JP5847156B2 - 肝細胞がんの処置方法 - Google Patents
肝細胞がんの処置方法 Download PDFInfo
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Description
特定の実施形態では、例えば以下が提供される:
(項目1)
肝細胞がん(HCC)の処置を必要とする個体におけるHCCを処置する方法であって、該個体にタキサンおよびアルブミンを含むナノ粒子を含む有効量の組成物を投与するステップを包含する、方法。
(項目2)
HCCの処置を必要とする個体におけるHCCを処置する方法であって、該個体に(a)タキサンおよびアルブミンを含むナノ粒子を含む有効量の組成物と、(b)有効量の少なくとも1つの他の薬剤とを投与するステップを含み、該他の薬剤が、微小管の分解を阻害する、方法。
(項目3)
前記ナノ粒子組成物と、前記他の薬剤とを、同時投与または逐次投与する、項目2に記載の方法。
(項目4)
前記ナノ粒子組成物と、前記他の薬剤とを、共時投与する、項目2に記載の方法。
(項目5)
前記他の薬剤が、微小管の分解を促進する分子を直接的または間接的に阻害する、項目2に記載の方法。
(項目6)
前記他の薬剤が、ABP1、ARHGAP4、HSPA8、LCP1、PACSIN2、RUNX1T1、STMN1、チューブリン、およびTUBB4からなる群より選択される分子を阻害する、項目2に記載の方法。
(項目7)
前記他の薬剤が、STMN1の阻害剤である、項目6に記載の方法。
(項目8)
前記他の薬剤が、STMN1に対するsiRNAである、項目7に記載の方法。
(項目9)
前記他の薬剤が、ガンボージまたはその誘導体である、項目7に記載の方法。
(項目10)
前記他の薬剤が、微小管のアセンブリーを促進する分子を直接的または間接的に活性化する、項目2に記載の方法。
(項目11)
前記他の薬剤が、ABI1、BCL2L11、CDC42、CHRM3、CNN3、CSMD1、DDOST、DOCK7、EHMT2、ENAH、ERMAP、ERLF1、HDAC5、LDLRAP1、MCF2、OLA1、RASA1、SHC2、STMN2、およびTRIP10からなる群より選択される分子を活性化する、項目2に記載の方法。
(項目12)
前記HCCが、肝細胞がん、HCCの線維層板状変異型、または混合型肝細胞胆管がんである、項目1から11のいずれか一項に記載の方法。
(項目13)
前記HCCが、早期HCC、非転移性HCC、原発性HCC、進行HCC、局所進行HCC、転移性HCC、寛解期HCC、再発性HCC、付加療法の状況でのHCC、または新補助療法の状況でのHCCである、項目1から11のいずれか一項に記載の方法。
(項目14)
タキサンおよびアルブミンを含むナノ粒子を含む前記組成物を非経口的に投与する、項目1から13のいずれか一項に記載の方法。
(項目15)
タキサンおよびアルブミンを含むナノ粒子を含む前記組成物を静脈内投与、動脈内投与、肝内投与、または門脈内投与する、項目14に記載の方法。
(項目16)
前記タキサンが、パクリタキセルである、項目1から15のいずれか一項に記載の方法。
(項目17)
前記組成物中の前記ナノ粒子の平均直径が、約200nm以下である、項目1から16のいずれか一項に記載の方法。
(項目18)
前記組成物中の前記ナノ粒子の平均直径が、約200nm未満である、項目17に記載の方法。
(項目19)
前記ナノ粒子中の前記タキサンが、アルブミンでコーティングされている、項目1から18のいずれか一項に記載の方法。
(項目20)
前記個体がヒトである、項目1から19のいずれか一項に記載の方法。
本明細書で用いられる「処置」または「処置すること」とは、臨床的な結果を含めた有益な結果または所望の結果を得るための手法である。本発明の目的では、有益または所望の臨床結果に、以下:疾患から結果として生じる1またはそれより多くの症状を緩和すること、疾患の程度を軽減すること、疾患を安定化させること(例えば、疾患の増悪を予防するかまたは遅延させること)、疾患の拡大(例えば、転移)を予防するかまたは遅延させること、疾患の再発を予防するかまたは遅延させること、疾患の進行を遅延させるかまたは緩徐化すること、疾患状態を改善すること、疾患の寛解(部分寛解または完全寛解)をもたらすこと、疾患を処置するのに必要とされる1またはそれより多くの他の医薬の用量を低減すること、疾患の進行を遅延させること、生活の質を向上させること、および/または生存を延長することのうちの1または複数が含まれるがこれらに限定されない。また、「処置」には、HCCの病理学的帰結の軽減も包含される。本発明の方法は、処置のこれらの側面のうちの任意の1または複数を意図する。
本発明は、個体(例えば、ヒト)におけるHCCを処置する方法であって、個体にタキサンおよびアルブミンを含むナノ粒子を含む有効量の組成物を投与するステップを含む方法を提供する。本発明はまた、個体(例えば、ヒト)におけるHCCを処置する方法であって、個体にa)タキサンおよびアルブミンを含むナノ粒子を含む有効量の組成物と、b)有効量の少なくとも1つの他の薬剤とを投与するステップを含み、前記他の薬剤が、微小管の分解を阻害する方法も提供する。後出におけるHCCを処置する方法に対する言及およびこれらについての説明は例示的なものであり、この説明は、組合せ療法を用いてHCCを処置する方法にも同等に当てはまり、これらの方法も包含することが理解される。
一部の実施形態における、タキサンおよびアルブミンを含むナノ粒子を含む組成物を投与する方法は、少なくとも1つの他の薬剤の投与と共に実施される。
一部の実施形態における本出願は、それを必要とする個体における肝細胞がん(HCC)を処置する方法であって、個体にタキサンおよびアルブミンを含むナノ粒子を含む有効量の組成物を投与するステップを含む方法を提供する。
個体(ヒトなど)に投与されるタキサンナノ粒子組成物の用量は、具体的な組成物、投与方式、および処置されるHCCの種類によって変化しうる。一部の実施形態では、組成物の量が、客観的な応答(部分的な応答または完全な応答など)を結果としてもたらすのに有効である。一部の実施形態では、タキサンナノ粒子組成物の量が、個体において完全な応答を結果としてもたらすのに十分である。一部の実施形態では、タキサンナノ粒子組成物の量が、個体において部分的な応答を結果としてもたらすのに十分である。一部の実施形態では、投与されるタキサンナノ粒子組成物の量(例えば、単独で投与される場合の)が、タキサンナノ粒子組成物により処置される個体の集団のうち、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約64%、約65%、約70%、約75%、約80%、約85%、または約90%のうちのいずれかを超える全体的な応答率をもたらすのに十分である。本明細書に記載される処置方法に対する個体の応答は、例えば、RECISTレベルに基づいて決定することができる。
上記の節で説明した投与レジメンは、単剤療法状況および組合せ療法状況のいずれにも適用される。以下では、組合せ療法のための投与方式をさらに説明する。
本明細書に記載されるナノ粒子組成物は、タキサン(パクリタキセルなど)と、アルブミン(ヒト血清アルブミンなど)(から本質的になる様々な実施形態において)含むナノ粒子を含む。水溶性が乏しい薬物(タキサンなど)のナノ粒子は、例えば、それらの各々が参照によりそれらの全体において組み込まれる、米国特許第5,916,596号;同第6,506,405号;同第6,749,868号;同第6,537,579号;および同第7,820,788号において開示され、また、米国特許出願公開第2006/0263434号および同第2007/0082838号;PCT特許出願第WO08/137148号においても開示されている。
本明細書に記載されるナノ粒子は、他の薬剤、賦形剤、または安定化剤を含む組成物中に存在させることができる。例えば、ナノ粒子の負のゼータ電位を増大させることにより安定性を増大させるために、1種または複数の負に荷電した成分を添加することができる。負に荷電したこのような成分には、グリココール酸、コール酸、ケノデオキシコール酸、タウロコール酸、グリコケノデオキシコール酸、タウロケノデオキシコール酸、リトコール酸、ウルソデオキシコール酸、デヒドロコール酸などからなる胆汁酸による胆汁酸塩、以下のホスファチジルコリン:パルミトイルオレオイルホスファチジルコリン、パルミトイルリノレオイルホスファチジルコリン、ステアロイルリノレオイルホスファチジルコリン、ステアロイルオレオイルホスファチジルコリン、ステアロイルアラキドイルホスファチジルコリン、およびジパルミトイルホスファチジルコリンが含まれるレシチン(卵黄)ベースのリン脂質を含めたリン脂質が含まれるがこれらに限定されない。他のリン脂質は、L−α−ジミリストイルホスファチジルコリン(DMPC)、ジオレオイルホスファチジルコリン(DOPC)、ジステアロイルホスファチジルコリン(distearyolphosphatidylcholine)(DSPC)、水素添加大豆ホスファチジルコリン(HSPC)、および他の関連化合物を含む。例えば、硫酸コレステリルナトリウムなど、負に荷電した界面活性剤または乳化剤もまた、添加剤として適する。
本発明はまた、本明細書に記載される方法のうちのいずれかで使用するためのキット、医薬、組成物、および単位剤形も提供する。
in vitroおよびin vivoの肝細胞がん(HCC)モデルにおけるナノ粒子(Nab−パクリタキセル)の有効性の評価
この実施例はin vitroおよびin vivoのHCCモデルにおけるNab−パクリタキセルの活性を実証する。
発現プロファイリングおよび情報科学的分析
43対のHCC腫瘍および隣接する非腫瘍肝臓についての遺伝子発現プロファイリングを、Wong N.ら、Clinical Cancer Research 11:1319〜26頁(2005年)により記載された方法に従って実施した。研究された症例の人口統計学的情報を表1に示す。3つの個体由来の正常な肝臓RNAをプールし、アレイハイブリダイゼーションにおける参照コントロールとして使用した(Ambion、Austin、TX;Clontech Laboratory Inc.、Palo Alto、CA;およびStrategene、La Jolla、California)。簡潔に言うと、試験試料由来の逆転写されたRNAおよび正常な肝臓のプールを、蛍光Cy5−dCTPまたはCy3−dCTPを用いて差次的に標識した。標識されたcDNAを、19K cDNAアレイに共ハイブリダイズした(Ontario Cancer Institute、Canada)。ScanArray 5000(Packard BioScience、UK)により捕捉されたハイブリダイズされたシグナルを、GenePix Pro4.0(Axon、CA)により分析した。重複したスポットおよび色素交換実験の結果を平均し、各転写産物に関する正規化された強度比を情報科学的分析に供し、悪性HCC形質転換に関与する影響力の大きい遺伝子を決定した。
ATCCから取得したヒト肝臓がん細胞株Hep3BおよびSK−HEP1を、10%ウシ胎仔血清を補足したGlutamax−1(Gibco−BRL、Grand Island、NY、USA)含有ダルベッコ変法イーグル培地中で培養した。HKCl−9を、(Chan K.Y.Y.ら、Modern Pathology 19:1546〜54頁(2006年)に記載のように)1%L−グルタミンおよび10%ウシ胎仔血清を補足したAIMV培地(Gibco−BRL)において培養した。すべての細胞を5%CO2の加湿雰囲気下で37℃において培養した。
細胞の生存度をMTTアッセイにより測定した。3000細胞/ウェルの密度で96−ウェルプレートにおいて成長させた細胞を、示されるように、薬物またはsiRNAトランスフェクションで処理した。パクリタキセル、ドセタキセルおよびNab−パクリタキセルを、0から40μg/mlの範囲のさまざまな濃度において48時間試験し、一方、ドキソルビシンは、0から150μg/mlの範囲の濃度において48時間試験した。形成されたホルマザンを570nmにおいて測定し、細胞の生存度を、3回の独立した実験での5つの複製物から最大吸光度の百分率として表す。細胞の生存を50%阻害した薬物の濃度(IC50)を、細胞の生存曲線から決定した。
滅菌18×18mmのガラスカバースリップにプレーティングした細胞を、24時間接着させ、その後、5ng/mlのNab−パクリタキセルまたは培地を用いて、さらに24時間処理した。4%パラホルムアルデヒド中に固定した細胞を、その後、1:100希釈の抗βチューブリン(Zymed、Invitrogen)と一緒にインキュベートした。二次抗体Alexa−598−結合抗マウス免疫グロブリン(Molecular Probes、Eugene、OR、USA)を1:200希釈で適用した。DAPI(Molecular Probes)中で対比染色した細胞の核を、蛍光顕微鏡(Nikon EFD−3、Japan)下で検査した。捕捉後の画像分析および画像スタックの処理を、analySISソフトウェアを使用して実施した。
細胞周期分布を、さまざまな濃度のNab−パクリタキセルに曝露後測定した。12時間後、剥離した細胞を含むすべての細胞を回収し、70%エタノール中で4℃において一晩固定した。固定した細胞を、フローサイトメトリ分析(BD FACSCalibur(商標)、Becton Dickinson)前に、RNase Aおよびヨウ化プロピジウムとともにインキュベートした。G0−G1、SおよびG2−M期の平均値を、2回の独立した実験から計算した。
TUNELアッセイを、In−Situ Cell Death Detection Kit(Roche Applied Science、Mannheim、Germany)の手順に従って実施した。簡潔には、さまざまな濃度のNab−パクリタキセルを用いて処理した細胞を固定し、TUNEL反応混合物と一緒に1時間、37℃においてインキュベートした。DAPI中で対比染色した細胞の核を、蛍光顕微鏡(Nikon EFD−3、Japan)により検査した。アポトーシス細胞の百分率を、少なくとも4つのランダムに選択された視野に基づいて計算し、合計で約200細胞であった。
siRNA配列は、STMN1 siGENOME SMARTpool(si−STMN1)およびsiCONTROL Non−Targeting siRNA(si−mock)を含んだ。すべてのsiRNAを、二本鎖RNA(Dharmacon)として化学的に合成し、Lipofectamine 2000(Invitrogen、Carlsbad、CA、USA)により、製造業者の指示書に従って細胞株に導入した。簡潔に言うと、細胞を、100nMのsiRNA(si−STMN1またはsi−mock)と一緒にインキュベートした。トランスフェクションの6時間後、培地を新鮮な成長培地と交換した。STMN1の発現をウエスタンブロットによりモニターし、少なくとも3日間発現が抑制されたことが示された。0μg/ml〜40μg/mlの範囲の濃度のパクリタキセルおよびNab−パクリタキセルを、siRNAのトランスフェクション後6時間目に適用した。細胞の生存度に関するMTTアッセイを48時間のときに実施し、IC50値を計算した。
Nab−パクリタキセルを用いて48時間処理した細胞および未処理のコントロール細胞からのタンパク質溶解産物を、Bradford Protein Assay(Bio−Rad Laboratories、Hercules、CA、USA)を使用して定量した。等量のタンパク質溶解産物(30〜60μg)をSDS−PAGEにより分離し、ニトロセルロース膜(Bio−Rad Laboratories)に電気転写(electrotransfer)した。使用した一次抗体は、抗STMN1(1:1000希釈)、抗PARP(1:1000希釈)(Santa Cruz Biotechnology、Heidelberg、Germany)、抗GAPDH(1:10,000希釈)(Millipore Corporation、Bedford、MA、USA)を含んだ。ペルオキシダーゼ結合体化二次抗体(抗GAPDHに関しては1:10,000希釈;他の一次抗体に関しては1:2000)(Santa Cruz)と一緒のインキュベーション後、タンパク質発現を、SuperSignal West Pico Chemiluminescent Substrate(Thermo Scientific、Rockford、IL、USA)を使用して検出した。
SK−HEP1ルシフェラーゼ安定クローンを、SK−HEP1細胞にホタルルシフェラーゼ発現ベクターをトランスフェクトすることによって調製し、500ug/mlのGeneticin(Gibco−BRL)を用いて4週間選択した。個別のコロニーを、生物発光活性に関してXenogen IVIS(登録商標)imager(Alameda、CA、USA)を使用してスクリーニングした。安定した発光の発現を有するクローンをin−vivo研究に使用した。
データは平均±SDで表した。スチューデントt検定、Kaplan−Meier生存曲線および一元ANOVA分析を、Graphpad Prism3.0ソフトウェアを使用して実施した。差は、P<0.05で統計的に有意とみなされた。
HCCの発症に関与する機能的オントロジー
マイクロアレイデータセット由来の遺伝子は、最初にランク付けされ、統計的な方法に従った有意な差次的発現の証拠により選択された。約1,000の重要な公知の遺伝子のIPA分析(上位5%パーセンタイルの変化)により、いくつかの有意な遺伝子オントロジーが示唆され、これらは、細胞のアセンブリおよび組織化、細胞の機能および維持、細胞死、細胞周期、細胞の組成、薬物および脂質の代謝ならびに小分子生化学を含んだ(図1)。特に、細胞のアセンブリおよび組織化のカテゴリーはもっとも有意な事象にランク付けされ、STMN1およびTUBB4などの微小管関連遺伝子の過剰提示が見出だされた(図1)。
STMN1発現の上昇を示したHCC細胞株についてのパクリタキセル、ドセタキセルおよびNab−パクリタキセルの効果を評価した(図2B)。タキサン系薬物に対する高度の感受性は、HCCを含む多くのがんに広範囲に使用されている化学療法剤のドキソルビシンと比較して、全般に、Hep3B、SK−HEP1およびHKCl−9において見出された(図2A)。顕著なことに、Nab−パクリタキセルは、試験した3種すべての細胞株において、もっとも少ない有効投与量でもっとも高い効能を示した。Nab−パクリタキセルについて得られたIC50は0.29±0.02nMから10.42±1.37nMにおよび、これはドキソルビシンの約1/44から1/1082であった(IC50値は105.95±10.58nMから455.93±35.72nMにおよぶ)(図2C)。
より高い程度の微小管重合がNab−パクリタキセル処理細胞において見出された(図3Aおよび3B)。さらにHep3BおよびSK−HEP1の両方において、フローサイトメトリ分析により、漸増濃度のNab−パクリタキセルを適用すると、G2/M集団の増加が見出されることが示され、用量依存性の細胞周期の停止を示唆している(P<0.05;図4B)。フローサイトメトリプロファイルは、Nab−パクリタキセルを用いた処理後に現れるサブG1(sub−G1)部分をさらに示した(図4A)。アポトーシス細胞の存在を、SK−HEP1およびHep3BにおいてTUNEL分析によりさらに確認し、これはTUNEL陽性細胞数が、使用したNab−パクリタキセルの量に対応することを示した(P<0.001;図4Cおよび図4D)。核タンパク質PARPの切断を、89kDa切断産物の存在をモニターすることによって決定した。PARPの切断は処理後12時間で明らかになり、48時間にわたって徐々に増加した(図4E)。
SK−HEP1/Luc+細胞をBALB/cヌードマウスに皮下注射し、in−vivoにおけるさまざまな組成物の抗腫瘍効果を検査した。発達した異種移植片を、処置の初日、その後週に2回、IVIS画像化およびカリパス測定により腫瘍サイズに関して測定した。図5Aは、時間とともに各処置群における腫瘍サイズ変化の百分率を示す。コントロールPBS群は、研究期間にわたって腫瘍サイズが徐々に増加することを示した。各処置群が腫瘍サイズの減少を示す一方で、ドキソルビシン、パクリタキセルおよびドセタキセル由来の毒性は特に重篤であり3回以内の注射で多くのマウスの大幅な体重減少および死亡をもたらした(図5Bおよび図5C)。体重減少は、Nab−パクリタキセル注射を用いても観察されたが、最も重篤ではなく、マウスは全般に、9日目の最終の注射後に体重が回復できた。Nab−パクリタキセルの抗腫瘍効果は高度に有意であり、コントロール群と比較して腫瘍サイズに対する相当な阻害が存在した(P=0.0007)。さらに、60%を上回るマウスが実験終了まで生存した(図5B)。
本発明者らはSTMNのノックダウンとNab−パクリタキセルとの間の相乗効果を観察した。図6Aは、1日目および3日日目のsiRNAノックダウン後のHep3BにおけるSTMN1タンパク質レベルを示す。Hep3Bにおける特異的STMN1ノックダウンは、トランスフェクション後3日のmockと比較して、細胞の生存度が約40%減少したことを示した(図6B)。タキサンを用いた比較研究(combinatory study)において、si−STMN1をトランスフェクトされたHep3Bは、Nab−パクリタキセルに対して7.7倍超、感受性であり(IC50、0.04±0.004nM対0.31±0.04nM)、パクリタキセルに対して、2.7倍超、感受性であった(IC50、1.95±0.28nM対5.17±0.06nM)(図6C)。対照的に、STMN1のノックダウンは、微小管を標的としない薬物であるドキソルビシンの感受性には効果がなかった。
Claims (13)
- 肝細胞がん(HCC)の処置を必要とする個体におけるHCCを処置するための組合せ物であって、該組合せ物は、(a)タキサンおよびアルブミンを含むナノ粒子を含む有効量の組成物と、(b)有効量の少なくとも1つの他の薬剤とを含み、該他の薬剤が、STMN1の阻害剤である、組合せ物。
- 前記組成物と、前記他の薬剤とが、同時投与または逐次投与されることを特徴とする、請求項1に記載の組合せ物。
- 前記組成物と、前記他の薬剤とが、共時投与されることを特徴とする、請求項1に記載の組合せ物。
- 前記他の薬剤が、ガンボージもしくはその誘導体、またはSTMN1に対するsiRNAである、請求項1に記載の組合せ物。
- 前記HCCが、肝細胞がん、HCCの線維層板状変異型、または混合型肝細胞胆管がんである、請求項1から4のいずれか一項に記載の組合せ物。
- 前記HCCが、早期HCC、非転移性HCC、原発性HCC、進行HCC、局所進行HCC、転移性HCC、寛解期HCC、再発性HCC、付加療法の状況でのHCC、または新補助療法の状況でのHCCである、請求項1から4のいずれか一項に記載の組合せ物。
- タキサンおよびアルブミンを含むナノ粒子を含む前記組成物が非経口的に投与されることを特徴とする、請求項1から6のいずれか一項に記載の組合せ物。
- タキサンおよびアルブミンを含むナノ粒子を含む前記組成物が静脈内投与、動脈内投与、肝内投与、または門脈内投与されることを特徴とする、請求項7に記載の組合せ物。
- 前記タキサンが、パクリタキセルである、請求項1から8のいずれか一項に記載の組合せ物。
- 前記組成物中の前記ナノ粒子の平均直径が、200nm以下である、請求項1から9のいずれか一項に記載の組合せ物。
- 前記組成物中の前記ナノ粒子の平均直径が、200nm未満である、請求項10に記載の組合せ物。
- 前記ナノ粒子中の前記タキサンが、アルブミンでコーティングされている、請求項1から11のいずれか一項に記載の組合せ物。
- 前記個体がヒトである、請求項1から12のいずれか一項に記載の組合せ物。
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