JP5937017B2 - Alk阻害剤に対する自然耐性または獲得耐性を有する癌の同定、評価および治療法 - Google Patents
Alk阻害剤に対する自然耐性または獲得耐性を有する癌の同定、評価および治療法 Download PDFInfo
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Description
前記患者からサンプルを採取し、前記サンプルを分析して、1つ以上の突然変異ALKポリヌクレオチド分子の存在を検出することを含み、
前記1つ以上の突然変異ALKポリヌクレオチド分子の存在が、前記被験体の前記ALK阻害剤を用いた治療に対する無応答性のリスクが増加したことを示唆する
方法を提供する。
前記患者からサンプルを採取し、前記サンプルを分析して、1つ以上の突然変異ALKポリペプチドの発現量、構造、および/または活性を検出することを含み、
前記1つ以上の突然変異ALKポリペプチドの存在が、前記被験体の前記ALK阻害剤を用いた治療に対する無応答性のリスクが増加したことを示唆する
方法を提供する。
マーカーの「変化量」またはマーカーの「変化レベル」という用語は、対照サンプルにおけるマーカーの発現量またはコピー数と比較した、ALK遺伝子変異および/または遺伝子産物(例えば、表1記載のマーカー)などのマーカーまたは染色体領域のコピー数の増減、および/または、癌サンプルにおける1つまたは複数の特定のマーカー遺伝子の発現量の増減のことをいう。マーカーの「変化量」という用語はまた、正常な対照サンプルにおけるマーカーのタンパク質レベルと比較した、例えば癌サンプルなどのサンプルにおけるマーカーのタンパク質レベルの増減も含む。
マーカーの「構造変化」という用語は、正常なまたは野生型の遺伝子またはタンパク質と比較した場合に、変異、あるいは、例えばマーカーの発現または活性に影響を及ぼす変異などのマーカー遺伝子またはマーカータンパク質内の変異の存在のことをいう。例えば、変異としては、限定はしないが、染色体間および染色体内の再配置、置換、欠失、および挿入変異が挙げられる。変異は、マーカーのコード領域または非コード領域に存在しうる。
アラニン(Ala, A) GCA, GCC, GCG, GCT
アルギニン(Arg, R) AGA, ACG, CGA, CGC, CGG, CGT
アスパラギン(Asn, N) AAC, AAT
アスパラギン酸(Asp, D) GAC, GAT
システイン(Cys, C) TGC, TGT
グルタミン酸(Glu, E) GAA, GAG
グルタミン(Gln, Q) CAA, CAG
グリシン(Gly, G) GGA, GGC, GGG, GGT
ヒスチジン(His, H) CAC, CAT
イソロイシン(Ile, I) ATA, ATC, ATT
ロイシン(Leu, L) CTA, CTC, CTG, CTT, TTA, TTG
リジン(Lys, K) AAA, AAG
メチオニン(Met, M) ATG
フェニルアラニン(Phe, F) TTC, TTT
プロリン(Pro, P) CCA, CCC, CCG, CCT
セリン(Ser, S) AGC, AGT, TCA, TCC, TCG, TCT
トレオニン(Thr, T) ACA, ACC, ACG, ACT
トリプトファン(Trp, W) TGG
チロシン(Tyr, Y) TAC, TAT
バリン(Val, V) GTA, GTC, GTG, GTT
終結シグナル(end) TAA, TAG, TGA
本発明は、少なくとも一部には、癌の治療における、ALK阻害剤の有効性の予測に関連した、例えば、ALK突然変異を含めたゲノムの特定部位の同定に基づいている。ALK遺伝子発現配列の分析は、ポリペプチドを少なくともある程度ALK阻害剤を用いた治療に対して耐性に変えうる、ALKポリペプチド(例えば、EML4−ALKポリペプチドを含めた表1記載の生体指標)に対する新しい変異の同定をもたらした。したがって、本明細書に記載されるさまざまな方法における、これら生体指標の1つ以上の存在および/または不存在は、本発明の範囲内にある。
本発明の1つの態様は、本発明のマーカーに対応するポリペプチドまたはこのようなポリペプチの一部をコードする核酸を含めた、本発明の生体指標に対応する単離核酸分子に関する。本発明の核酸分子は、本明細書において同定されたALKまたはALK関連ゲノム(例えば、生殖細胞系および/または体細胞)領域に存在する核酸分子、および/または、ALKまたはALK関連(例えば、EML4−ALK)ポリペプチドをコードする、核酸分子を含む。一部の実施の形態では、本発明の核酸分子は、表1に提示される核酸配列(nucleic sequences)、またはそれらの断片を含む、それらから実質的になる、またはそれらからなる。本発明の単離核酸分子はまた、本発明のマーカーに対応するポリペプチドをコードする核酸分子およびこのような核酸分子の断片を含めた、本発明のマーカーに対応する核酸分子を同定するためのハイブリダイゼーションプローブとしての使用に十分な核酸分子を含み、例えば、核酸分子を増幅または変異させるためのPCRプライマーとしての使用に適したものなどが挙げられる。本明細書では「核酸分子」という用語には、DNA分子(例えば、cDNAまたはゲノムDNA)およびRNA分子(例えば、mRNA)および、ヌクレオチド類似体を使用して生成したDNAまたはRNAの類似体が含まれることが意図されている。核酸分子は一本鎖または二本鎖であって差し支えない;ある特定の実施の形態では、核酸分子は二本鎖DNAである。
本発明の1つの態様は、本発明の個別のマーカーに対応する単離タンパク質、およびそれらの生物学的に活性な部分に関連する。1つの実施の形態では、マーカーに対応する天然のポリペプチドは、標準的なタンパク質精製法を使用した適切な精製スキームによって、細胞源または組織源から単離することができる。別の実施の形態では、本発明のマーカーに対応するポリペプチドは、遺伝子組み換え技術によって産生される。組み換え発現に替えて、本発明のマーカーに対応するポリペプチドは、標準的なペプチド合成法を使用して化学的に合成することもできる。
本発明のもう1つの態様は、本発明のマーカーに対応するポリペプチド(またはこのようなポリペプチドの一部)をコードする核酸を含む、発現ベクターなどのベクターに関する。本明細書では、「ベクター」という用語は、別の核酸に結合して輸送することができる核酸分子を表す。ベクターの1つの型は「プラスミド」であり、これは、追加のDNA断片が連結する環状二重鎖DNAループを表す。別のタイプのベクターは、追加のDNA断片がウイルスゲノムに連結されうる、ウイルスベクターである。ある特定のベクターは、それらが導入される宿主細胞において自己複製することができる(例えば、細菌の複製起点を有する細菌ベクターおよびエピソーム哺乳類ベクター)。他のベクター(例えば、非エピソーム哺乳類ベクター)は、宿主細胞への導入の際に宿主細胞のゲノムに組み込まれ、宿主ゲノムとともに複製される。さらには、ある特定のベクター、すなわち発現ベクターは、動作可能に連結した遺伝子の発現を検出することができる。一般に、遺伝子組み換え技術に有用な発現ベクターは、しばしば、プラスミド(ベクター)の形態をしている。しかしながら、本発明は、同等の機能を果たす、ウイルスベクター(例えば、複製欠損レトロウイルス、アデノウイルスおよびアデノ随伴ウイルス)など、発現ベクターの他の形態も含むことが意図されている。
キットは、少なくとも1種類の試薬、例えば、本発明のマーカーを特異的に検出するためのプローブを含む、いずれかの製品(例えば、パッケージまたは容器)であり、前記製品は、本発明の方法を実施するためのユニットとして、宣伝、流通、または販売される。本発明の組成物、キット、および方法を用いて本発明の方法を実施する場合、本発明のALK遺伝子変異および/または遺伝子産物(例えば、表1記載のマーカー)は、対応するステージ、悪性度、組織型、または良性/前癌性/悪性の性質を有する癌を患っている被験体の少なくとも約20%、少なくとも約40%、少なくとも約60%、少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約99%または100%に、陽性結果が得られるように選択されうる。ある特定の実施の形態では、本発明のマーカーまたはマーカー群は、母集団について約10%を超えるPPV(陽性予測値)が得られるように選択されうる(例えば、99.5%を超えるアッセイ特異性に加えて)。
本発明はまた、個人を予防治療するために、診断分析、薬理ゲノム学、および臨床試験のモニタリングを予測目的で用いる、予測医学の分野も対象とする。したがって、本発明の1つの態様は、癌を有するまたは癌を発現するリスクのある個人がALK阻害剤介在性の治療に反応を示す可能性の高さを判定することを目的とした、本発明の1つ以上のマーカーに対応するポリペプチドまたは核酸の量、構造、および/または活性を決定するためのアッセイに関する。
ALK遺伝子変異および/または遺伝子産物(例えば、表1記載のマーカー)を評価する方法は、ハイブリダイゼーションに基づいたアッセイを含めて当業者に周知である。例えば、サンプル中のコード化核酸のコピー数を評価する1つの方法は、サザンブロット法に関する。サザンブロット法では、ゲノムDNA(典型的には、断片化され、電気泳動ゲル上で分離される)は、標的領域に特異的なプローブとハイブリッド形成される。標的領域用のプローブに由来するハイブリダイゼーションシグナルの強度と、正常なゲノムDNA(例えば、同一または関連する細胞、組織、臓器などの非増幅部分)の分析から得た対照プローブ信号との比較は、標的核酸の存在/不存在および相対コピー数の推定値を提供する。あるいは、ノーザンブロット法は、サンプル中のコード化核酸のコピー数の推定に用いられうる。ノーザンブロット法では、mRNAは、標的領域に特異的なプローブとハイブリッド形成される。標的領域用のプローブから得たハイブリダイゼーションシグナルの強度と、正常なmRNA(例えば、同一または関連する細胞、組織、臓器などの非増幅部分)の分析から得られた対照プローブ信号との比較は、標的核酸の存在/不存在および相対コピー数の推定を提供する。
標的領域外での染色体プローブとDNAとの非特異的結合は、一連の洗浄によって除去することができる。各洗浄における塩の温度および濃度を変化させて、洗浄のストリンジェンシーを調節する。例えば、高ストリンジェンシー条件では、洗浄は、約65℃〜約80℃で、0.2倍〜約2倍のSSC、および約0.1%〜約1%のNonidet P−40(NP40)などの非イオン性洗剤を使用して行うことができる。ストリンジェンシーは、洗浄温度を低下させることによって、または洗浄中の塩濃度を増大させることによって下げることができる。一部の用途では、反復配列のハイブリダイゼーション容量をブロックすることが必要である。よって、一部の実施の形態では、非特異的ハイブリダイゼーションのブロックにtRNA、ヒトゲノムDNA、またはCot−I DNAが用いられる。
マーカーの発現量についても分析することができる。本発明のマーカーの発現は、転写分子またはタンパク質の発現を検出するための幅広い周知の方法で評価されうる。これらの方法の非限定的な例としては、分泌された、細胞表面タンパク質、細胞質タンパク質、または核タンパク質の検出用の免疫学的方法、タンパク質精製法、タンパク質の機能または活性の分析法、核酸ハイブリダイゼーション法、核酸の逆転写法、および核酸増幅法が挙げられる。
マーカータンパク質の活性またはレベルもまた、発現ポリペプチドの検出または定量によって検出および/または定量することができる。ポリペプチドは、当業者に周知の多くの手段のいずれかによって検出または定量することができる。これらには、電気泳動法、キャピラリー電気泳動、高性能液体クロマトグラフィー(HPLC)、薄層クロマトグラフィー(TLC)、高拡散クロマトグラフィーなどの生化学的分析方法、または、流体またはゲル沈降素反応、免疫拡散法(一元または二元)、免疫電気泳動法、ラジオイムノアッセイ(RIA)、酵素結合免疫吸着検定法(ELISA)、免疫蛍光分析、ウエスタンブロット法、免疫組織化学的方法などのさまざまな免疫学的方法が含まれうる。当業者は、細胞が本発明のマーカーを発現するか否かの判定に使用するため、既知のタンパク質/抗体検出方法を容易に適合させることができる。
本発明はまた、変化、例えば変異などの構造的変化の存在を評価する方法も提供する。
本発明は、さらに、ALKポリペプチド(例えば、EML4−ALKポリペプチド)を阻害する物質を同定し、それによって癌細胞の増殖、成長、分化、アポトーシス、および/または転移を阻害するための方法も提供する。この方法は、試験化合物をALKポリペプチド(例えば、表1記載のポリペプチド)と接触させることを含む。一部の実施の形態では、ALKポリペプチドは、1つ以上のALK阻害剤による阻害に対する部分反応性または非反応性のリスクを増大させる変異体(例えば、表1記載のポリペプチド)を含む。腫瘍転移の阻害剤である化合物は、ALKポリペプチド変異体の活性(例えば、ATP結合などのリガンド結合および/またはチロシンキナーゼ活性を含む)における試験化合物の効果を決定することによって同定されうる。特定の例では、試験化合物の不存在下における活性と比較してチロシンキナーゼ活性を阻害する試験化合物は、腫瘍転移の阻害剤として同定される。その化合物がALK変異体の活性を阻害する場合、該化合物は腫瘍成長または転移を阻害する能力についてさらに評価されうる。
本明細書に開示される方法は、表1に記載される本発明の新しい生体指標(例えば、ALK突然変異体)の阻害剤を用いた治療候補として被験体を同定し、腫瘍の細胞死を誘発し、腫瘍成長を低減し、または腫瘍転移のリスクを低下させることを含む。ALKポリペプチドの阻害剤は当業者に既知である。例えば、PF−02341066、PDD、2−メチル−11−(2−メチルプロピル)−4−オキソ−4,5,6,11,12,13−ヘキサヒドロ−2H−インダゾロ[5,4−a]ピロロ[3,4−c]カルバゾール−8−イル[4−(ジメチルアミノ)ベンジル]カルバメート、(1S,2S,3R,4R)−3−({5−クロロ−2−[(1−エチル−2,3,4,5−テトラヒドロ−6−メトキシ−2−オキソ−1H−1−ベンゾアゼピン−7−イル)アミノ]−4−ピリミジニル}アミノ)ビシクロ[2.2.1]ヘプト−5−エン−2−カルボキサミド、およびNVP−TAE684が挙げられる(例えば、PNAS 104:270-275, 2007; Choi, Y.L. et al. (2008) Cancer Res. 68:4971-2976;およびBiochemistry 48:3600-3609, 2009参照。これらは、参照することによって本明細書に組み込まれる)。
本明細書に記載されるすべての刊行物、特許、および特許出願は、参照することにより各個別の刊行物、特許、および特許出願が組み込まれることを明確かつ個別に示唆されている場合、参照することによってその全体が本明細書に組み込まれる。矛盾する場合には、本明細書における定義を含めて、本願は制御される。
a.DNAの配列決定
EZ1 system(Qiagen社製(米国カリフォルニア州ヴァレンシア所在))を使用して抽出した試料RNAからオリゴ(dT)でプライミングしたcDNAを生成し、PrimeSTAR(登録商標)HS DNA polymerase(Takara Bio Inc.社製(日本国滋賀県所在))および、プライマーであるALK−TK−F(5’−TACAACCCCAACTACTGCTTTGCT−3’)およびALK−TK−R1(5’−AGGCACTTTCTCTTCCTCTTCCAC−3’)を用いた30サイクル(98℃で10秒間および68℃で1分間で構成される)のポリメラーゼ連鎖反応(PCR)に供した。次に、ALKのキナーゼドメインに対応するPCR産物を断片化し、Illumina Genome Analyzer II(GAII)を用いて、paired−end sequencing system(Illumina社製(米国カリフォルニア州サンディエゴ所在))を使用して両端から76塩基について配列決定した。すべての塩基について、PCRプライマー配列の存在およびQ値≧20に基づいて、未処理の読み取りデータを質的にフィルタリングした。次に、Bowtieアルゴリズムを用いて(ワールドワイドウェブのbowtie-bio.sourceforge.net/index.shtmlで利用可能)、フィルタを通過した読み取りをALKのcDNA配列とアラインメントした。
FLAGタグ化したEML4−ALKとマウスCD8を同時発現させるために、FLAGエピトープタグ化EML4−ALK Variant1をコードしたcDNA(Soda , M. et al. (2007) Nature 448:561-566)をpMX-iresCD8レトロウイルスベクター(Yamashita Y. et al. (2001) J. Biol. Chem. 276:39012-39020)に挿入した。ALKのC1156YおよびL1196M変異に対応するヌクレオチド変化を、個別に、またはEML4−ALK(C1156Y)、EML4−ALK(L1196M)、またはEML4−ALK(C1156Y/L1196M)の発現と組み合わせて、プラスミドに導入した。パッケージング細胞株BOSC23(Pear, W.S. et al. (1993) Proc. Natl. Acad. Sci. USA 90:8392-8396)を利用して、これらのプラスミドに基づいた組み換えレトロウイルスを生成し、その組み換えレトロウイルスを使用してマウスのインターロイキン3依存性細胞株BA/F3(Palacious, R. et al. (1985) Cell 41:727-734)を感染させた。miniMACS細胞分離カラムおよびCD8に対する抗体と結合させた電磁ビーズ(双方ともMiltenyi Biotec社製(ドイツ国グラードバッハ所在))を使用して、得られたCD8陽性細胞を精製した。Selleck社からPF−02341066を入手した。
患者は、喫煙歴のない28歳の男性であり、2008年4月にT4N3M1の臨床病期にある肺腺癌と診断された。腫瘍はEGFR変異を包含しなかったことを考えれば、患者は従来の化学療法によって治療され、疾患が進行し、脳および骨に多発性転移の形成を生じる結果となった。2008年11月には、痰の逆転写PCR分析ならびに生検試料の蛍光in situハイブリダイゼーション分析によって、腫瘍にEML4−ALK Variant1のmRNAの存在が確認された。したがって、PF−02341066のトライアルに患者を登録し、患者の一般状態に顕著な改善が見られた(レベル4から2への引き下げ)。患者は治療に対して「部分反応」を示したが、患者の胸水は完全には根絶されなかった。治療5ヶ月後、腫瘍は突然、再び増殖し始め、両肺に胸水および多発性の癌結節の形成が増大する結果となった。患者は2009年5月にトライアルから除外され、その後、分子分析のために胸水を採取した。
これらのアミノ酸変化がALK阻害剤に対するEML4−ALKの感受性に影響を及ぼすか否かについて試験した。野生型 EML4−ALK、単一の突然変異体であるEML4−ALK(C1156Y)およびEML4−ALK(L1196M)、および二重変異体EML4−ALK(C1156Y/L1196M)を、BA/F3細胞に個別に発現させ、次に、細胞をALK阻害剤に曝露した。PF−02341066は、濃度依存性で、野生型のEML4−ALKを発現するBA/F3細胞の増殖を阻害した(図4A)。対照的に、C1156YまたはL1196Mの突然変異体を発現する細胞は、この薬剤に対する感受性を顕著に低下させることを明らかにし、繰り返し実験により、EML4−ALK(L1196M)を発現するBA/F3細胞が、EML4−ALK(C1156Y)を発現するものよりもPF−02341066に対して耐性が大きいことが示された(図3)。両変異の存在は、PF−02341066に対する細胞の耐性に相加効果を生じなかった。よって、これらのデータは、C1156YおよびL1196Mの変異が、それぞれ、この薬剤に対する耐性を与えることを示した。
図5は、関連キナーゼであるインスリン受容体の結晶構造に基づいた、ALKのキナーゼドメインの三次元構造モデルにおけるCys1156およびLeu1196の部位を示している。前者の残基は、予測らせんαCのアミノ末端に隣接し、かつ、ATP結合ポケットの上蓋の近くに配置される。他のチロシンキナーゼのこの位置では活性化突然変異は報告されていない。ALKのLeu1196は、ABL1のThr315およびEGFRのThr790に対応し、これらはそれぞれ、これらのキナーゼにおいてTKIに対する耐性を与える、最も高頻度で獲得された変異の部位である(Deininger, M. et al. (2005) Blood 105:2640-2653; Linardou, H. et al. (2009) Nat. Rev. Clin. Oncol. 6:352-366)。この「ゲートキーパー」部位は、ATP結合ポケットの底部表面に位置し(図5)、この位置における嵩ばった側鎖を有するアミノ酸の存在が、多くのTKIの結合を妨げることが知られている(Shah, N.P. et al. (2002) Cancer Cell 2:117-125; Tsao, M.S. et al. (2005) N. Engl. J. Med. 353:133-144)。
当業者は、本明細書に記載される発明の特定の実施の形態に対する多くの等価物を認識するか、または、単に日常的な実験のみを利用して解明することができるであろうであろう。このような等価物は添付の特許請求の範囲に包含されることが意図されている。
Claims (29)
- PF−02341066を用いた治療に対する無応答性のリスクが増加した、癌を有する被験体または癌を発現するリスクを有する被験体を同定するための組成物であって、サンプルを分析して1つ以上の突然変異ALKポリヌクレオチド分子の存在を検出するための核酸を含み、
前記1つ以上の突然変異ALKポリヌクレオチド分子は、1156位および/または1196位に変異を有する突然変異ALKポリペプチドをコードし、
前記1つ以上の突然変異ALKポリヌクレオチド分子の存在が、前記被験体がPF−02341066を用いた治療に対する無応答性の増加したリスクを有することを示唆する、組成物。 - PF−02341066を用いた治療に対する無応答性のリスクが増加した、癌を有する被験体または癌を発現するリスクを有する被験体を同定するための組成物であって、サンプルを分析して、1156位および/または1196位に変異を有する1つ以上の突然変異ALKポリペプチドの発現量、構造、および/または活性を検出するためのタンパク質を含み、
前記1つ以上の突然変異ALKポリペプチドの存在が、前記被験体がPF−02341066を用いた治療に対する無応答性の増加したリスクを有することを示唆する、組成物。 - 前記被験体が、ALK阻害剤を用いた治療を以前に受けていないか、またはALK阻害剤を用いた治療を以前に受けていて、前記ALK阻害剤に対して少なくとも部分耐性を発現している、請求項1または2記載の組成物。
- 前記癌が、未分化大細胞リンパ腫、神経芽細胞腫、乳癌、結腸直腸癌、炎症性筋線維芽細胞性腫瘍、および非小細胞肺癌からなる群より選択される、請求項1または2記載の組成物。
- 前記サンプルが、痰、気管支肺胞洗浄、胸水、組織、全血、血清、血漿、頬腔擦取物、唾液、脳脊髄液、尿、排泄物、循環腫瘍細胞、循環核酸、および骨髄からなる群より選択される、請求項1または2記載の組成物。
- 前記サンプルが組織であり、前記組織が腫瘍または癌の組織である、請求項5記載の組成物。
- 前記サンプルが細胞を含む、請求項1または2記載の組成物。
- 前記1つ以上のALK突然変異体が核酸ハイブリダイゼーション分析によって評価される、請求項1記載の組成物。
- 前記1つ以上のALK突然変異体がポリメラーゼ連鎖反応によって評価される、請求項1記載の組成物。
- 前記1つ以上の突然変異ALKポリペプチドの発現量が、前記1つ以上の突然変異ALKポリペプチドに特異的に結合する試薬を使用して検出される、請求項2記載の組成物。
- 前記試薬が、抗体、抗体誘導体、および抗体フラグメントからなる群より選択される、請求項10記載の組成物。
- 前記1つ以上の突然変異ALKポリペプチドの量、構造および/または活性が対照サンプルと比較される、請求項2記載の組成物。
- 前記1つ以上のALK突然変異体が、第1の時点およびその後の少なくとも1つの時点において評価される、請求項1または2記載の組成物。
- 前記サンプルが、生殖細胞系または体細胞ゲノムDNAを含む、請求項1または2記載の組成物。
- ALK阻害剤を用いた治療に対する癌患者の化学的感受性を請求項1〜14いずれか1項記載の組成物を用いて判定するキットであって、
1つ以上の突然変異ALKポリヌクレオチド分子またはポリペプチドに特異的に結合する試薬、および使用説明書を含み、
前記1つ以上の突然変異ALKポリヌクレオチド分子またはポリペプチドは、1156位に変異を有する突然変異ALKポリペプチドをコードする突然変異ALKポリヌクレオチド、または1156位に変異を有するALKポリペプチドである、キット。 - ALK阻害剤をさらに含む、請求項15記載のキット。
- 前記試薬が、1つ以上のポリヌクレオチドプローブを含み、該プローブのそれぞれが、1156位に変異を有する突然変異ALKポリペプチドをコードする突然変異ALKポリヌクレオチドのヌクレオチド配列に相補的なポリヌクレオチド配列を含む、請求項15記載のキット。
- 前記プローブが、約50〜107個のヌクレオチド長を有するポリヌクレオチドを含む、請求項17記載のキット。
- 前記プローブが、オリゴヌクレオチド、cDNA分子、RNA分子、および核酸塩基を含む合成遺伝子プローブからなる群より選択される請求項17記載のキット。
- 前記試薬が、1156位に変異を有する突然変異ALKポリペプチドに対する、抗体、および抗体誘導体、および抗体フラグメントを含むことを特徴とする請求項15記載のキット。
- 試験化合物が1つ以上の突然変異ALKポリペプチドの活性を調節するか否かを判定する方法であって、
(a)1156位に変異を有する1つ以上の突然変異ALKポリペプチドをコードする構成体をトランスフェクトされた哺乳動物細胞を前記試験化合物と試験管内で接触させ、
(b)前記1つ以上の突然変異ALKポリペプチドの活性について前記哺乳動物細胞を評価することを含み、
対照実験と比較して、前記試験化合物の存在下で活性が有意に変調された場合に、前記試験化合物が、前記1つ以上の突然変異ALKポリペプチドの調節剤として同定される、方法。 - 前記対照が、野生型ALKポリペプチドを発現する哺乳動物細胞を含む、請求項21記載の方法。
- 前記1つ以上の突然変異ALKポリペプチドの活性が、ATP結合、チロシンキナーゼ活性、癌細胞増殖、腫瘍成長、腫瘍数、アポトーシス、および腫瘍転移からなる群より選択される、請求項22記載の方法。
- 前記対照実験が、前記試験化合物の不在下で、前記1つ以上の突然変異ALKポリペプチドを発現する哺乳動物細胞を含む、請求項21記載の方法。
- 前記1つ以上の突然変異ALKポリペプチドの活性が、ATP結合、チロシンキナーゼ活性、癌細胞増殖、腫瘍成長、腫瘍数、アポトーシス、および腫瘍転移からなる群より選択される、請求項24記載の方法。
- 前記1つ以上の突然変異ALKポリヌクレオチド分子は、
G4374A突然変異を有する突然変異ALK cDNA;および
C4493A突然変異を有する突然変異ALK cDNAからなる群より選択される、請求項1記載の組成物。 - 前記1つ以上の突然変異ALKポリペプチド分子は、
Cys1156Tyr突然変異を有する突然変異ALKタンパク質;および
Leu1196Met突然変異を有する突然変異ALKタンパク質からなる群より選択される、請求項2記載の組成物。 - 前記1つ以上の突然変異ALKポリヌクレオチドまたはポリペプチド分子は、
G4374A突然変異を有する突然変異ALK cDNA、または
Cys1156Tyr突然変異を有する突然変異ALKタンパク質である、請求項15記載のキット。 - 前記ALK阻害剤はPF−02341066である、請求項16記載のキット。
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- 2011-02-04 CA CA2786974A patent/CA2786974C/en active Active
- 2011-02-04 US US13/576,508 patent/US9018230B2/en active Active
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- 2011-02-04 ES ES11739469.2T patent/ES2660149T3/es active Active
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Also Published As
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EP2531858A2 (en) | 2012-12-12 |
WO2011095894A2 (en) | 2011-08-11 |
CN103937877A (zh) | 2014-07-23 |
CA2786974A1 (en) | 2011-08-11 |
EP2531858A4 (en) | 2013-08-07 |
ES2660149T3 (es) | 2018-03-21 |
KR101843967B1 (ko) | 2018-03-30 |
CN102844664A (zh) | 2012-12-26 |
NZ601606A (en) | 2014-06-27 |
US9018230B2 (en) | 2015-04-28 |
MX336498B (es) | 2016-01-21 |
AR080361A1 (es) | 2012-04-04 |
TW201144807A (en) | 2011-12-16 |
AU2011212165B2 (en) | 2016-03-03 |
CA2786974C (en) | 2018-05-01 |
TWI518325B (zh) | 2016-01-21 |
MX2012008914A (es) | 2012-11-30 |
RU2012133318A (ru) | 2014-03-10 |
WO2011095894A3 (en) | 2012-03-01 |
KR20120130329A (ko) | 2012-11-30 |
HK1197922A1 (zh) | 2015-02-27 |
SG182766A1 (en) | 2012-08-30 |
ZA201205831B (en) | 2013-05-29 |
CN103937877B (zh) | 2016-09-28 |
US20130203810A1 (en) | 2013-08-08 |
AU2011212165A1 (en) | 2012-09-20 |
RU2589834C2 (ru) | 2016-07-10 |
JP2013518579A (ja) | 2013-05-23 |
EP2531858B1 (en) | 2018-01-10 |
BR112012019215A2 (pt) | 2016-10-25 |
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