ接合性欠失を保有する実質的に全てのヒト結腸直腸腫瘍において起こる(図1C)。
POLR2A喪失細胞は、POLR2A阻害に対し高度に感受性である
POLR2A阻害に対する、TP53/POLR2Aヘミ接合性喪失ありまたはなしの細胞の感受性を評価するために、POLR2A中立細胞(HCT116、SW480)およびPOLR2A喪失細胞(SW837、SNU283)のパネルをα−アマニチンで処理した。高濃度(≧1μg ml−1)でのα−アマニチン処理は、全4種の細胞株において細胞成長を劇的に阻害し、完全な細胞死を引き起こした。しかし、0〜1.0μg ml−1の濃度において、α−アマニチン阻害は、POLR2A喪失細胞において、対照POLR2A中立細胞よりも有意に高いレベルの細胞殺滅効果を有した(図2Aおよび図2B)。最大半量阻害濃度(IC50)は、POLR2A中立細胞に対して約1.0μg ml−1であり、これは、POLR2A喪失細胞のものよりも10倍大きかった。対照的に、POLR2A喪失細胞は、非特異的転写阻害剤であるアクチノマイシンD処理に対し、いかなるより高い感受性も示さなかった(図7A)。次に、直接的競合アッセイを使用して、POLR2A喪失細胞の脆弱性を評価した。細胞増殖速度を、対照またはPOLR2A特異的shRNAを発現する対照細胞およびGFP陽性細胞の間で比較した。2種の独立したshRNAは、検査した全細胞株において、POLR2A発現を50%〜70%ノックダウンした(図7B)。6継代にわたって培養した後に、POLR2A shRNAを安定して発現するPOLR2A中立細胞(HCT116、SW480)は、対照shRNAを発現する対応する細胞の増殖と比較して、やや低下した増殖しか示さなかった(図7C)。しかし、POLR2A喪失細胞(SNU283、SW837)におけるPOLR2Aのサイレンシングは、著しく低下した増殖をもたらし、POLR2Aのヘミ接合性喪失が、がん細胞を、さらなるPOLR2A阻害を受け易くすることを示唆した。ドキシサイクリン(Dox)誘導性POLR2A shRNAを安定に発現するHCT116細胞株およびSNU283細胞株を作製した(図7D)。POLR2Aの有意なノックダウンにもかかわらず、HCT116細胞が、増殖し続けた一方で、SNU283細胞は、重度のG1細胞周期停止およびアポトーシスを示した(図2C、図2Dおよび図7E〜図7G)。およそ50%のPOLR2A発現減少(30〜100ng ml−1のDoxの添加による)は、SNU283細胞の増殖を際立って低下させたが、HCT116細胞には中程度の効果しかなかった(図2D)。次に、POLR2A喪失SNU283細胞株およびSW837細胞株においてレスキュー実験を行った。両方の細胞株における外因的POLR2Aの漸進的な再発現は、α−アマニチンに対するそれらの抵抗性を、POLR2A中立HCT116細胞およびSW480細胞に匹敵するレベルまで回復させた(図2E、図2Fおよび図8A〜図8B)。
POLR2A阻害に対するPOLR2A喪失細胞の感受性は、p53に非依存的である
RNAポリメラーゼの遮断は、p53蓄積および活性化をもたらし得る(Derheimerら、2007年)。POLR2A阻害に対する細胞応答におけるp53の効果を試験するために、TP53およびPOLR2Aの随伴性欠失を、HCT116細胞株およびxhCRC細胞株において再現した(図3Aおよび図10A〜図10C)。単離したばかりの異種移植したヒト結腸直腸腫瘍からxhCRC細胞株(TP53+/+;POLR2A+/+)を確立し、これは、in vivoにおける増強された腫瘍形成能を実証した(Luら、2013年)。僅かに増加した細胞増殖を除いて、α−アマニチンに対するそれらの感受性の有意な変化は、TP53のヘミ接合性欠失を有するxhCRC細胞およびHCT116細胞の両方において観察されなかった。対照的に、POLR2Aのヘミ接合性喪失は、それらのTP53状態に関係なく、α−アマニチン処理に対してこれらの細胞を著しく感受性にした(図3B、図3Cおよび図10D〜図10F)。RNAポリメラーゼIIは、治療抵抗性腫瘍細胞を含むいかなる種類の細胞にとっても必須の機能である、mRNA合成を担当する。結腸直腸がんのための3種の主要な化学療法薬物(5−フルオロウラシル(5−FU)、オキサリプラチンおよびSN−38)に対するPOLR2A中立細胞およびPOLR2A喪失細胞の薬物感受性を試験した。α−アマニチンによるPOLR2Aの阻害は、POLR2A喪失xhCRC細胞において全3種の薬物の細胞殺滅効果を有意に増強したが、POLR2A中立細胞には顕著な効果がなく(図3D)、がん療法におけるPOLR2A喪失結腸直腸腫瘍の治療に対する脆弱性を示唆していた。遊離α−アマニチンは、肝細胞の膜において排他的に発現されるトランスポーターであるOATP1B3によって特異的に結合されるため、肝臓に対して毒性がある(Letschertら、2006年)。しかし、α−アマニチンは、特異的な抗体とコンジュゲートされた場合、もはやOATP1B3の基質ではない(Letschertら、2006年;Moldenhauerら、2012年;FaulstichおよびFiume、1985年)。この戦略は、臨床適用の際のα−アマニチンの毒性を克服する。腺癌の大部分で過剰発現されるがん抗原であるEpCAMに対するモノクローナル抗体(HEA125)にコンジュゲートされたα−アマニチン(ama−HEA125)(Moldenhauerら、2012年;Wentら、2004年)を使用した。ama−HEA125コンジュゲートは、p53非依存的様式でPOLR2A喪失xhCRCがん細胞およびHCT116がん細胞を選択的に死滅させ、in vitroでα−アマニチンの有効用量を少なくとも10,000分の1に低下させた(IC50約0.01ng ml−1)(図3Eおよび図10G)。
POLR2Aの抑制は、POLR2A喪失腫瘍成長を選択的に阻害する
in vivoにおけるPOLR2A阻害の抗腫瘍効果を検査するために、Dox誘導性POLR2A shRNAを発現するHCT116細胞およびSNU283細胞を、免疫低下したSCID BALB/cマウスに皮下注射した。初期腫瘍確立後に、飲料水中Doxの投与は、POLR2A発現を抑制し、結果的に、SNU283由来腫瘍の成長を阻害した(図4A)。しかし、対照およびPOLR2AノックダウンHCT116由来腫瘍の間に実質的な差は観察されなかった。病理組織学的解析は、POLR2Aノックダウン(Dox:1.0μg ml−1)SNU283腫瘍が、対応する対照腫瘍と比較して、細胞増殖(Ki67染色)が有意に低下し、しかしアポトーシス細胞(切断型カスパーゼ−3染色)は増えていたことを実証した(図11A〜図11B)。対照的に、対照またはPOLR2AノックダウンHCT116腫瘍において、有意な変化は観察されなかった。しかし、POLR2Aのヘテロ接合性欠失は、Dox誘導性POLR2A shRNAの抑制に対してPOLR2A+/−HCT116由来腫瘍を感受性にした(図11C)。次に、同所性腫瘍モデルを用いて、POLR2A阻害の効果を検査した。POLR2A中立HCT116細胞およびPOLR2A喪失HCT116細胞を、SCIDマウスの盲腸壁に注射した。同所性腫瘍が確立されたら、マウスに、飲料水中Dox(1.0μg ml−1)を投与した。腫瘍のin vivo生物発光イメージングは、Dox誘導性POLR2A阻害が、POLR2A喪失腫瘍における腫瘍成長動態の有意な減少をもたらしたが、対照POLR2A中立腫瘍においてはもたらさなかったことを実証した(図4B〜図4C)。3週間のDox処置後に、POLR2A中立腫瘍群において大きな腫瘍が視認可能だった一方、POLR2A喪失群においては、有意に低下した腫瘍成長が観察されたまたは視認可能な腫瘍は観察されなかった。in vivoにおけるPOLR2Aサイレンシングの有効性をさらに検査するために、ナノリポソーム送達プラットフォーム、DOPC(1,2−ジオレオイル−sn−グリセロ−3−ホスファチジルコリン)を、POLR2A siRNAの全身性送達のために使用した(Pecotら、2014年)。2種の特異的POLR2A siRNAでは、同質遺伝子的HCT116細胞株においてPOLR2Aタンパク質のノックダウンが80%を超えた(図12A)。1.0×106個の同質遺伝子的HCT116細胞の同所性注射の10日後に、マウスを処置群にランダムに割り当てた(n=10匹のマウス/群)。DOPCナノリポソームに取り込まれたsiRNAの1週間に2回の処置を開始した(図12B)。4週間の全身療法後に、対照siRNA−DOPC処置と比較して、125μg kg−1のPOLR2A siRNA−DOPC処置群におけるマウスは、POLR2A喪失腫瘍の成長が著しく低下していたが、POLR2A中立腫瘍は、1,000μg kg−1のPOLR2A siRNA−DOPCの用量においてのみ有意に成長が阻害された(図12C〜図12F)。
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参考文献
以下の参考文献は、本明細書に記載のものを補足する例示的な手続き上のまたは他の詳細をもたらすものである限りでは、参照により本明細書に具体的に組み込まれる。
米国特許第4,870,287号
米国特許第5,091,513号
米国特許第5,739,169号
米国特許第5,760,395号
米国特許第5,801,005号
米国特許第5,824,311号
米国特許第5,830,880号
米国特許第5,846,945号
米国特許出願公開第2005/0214860号
米国特許出願公開第2009/0304666号
PCT公開第WO2012/119787号
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Claims (17)
- がんを有する患者の処置における使用のための組成物であって、該がんの細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照発現レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を示し、該組成物が治療有効量のPOLR2A阻害剤を含み、該POLR2A阻害剤が、アマトキシンを含み、該アマトキシンが、腫瘍関連抗原に特異的に結合する抗体にコンジュゲートされている、組成物。
- 前記抗体が、抗EpCAM抗体である、請求項1に記載の組成物。
- 前記POLR2A遺伝子産物が、mRNAであり、該mRNAの発現のレベルが、ノーザンブロッティング、逆転写定量的リアルタイムPCR(RT−qPCR)、ヌクレアーゼプロテクション、トランスクリプトーム解析、ハイブリダイゼーションアッセイ、チップに基づく発現プラットフォームまたはインベーダーRNAアッセイプラットフォームによって決定され得るか、または、
前記POLR2A遺伝子産物が、タンパク質であり、該タンパク質の発現のレベルが、質量分析、ウエスタンブロット、ELISA、免疫沈降、免疫組織化学的検査またはラジオイムノアッセイによって決定され得る、請求項1または2いずれかに記載の組成物。 - 前記参照発現レベルが、非がん性細胞における発現レベルである、請求項1〜3のいずれかに記載の組成物。
- 前記TP53遺伝子の前記ヘミ接合性喪失または前記POLR2A遺伝子の前記ヘミ接合性喪失が、ゲノムハイブリダイゼーション技法、PCR解析または制限断片解析によって決定される、請求項1〜4のいずれかに記載の組成物。
- 前記がん細胞が、肺がん細胞、脳がん細胞、乳がん細胞、肝臓がん細胞、卵巣がん細胞、結腸直腸がん細胞、前立腺がん細胞または膵臓がん細胞である、ならびに/あるいは
前記がん細胞が、転移性、再発性または多剤耐性である、請求項1〜5のいずれかに記
載の組成物。 - 少なくとも第2の抗がん療法薬、好ましくは、化学療法剤、最も好ましくは、5−フルオロウラシル、オキサリプラチンまたはSN−38をさらに含む、請求項1〜6のいずれかに記載の組成物。
- 前記患者が、ヒトまたは非ヒト哺乳動物である、請求項1〜7のいずれかに記載の組成物。
- 前記患者が、少なくとも1ラウンドの抗がん療法を以前に受けたことがある、請求項1〜8のいずれかに記載の組成物。
- がんを有する患者を処置するための組成物であって、該組成物は、POLR2A阻害剤を含み、該患者は、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むがん細胞を有すると決定されており、
該組成物は、POLR2A阻害剤の治療有効量で、該患者に投与されることを特徴とし、該POLR2A阻害剤が、アマトキシンを含み、該アマトキシンが、腫瘍関連抗原に特異的に結合する抗体にコンジュゲートされている、組成物。 - (i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を、POLR2A阻害剤による処置のための患者の選択の指標とするin vitro方法であって、該患者由来のがん細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むかどうかを決定するステップを含み、該患者由来のがん細胞が、(i)該TP53遺伝子のヘミ接合性喪失;(ii)該POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含む場合、そのことは、該患者が、POLR2A阻害剤による処置のために選択されることを示すことを特徴とし、該POLR2A阻害剤が、アマトキシンを含み、該アマトキシンが、腫瘍関連抗原に特異的に結合する抗体にコンジュゲートされている、in vitro方法。
- 前記決定するステップに関する報告、好ましくは、書面または電子の報告を提供するステップをさらに含み、好ましくは、前記報告が、前記患者、医療費支払者、医師、保険代理人または電子システムに提供される、請求項11に記載の方法。
- 前記方法が、前記がんの細胞が、(i)前記TP53遺伝子のヘミ接合性喪失;(ii)前記POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むかどうかを決定する検査の結果を得るステップを含む、請求項11〜12のいずれかに記載の方法。
- (i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少の存在を、がん患者のための薬物療法の選択の指標とするin vitro方法であって、
該がんの細胞における(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少の存在を検出するステップを含み、
該がんの細胞において(i)該TP53遺伝子のヘミ接合性喪失が検出される;(ii)該POLR2A遺伝子のヘミ接合性喪失が検出される;または(iii)参照レベルと
比べたPOLR2A遺伝子産物の発現のレベル減少が検出される場合、そのことは、薬物療法としてPOLR2A阻害剤が選択されることを示すことを特徴とし、
該POLR2A阻害剤が、アマトキシンを含み、該アマトキシンが、腫瘍関連抗原に特異的に結合する抗体にコンジュゲートされている、in vitro方法。 - 前記方法は、治療有効量の前記POLR2A阻害剤が前記患者に投与されることを示すことを特徴とする、請求項14に記載の方法。
- 被験体におけるがんの処置における使用のためのPOLR2A阻害剤を含む組成物であって、該がんの細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むことが決定されており、該POLR2A阻害剤が、アマトキシンを含み、該アマトキシンが、腫瘍関連抗原に特異的に結合する抗体にコンジュゲートされている、組成物。
- がんの処置のための医薬の製造におけるPOLR2A阻害剤の使用であって、該がんの細胞が、(i)TP53遺伝子のヘミ接合性喪失;(ii)POLR2A遺伝子のヘミ接合性喪失;または(iii)参照レベルと比べたPOLR2A遺伝子産物の発現のレベル減少を含むことが決定されており、該POLR2A阻害剤が、アマトキシンを含み、該アマトキシンが、腫瘍関連抗原に特異的に結合する抗体にコンジュゲートされている、使用。
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