JP6445573B2 - ヒト患者の固形腫瘍の治療に用いるためのホスホジエステラーゼ阻害剤含有組成物 - Google Patents
ヒト患者の固形腫瘍の治療に用いるためのホスホジエステラーゼ阻害剤含有組成物 Download PDFInfo
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Description
試験サンプル中のPDE3タンパク質発現に関連する悪性腫瘍を検出する方法であって、以下の工程(a)〜(d)を含む方法。
(a)サンプルを、PDE3A酵素又はPDE3B酵素に特異的に結合する抗体と接触させ、但し該サンプルは、PDE3A酵素及び/又はPDE3B酵素を発現する腫瘍を含む疑いのある組織から採取したものであり、
(b)サンプルと抗体とを、免疫複合体形成に十分な時間と条件下でインキュベートし、
(c)抗原と抗体の間の免疫複合体形成の有無を検出し、そして
(d)免疫複合体形成の存在を悪性腫瘍の指標として、悪性腫瘍の有無を検出する。
PDE3A酵素及び/又はPDE3B酵素を発現する腫瘍を有するヒト患者がホスホジエステラーゼ3酵素類の阻害剤による治療に応答するか否かを検出・分析するための方法であって、以下の工程を含む方法。
−該患者から得た腫瘍サンプル中のホスホジエステラーゼ3A酵素及びホスホジエステラーゼ3B酵素の発現レベルを定量し、そして、
−該患者の腫瘍サンプルが、健康な対照組織サンプルよりもホスホジエステラーゼ3A酵素及び/又はホスホジエステラーゼ3B酵素の高い発現レベルを示す場合には、該患者をホスホジエステラーゼ3酵素類の阻害剤による治療のために選抜する。
アナグレリドの化学名は、6,7−ジクロロ−1,5−ジヒドロイミダゾ[2,1−b]キナゾリン−2(3H)−オンである。しかし、本願明細書では、「アナグレリド」という用語を、アナグレリドの非毒性で薬学的に許容される酸付加塩を包含する意味で用いる。したがって、「アナグレリド」という用語は、親化合物のみならず、全てのそのような塩を包含するものである。アナグレリドの好ましい塩の例としては、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、(低級)アルキル硫酸塩、(低級)アルキルスルホン酸塩、(低級)アリールスルホン酸塩、リン酸塩、硫酸塩、マレイン酸塩、フマル酸塩、コハク酸塩、酒石酸塩、及びクエン酸塩が挙げられる。本発明においてアナグレリド塩酸塩は特に好ましい酸付加塩である。アナグレリドの調製方法は、たとえば、米国特許第5,391,737号に記載されている。
(a)サンプルを、PDE3A酵素又はPDE3B酵素に特異的に結合する抗体と接触させ、但し該サンプルは、消化管間質腫瘍(GIST)、脂肪肉腫、又はPDE3A及び/又はPDE3B酵素を発現する他の腫瘍を含む疑いのある組織から採取したものであり、
(b)サンプルと抗体とを、免疫複合体形成に十分な時間と条件下でインキュベートし、
(c)抗原と抗体の間の免疫複合体形成の有無を検出し、そして
(d)免疫複合体形成の存在を悪性腫瘍の指標として、悪性腫瘍の有無を検出する。
−該患者から得た腫瘍サンプル中のPDE3A酵素及び/又はPDE3B酵素の発現レベルを定量し、そして、
−該患者の腫瘍サンプルが、組織学的に正常な対照組織サンプルよりもホスホジエステラーゼ3A酵素及び/又はホスホジエステラーゼ3B酵素の高い発現レベルを示す場合には、該患者をホスホジエステラーゼ3酵素類の阻害剤による治療のために選抜する。
組織材料
ホルマリンで固定されパラフィンに包埋された腫瘍組織サンプルを回収し同定した。組織サンプルの使用と分析についての許可は、フィンランド国立法医学局(the National Authority for Medico legal Affairs of Finland)と研究倫理審査委員会(Institutional Review Board)から得た。本研究においては、200個を超えるGISTを含めて、合計36種類の組織学的癌及び700個を超える腫瘍を分析した。
GeneSapiensデータベース(http://ist.genesapiens.org/)は、組織学的に正常なヒト組織サンプルと癌組織サンプルの両方からなる9783個の組織サンプルからの遺伝子発現データを含む(Kilpinen,S. 2008)。
ホルマリンで固定されパラフィンに包埋された組織サンプルを、PDE3AとPDE3Bの発現について分析した。5μmの切片を切り出してSuperFrost(登録商標)+ スライド(Menzel-Glaser)に乗せた。切片からキシレンでパラフィンを取り除き、アルコールシリーズで水和した。1%過酸化水素を用いて内在性ペルオキシダーゼ活性をブロックした。免疫組織化学のための抗原の回収を、オートクレーブを用いてクエン酸ナトリウム(0.01mol/L、pH 6.0)中で行った(120℃で2分間)。PDE3A免疫染色のための第1抗体はポリクローナル ウサギ抗PDE3A抗体(希釈倍率 1:100;米国、ミズーリ州、セントルイス、SIGMA製)を用い、PDE3B免疫染色のための第1抗体はポリクローナル ウサギ抗PDE3B抗体(希釈倍率 1:20;米国、ミズーリ州、セントルイス、SIGMA製)を用いた。第1抗体を PowerVision 前抗体ブロッキング溶液で希釈して、室温で30分間インキュベートした。第1抗体の結合は、BrightVision+ Histostaining キット(オランダ国、ダイフェン、Immunologic BV製)を製造者の使用説明書に従って用いて検出した。腫瘍細胞中の調べたタンパク質の発現を以下のように評価した。陰性(染色した腫瘍細胞中の10%未満)又は陽性[弱い染色強度(+)、中程度の染色強度(++)、又は強い染色強度(+++)]。
mRNAを、High Pure RNA Paraffin kit(ドイツ国、マンハイム、Roche Diagnostics GmbH製)を用いてホルマリン固定パラフィン包埋組織ブロックから抽出するか、または、High Pure RNA Isolation Kit (Roche Diagnostics GmbH製)を用いてGIST細胞系から抽出した。mRNAを、SuperScript(登録商標)VILO(商標)cDNA Synthesis Kit(アメリカ合衆国、カルフォルニア州、カールスバッド、Invitrogen製)を製造者の使用説明書に従って用いて、cDNAに逆転写した。
GIST882は、K642E変異体KITオンコプロテイン(Tuveson,D.A. 2001)をコードするKITエクソン13にホモ接合型ミスセンス変異を有する主要ヒトGIST細胞系である。GIST48は、イマチニブ療法における最初の臨床応答の後に進行するGISTから産生されるGIST細胞系である。GIST48は、主要なエクソン11ミスセンス変異と二次的なエクソン17ミスセンス変異とを有する(Bauer,S. 2006)。LPS141は、患者由来の脱分化型脂肪肉腫から確立された脂肪肉腫細胞系である(Snyder, E.L. 2009)。細胞系は、20%のウシ胎児血清(FBS)と2%のペニシリン/ストレプトマイシンとを補ったRPMI 1640 培地(アメリカ合衆国、カルフォルニア州、GIBCO製)で培養した。
4つの異なるPDE3阻害剤を、PDE3酵素の活動を封止するために用い、2つの異なるキナーゼ阻害剤を、KIT及びPDGFRAの活動を封止するために用いた。シロスタゾール、ミルリノン及びアムリノンをSigma(アメリカ合衆国、ミズーリ州、セントルイス)から購入し、アナグレリド塩酸塩をTocris Bioscience(英国、ブリストル)から購入した。イマチニブ及びニロチニブ(KIT特異的阻害剤、Novartis製)をCayman Chemical Company(アメリカ合衆国、ミシガン州、アナーバー)から購入した。イマチニブは、水中で再構成した。他のすべての阻害剤は、DMSO中で再構成した。事前分析において、多数の異なる薬剤濃度(0〜100μmol/L)を用いて、GIST細胞系におけるPDE3阻害剤の有効投与量を同定した。増殖への効果をxCELLigence System 及び RTCA DP instrument(アメリカ合衆国、カルフォルニア州、サンディエゴ、Acea Biosciences製)を用いて分析した。さらなる分析に用いた最終的な阻害剤濃度は、イマチニブ及びニロチニブについては0.5μmol/Lであり、PDE3阻害剤については10μmol/Lであった。アナグレリド塩酸塩による処理の後の細胞のアポトーシスへの進行を、Click-iT TUNEL Alexa Fluor 488 Imaging Assay(アメリカ合衆国、カルフォルニア州、カールスバッド、Invitrogen製)を製造者の使用説明書に従って用いて、8個のデュープリケート ウェルにおいて分析した。アポトーシスへの進行は、当該薬剤処理の48時間後及び96時間後に測定した。
細胞増殖をMTTアッセイ(アメリカ合衆国、インディアナ州、インディアナポリス、Roche Diagnostics製)と、RTCA DP instrumentを用いるxCELLigence System(Acea Biosciences製)によって調べた。MTTアッセイのために、GIST882細胞を1.5×104個の細胞/ウェルの密度で植え付け、GIST48細胞を2.0×104個の細胞/ウェルの密度で植え付け、LPS141細胞を5.0×103個の細胞/ウェルの密度で植え付けた。インキュベーションの最後に、8個のデュープリケート ウェルについて、各ウェルに10μLのMTT試薬を加えて37℃で4時間インキュベートして、細胞増殖を分析した。プレートを、Multiscan EX Microplate photometer(アメリカ合衆国、イリノイ州、ロックフォード、Thermo Scientific製)を用いて波長540nmで読み取った。xCELLigence増殖アッセイのために、GIST48細胞とGIST882細胞を2.5×104個の細胞/ウェルの密度で植え付けた。GIST882細胞を植え付ける前に、Collagen I Rat Tail(アメリカ合衆国、カルフォルニア州、カールスバッド、Invitrogen製)を製造者の使用説明書に従って用いて、ウェルにコラーゲンの薄膜を形成し、最終コラーゲン濃度7.5μg/mLとした。
グループ間の差をクラスカル−ウォリス検定又はマン−ホイットニーのU検定により解析した。P値は両側検定したものである。
GeneSapiensデータベース
GeneSapiensデータベース(http://ist.genesapiens.org/)を用いて、ホスホジエステラーゼ3A酵素mRNAとホスホジエステラーゼ3B酵素mRNAは、他の種類の腫瘍よりもGISTと脂肪肉腫において強く発現することを突きとめた。
癌組織におけるPDE3の発現を805個の患者サンプルにおいて腫瘍組織マイクロアレイを用いて調べた。PDE3Aの発現を、GISTの93%において検出し、脂肪肉腫の33%において検出し、他の種類の腫瘍においても、しばしばではないが、検出した(表1)。GISTの大半においてPDE3Aの免疫染色の強度は中度又は高度であった。GIST以外の腫瘍の11%未満がPDE3Aの発現を示した。PDE3Bの発現は、GISTの66%及び脂肪肉腫の19%で検出された。GIST以外の腫瘍の4%がPDE3Bの発現を示した。調査したうちのGIST以外の腫瘍の内訳は、乳房の癌腫、前立腺の癌腫、卵巣の癌腫、結腸の癌腫、子宮の癌腫、膵臓の癌腫、肝臓の癌腫、膀胱の癌腫、腎臓の癌腫、肺の癌腫、及び胆管の癌腫;及び、神経膠腫、胚細胞腫瘍、肉腫、黒色腫、神経鞘腫、髄膜腫、リンパ上皮腫、神経芽細胞腫、及び膨大細胞腫である。
xCELLigence System 及び RTCA DP instrument(Acea Biosciences製)を用いて行った分析では、10μmol/L以上の濃度のアナグレリドとアムリノンは、GIST細胞培養に対してはいくらかの抗増殖効果を示したが、シロスタゾールとミルリノンは細胞増殖に影響しなかった。PDE3阻害剤の、LPS141細胞系、GIST882細胞系、及びGIST48細胞系への効果をより詳細に調べるために、PDE3阻害剤の最終濃度10μmol/Lで細胞を96時間培養し、増殖への薬剤効果をMTTアッセイで測定し、ニロチニブ(0.5μmol/L)の抗増殖効果と比較した。4日間の培養により、アナグレリド塩酸塩は、DMSOと比較して、GIST882細胞とLPS141細胞の増殖に影響する唯一のPDE3阻害剤であることが分かった。GIST48細胞の増殖に有意に影響するPDE3阻害剤はなかった(図1)。次に、アナグレリド塩酸塩(10μmol/L)をイマチニブ(0.5μmol/L)による処理と組み合わせた場合の効果を、GIST細胞系を用いて調べた。再び、4日間の培養により、GIST882細胞系のみが影響を受け、薬剤の組み合わせは、細胞への相乗的な抗増殖効果を示した(図2)。
現在の治療法の場合、多くのGIST患者の病状は進行する。いくつかのIII型受容体チロシンキナーゼの阻害剤であるメシル酸イマチニブは、進行したGISTの進行を阻害する(Demetri,G.D. 2002)。大半のGISTはKIT又はPDGFRAに発癌性の変異を有しており(Hirota,S. 1998; Heinrich,M.C. 2003)、これらがイマチニブ療法の主要なターゲットとされる。GISTの一部には、チロシンキナーゼ阻害剤への応答を欠くものや、しばしば二次変異によりチロシンキナーゼ阻害剤への耐性を生じるものがある。本発明においては、PDE3AとPDE3Bが新たな有望な免疫マーカーであり、また、GIST、脂肪肉腫、及びPDE3酵素類を発現する他の腫瘍の新たな治療ターゲットであることを示す。
配列番号2:オリゴヌクレオチドプライマー
配列番号3:オリゴヌクレオチドプライマー
配列番号4:オリゴヌクレオチドプライマー
配列番号5:オリゴヌクレオチドプライマー
配列番号6:オリゴヌクレオチドプライマー
配列番号7:オリゴヌクレオチドプライマー
配列番号8:オリゴヌクレオチドプライマー
Claims (10)
- ホスホジエステラーゼ3A酵素及び/又はホスホジエステラーゼ3B酵素を発現するヒト患者の固形腫瘍の治療に用いるための、アナグレリド又はその塩を含む組成物であって、該固形腫瘍が消化管間質腫瘍(GIST)又は脂肪肉腫であることを特徴とする組成物。
- 該固形腫瘍が、ホスホジエステラーゼ3A酵素mRNA若しくはタンパク質及び/又はホスホジエステラーゼ3B酵素mRNA若しくはタンパク質を健康な対照組織よりも高度に発現する細胞を含むことが検出される請求項1に記載の組成物。
- アナグレリド塩酸塩を含む請求項1又は2に記載の組成物。
- 更にチロシンキナーゼ阻害剤を含む請求項1〜3のいずれかに記載の組成物。
- 該チロシンキナーゼ阻害剤が、KITと血小板由来成長因子受容体とに特異的であり、ニロチニブ、スニチニブ、レゴラフェニブ、イマチニブ、メシル酸イマチニブ、マシチニブ、ドビチニブ、ポナチニブ、パゾパニブ、ソラフェニブ、ダサチニブ、バタラニブ、及びクレノラニブからなる群より選ばれる請求項4に記載の組成物。
- 該組成物の患者への投与を、チロシンキナーゼ阻害剤を含む他の組成物と組み合わせて、同時投与又は順次投与の形で行う請求項4又は5に記載の組成物。
- 薬学的に許容されるバッファー、担体又はアジュバントを含む医薬組成物である請求項1〜6のいずれかに記載の組成物。
- 該医薬組成物が、徐放性、遅延放出性、又は持効性のための処方がなされているか、又は、該医薬組成物が徐放性処方と即時放出性処方との混合物である請求項7に記載の組成物。
- アナグレリド又はその塩の、ホスホジエステラーゼ3A酵素及び/又はホスホジエステラーゼ3B酵素を発現するヒト患者の固形腫瘍の治療用薬剤の製造のための使用であって、該固形腫瘍が消化管間質腫瘍(GIST)又は脂肪肉腫であることを特徴とする使用。
- 該固形腫瘍が、ホスホジエステラーゼ3A酵素mRNA若しくはタンパク質及び/又はホスホジエステラーゼ3B酵素mRNA若しくはタンパク質を健康な対照組織よりも高度に発現する細胞を含むことが検出される請求項9に記載の使用。
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