JP6929231B2 - Rtk突然変異細胞を有する患者を処置するための組成物及び方法 - Google Patents
Rtk突然変異細胞を有する患者を処置するための組成物及び方法 Download PDFInfo
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Description
本出願は、2015年5月29日に出願された米国仮特許出願第62/168,237号、及び2016年3月17日に出願された米国仮特許出願第62/309,900号に対する優先権を主張するものである。上記参照出願の内容は、明白にその全体が参照により本明細書に組み込まれる。
添付の配列表のデータが参照により本出願に組み込まれる。名称IGNYT.051WO_Sequence Listingの添付の配列表テキストファイルは、2016年5月5日に作成され、69KBである。このファイルは、Windows OSを使用するコンピュータでMicrosoft Wordを使用して評価することができる。
本開示は、癌患者、例えば、以前に1つ以上の化学療法剤により処置されており、1つ以上の化学療法剤に対して少なくとも部分的な耐性を持つようになった癌患者を処置するための組成物及び方法に関する。
単数形「a」、「an」、及び「the」は、文脈が明らかに別のことを規定していない限り、複数の言及を含む。例えば、「a cell(細胞)」という用語は、それらの混合物を含む1つ以上の細胞を含む。「A及び/またはB」は、本明細書中では以下の選択肢のすべてを含んで使用される:「A」、「B」、「AまたはB」、及び「A及びB」。
ニューロトロフィンは、受容体チロシンキナーゼ(RTK)のtrkファミリーによる結合及びシグナル伝達によって脊椎動物の神経系のニューロンの生存及び分化の多くの局面を制御する。神経系において重要な役割を有するRTKをコードする遺伝子ファミリーは、進化の過程で高度に保存されてきたことが示された(Gad et al., J. Neurobiol. Jul;60(1):12−20, 2004)。受容体チロシンキナーゼの例としては、上皮増殖因子受容体ファミリー(EGFR)、血小板由来増殖因子受容体(PDGFR)ファミリー、血管内皮増殖因子受容体(VEGFR)ファミリー、神経成長因子受容体(NGFR)ファミリー、線維芽細胞成長因子受容体ファミリー(FGFR)インスリン受容体ファミリー、エフリン受容体ファミリー、Metファミリー、及びRorファミリーが挙げられるが、これらに限定されるものではない。それぞれのファミリーは、特徴的な構造的及び/または機能的類似点を持っている1つ以上のファミリーメンバーを含む場合もある。
一態様において、本開示は、患者の癌を処置するための方法を提供し、本方法は、(a)患者からの生体サンプル中の1つ以上の分子改変の存在の情報を得ることであって、1つ以上の分子改変は、1つ以上の受容体チロシンキナーゼポリペプチドに1つ以上の突然変異を含み、1つ以上の受容体チロシンキナーゼポリペプチドは、TrkA、TrkB、TrkC、ALK及びROS1から選択される、得ることと;(b)癌の処置に適した化学療法剤を選択することと;(c)治療有効量の選択された化学療法剤を患者に投与することとを含む。
この実施例は、エントレクチニブ耐性KM12細胞株及びエントレクチニブ耐性BA/F3−TEL/TRKA細胞株の形成について記載する。
この実施例は、親KM12細胞及びエントレクチニブ耐性KM12細胞においてRTK阻害薬、例えば、エントレクチニブの抗増殖活性を評価するために開発された一般的な手順について記載する。親KM12株及びエントレクチニブ耐性KM12株の細胞を、トリプシン処理し、96ウェルアッセイホワイトプレート(Costar #3610)の各ウェル当たり5,000細胞で播いた後、エントレクチニブを含まない完全培地で一晩、インキュベートした。次の日、異なる濃度のそれぞれのRTK阻害薬、例えば、エントレクチニブ(0から1μM)を、ウェルに添加した。各処理条件を2回実施した。同様に、Ba/F3−Tel/TrkA細胞を、96ウェルアッセイホワイトプレート(Costar #3610)の各ウェル当たり5,000細胞でエントレクチニブを含まない完全培地に播き、次の日に、二つ組で異なる濃度のそれぞれのRTK阻害薬、例えば、エントレクチニブ(0から1μM)で処理した。3日間のインキュベーション後、細胞生存率をCellTiter−Glo(登録商標)試薬(Promega)を使用したルシフェラーゼに基づくATPレベル検出により測定し、IC50を可変の傾きを用いた4−パラメータ曲線フィッティングにより求めた。
この実施例は、野生型タンパク質TPM3−TrkAまたはTPM3−TrkA−G595R融合タンパク質のいずれかを発現するトランスジェニックBa/F3細胞を形成するために実施された研究について記載する。TPM3−TrkA融合物をコードするcDNAを、PCR−ベースの技術によってKM12親細胞株及びエントレクチニブ耐性細胞からクローン化した後、レンチウイルスベクターpVL−EF1a−MCS−IRES−Puro(BioSettia、サンディエゴ、カリフォルニア州)に挿入した。直接シークエンシングによりcDNA挿入を確認した後、TPM3−TrkA cDNAまたはTPM3−TrkA−G595R cDNAのいずれかを含む水泡性口内炎ウイルスGP(VSVG)シュードタイプレンチウイルスを、8μg/mLのポリブレン(EMD Millipore)により異なる感染効率(MOI)でネズミIL−3依存性プロB細胞Ba/F3に形質導入した。形質導入Ba/F3細胞を10%FBS及び1μg/mLのピューロマイシンを加えたネズミIL−3含有RPMI培地において2週間選択した。安定した細胞プールを、ネズミIL−3を含まない10%FBS(ウシ胎仔血清)を加えたRPMI培地(GIBCO(登録商標))において4週間さらに選択した。
親KM12細胞の6つのサンプル(各処理における複製サンプル)を、0.01%のDMSO(v/v)、1nMのエントレクチニブ、3nMのエントレクチニブ、または10nMのエントレクチニブで約2週間処理した。細胞の形態及び倍加時間に明らかな変化は観察されなかった。2週間の処理の終わりに、10nMのエントレクチニブで処理したKM12細胞の複製サンプルを、30nMのエントレクチニブを含有する増殖培地において培養した。これらのKM12−10nM処理細胞に関してやや遅い増殖速度が観察された。図5に示されるとおり、3日間の増殖阻害調査では、DMSO(ビヒクル)及び1〜10nMのエントレクチニブにおいて培養したKM12細胞(セットA)は、増殖阻害曲線の重なり及び類似のIC50値を示した(表3及び図5)。しかしながら、KM12−30nM−A処理細胞は、上にシフトした増殖曲線及びIC50値の約2倍の増加を示し(表3)、これは、エントレクチニブに対する感受性の低下を示す。
親Ba/F3−Tel/TrkA細胞をRTK阻害薬、エントレクチニブにより上記実施例4に記載される処置計画で処理した。実施例4に記載されている手順を使用することによってエントレクチニブ耐性Ba/F3−Tel/TrkA細胞を単離し、続いて特徴づけた。10nMエントレクチニブ耐性Ba/F3−Tel/TrkAの細胞プールを2週間の選択後に確立した(図9)。意外なことに、図11A及び11Bに示されるとおり、10nMエントレクチニブ耐性Ba/F3−Tel/TrkA−10nMA細胞プールは、対照親株のものより100倍超高いIC50を示し、これは、これらの細胞のエントレクチニブに対する感受性の劇的な低下を示す。図15に示されるとおり、これらのエントレクチニブ耐性Baf3−trkA(A)細胞は、エントレクチニブ耐性KM12細胞株に関して実施例4において上で述べたのと同じG667C及びG595R突然変異を持つことがわかった。さらに、図19に示されるとおり、12nMのエントレクチニブのBa/F3−Tel/TrkAの異なる処理は、結果として複数のクローンにG667C変化をもたらし、これはまた実施例4において上で述べたエントレクチニブ−KM12耐性細胞において特定された同じ変化であった。
この実施例は、G595RまたはG667C突然変異のいずれかを持っている突然変異KM12及びBa/F3−tel/trkA細胞の増殖を阻害する能力に関して多くの化学化合物をスクリーニングするために上記実施例2に記載されている実験手順を使用して実施した調査について記載する。そのような化合物は、特定されると、受容体チロシンキナーゼの阻害薬に対して耐性を持つようになった癌患者の処置に有用であろう。この実験では、Ba/F3−tel/trkA、Ba/F3−tel/trkA−10nMA(G595R)、KM12−DMSO、KM12−30nM101−B(G667C)、KM12−100nM101−B(G667C)、KM12−300nM101−B(G595R)の細胞株のそれぞれを多くの化学化合物に対してスクリーニングした。そのような化合物の適例を表2及び8〜9に列挙する。
この実施例は、野生型及びさまざまな突然変異を持つ突然変異Ba/F3−tel/TrkA細胞の増殖を阻害するエントレクチニブ及びLOXO−101化合物の能力を調査するために上記実施例2に記載されている実験手順を使用して実施した調査について記載する。この実験では、エントレクチニブ及びLOXO−101のそれぞれを表10の変異体に対してスクリーニングした。
この実施例は、野生型及びさまざまな突然変異を持つ突然変異Ba/F3−tel/trkA細胞の増殖を阻害するエントレクチニブ、LOXO−101、及びスタウロスポリン化合物の能力を調査するために、上記実施例2に記載されている実験手順を使用して実施した調査について記載する。この実験では、エントレクチニブ、LOXO−101、及びスタウロスポリンのそれぞれを表11の変異体に対してスクリーニングした。
Claims (13)
- 癌腫瘍を有する患者を処置するための薬剤の製造におけるTrk阻害化合物の使用であって、前記腫瘍は、突然変異Trkタンパク質をコードする核酸を含むことが決定され、前記突然変異Trkタンパク質は、配列番号:1に記載のTrkAポリペプチドのV573、F589及びG667から選択されるアミノ酸位置において少なくとも1つの突然変異を含み、
前記Trk阻害化合物は、
前記V573のアミノ酸位置において突然変異を含むTrkAポリペプチドに対し、エントレクチニブ、及び/又は(3S)−N−[5−[(2R)−2−(2,5−ジフルオロフェニル)−1−ピロリジニル]ピラゾロ[1,5−a]ピリミジン−3−イル]−3−ヒドロキシ−1−ピロリジンカルボアミド(LOXO−101)であり、
前記F589のアミノ酸位置において突然変異を含むTrkAポリペプチドに対し、エントレクチニブ、及び/又はスタウロスポリンであり、
前記G667のアミノ酸位置において突然変異を含むTrkAポリペプチドに対し、エントレクチニブ、(3S)−N−[5−[(2R)−2−(2,5−ジフルオロフェニル)−1−ピロリジニル]ピラゾロ[1,5−a]ピリミジン−3−イル]−3−ヒドロキシ−1−ピロリジンカルボアミド(LOXO−101)(但し、該LOXO−101をBa/F3−TPM3−NTRK1−G667C細胞株に用いることを除く。)、スタウロスポリン、及びN−[5−(3,5−ジフルオロ−ベンゼンスルホニル)−1H−インダゾール−3−イル]−2−((R)−2−メトキシ−1−メチル−エチルアミノ)−4−(4−メチル−ピペラジン−1−イル)ベンズアミドからなる群より選択される少なくとも1つである、使用。 - 前記1つ以上のアミノ酸突然変異は、前記TrkAポリペプチドのアミノ酸残基V573に対応する位置にある、請求項1に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、ValからMetへの置換(V573M)である、請求項2に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、前記TrkAポリペプチドのアミノ酸残基F589に対応する位置にある、請求項1に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、PheからLeuへの置換(F589L)である、請求項4に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、前記TrkAポリペプチドのアミノ酸残基G667に対応する位置にある、請求項1に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、GlyからCysへの置換(G667C)である、請求項6に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、GlyからAlaへの置換(G667A)である、請求項6に記載の使用。
- 前記1つ以上のアミノ酸突然変異は、GlyからSerへの置換(G667S)である、請求項6に記載の使用。
- 前記癌は、未分化大細胞リンパ腫(ALCL)、結腸直腸癌(CRC)、胆管細胞癌、胃癌、膠芽腫(GBM)、平滑筋肉腫、メラノーマ、非小細胞肺癌(NSCLC)、肺扁平上皮癌、神経芽腫(NB)、卵巣癌、膵癌、前立腺癌、甲状腺髄様癌、乳癌、乳頭様甲状腺癌、またはそれらの任意の組み合わせから選択される、請求項1から9のいずれか1項に記載の使用。
- 前記腫瘍は、核酸シークエンシング、核酸増幅ベースのアッセイ、核酸ハイブリダイゼーションアッセイ、比較ゲノムハイブリダイゼーション、リアルタイムPCR、定量的逆転写PCR(qRT−PCR)、PCR−RFLPアッセイ、HPLC、質量分析ジェノタイピング、次世代シークエンシング(NGS)、またはそれらの任意の組み合わせから選択される分析アッセイを使用して突然変異Trkタンパク質をコードする核酸を含むことが決定される、請求項1から10のいずれか1項に記載の使用。
- 前記分析アッセイは、対立遺伝子特異的ポリメラーゼ連鎖反応または次世代シークエンシングである、請求項11に記載の使用。
- 前記分析アッセイは、腫瘍サンプルからの核酸を、前記1つ以上の突然変異をコードする核酸配列と相補的な核酸配列を含み、検出可能な標識をさらに含む核酸プローブと接触させることを含む核酸ハイブリダイゼーションアッセイである、請求項11に記載の使用。
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HK1252821A1 (zh) | 2019-06-06 |
CN107849113A (zh) | 2018-03-27 |
JP7219791B2 (ja) | 2023-02-08 |
EP3303382A1 (en) | 2018-04-11 |
US20180177792A1 (en) | 2018-06-28 |
CA2987281A1 (en) | 2016-12-08 |
AU2016270321B2 (en) | 2020-09-10 |
AU2016270321A1 (en) | 2017-12-14 |
AU2016270321A2 (en) | 2018-01-04 |
MA43943A (fr) | 2018-12-12 |
JP2021156893A (ja) | 2021-10-07 |
WO2016196141A1 (en) | 2016-12-08 |
US20210322439A1 (en) | 2021-10-21 |
JP2018521973A (ja) | 2018-08-09 |
CN107849113B (zh) | 2022-03-22 |
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