JP2019529420A - リポソームアンチセンスオリゴヌクレオチドとの併用療法 - Google Patents
リポソームアンチセンスオリゴヌクレオチドとの併用療法 Download PDFInfo
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Abstract
Description
1.発明の分野
本発明は、総じて医薬の分野に関する。より詳しくはそれは、Grb2を指向するアンチセンスオリゴヌクレオチドを含む併用療法によるがんの処置に関する。
米国がん協会は、2015年に米国内で新たに慢性骨髄性白血病(CML)と診断された患者は約6,600名、CMLで亡くなったのは約1,140名であったと見積もっている。CMLと診断された時の平均年齢は64歳あたりである。ほぼ半数の症例は65歳以上の人で診断されている。この類の白血病に罹患するのは主に成人であり、子供にみられることは稀である。CMLは、慢性期、移行期及び芽球期に区別される。ほとんどのCML患者は疾患の慢性期に診断される。慢性期のCML患者は、処置されない場合には急速に疾患の移行期及び芽球期に進行し得る。
I.成長因子受容体結合タンパク質2(Grb2)
grb2遺伝子は、ヒト染色体領域17q22−qterに対応付けられ、白血病では重複する領域であるが、これはgrb2遺伝子産物のコピー数の増加を招き得る。Grb2は、マウス造血細胞の形質転換、及び高レベルの発がん性チロシンキナーゼを発現するヒト白血病細胞の増殖にとって重要であるため、Grb2の阻害は白血病の自然の過程に著しい影響を与え得る。
Grb2の機能を阻害する多様な方策が研究されてきた。1つの方策は、欠失非機能性SH2ドメインを有する、Grb2の代替スプライス形態をクローニングすることを含む(Fath,1994)。コードされるGrb3−3タンパク質はリン酸化EGFRに結合することがない、というのも欠失した残基はGrb2がホスホチロシン残基に結合するのに不可欠であるからである。しかしながら、Grb3−3は機能性SH3を保持している。それゆえ、Grb3−3はグアニンヌクレオチド交換因子の結合においてGrb2と競合することができる。Fath et al.(1994)による試験において、Grb3−3をSwiss 3T3線維芽細胞にマイクロインジェクションすることは、それがアポトーシスを経ることを誘導した。これらのクローンは、グアニンヌクレオチド交換因子の結合においてGrb2と競合するように企図されている。
成長因子受容体結合タンパク質2(Grb2)は、発がん性チロシンキナーゼ、例えばBcr−Ablによって利用されてRas経路を活性化させる。Grb2は、線維芽細胞を形質転換させマウスに白血病様疾患を誘導するBcr−Ablによって必要とされる。grb2 mRNAに特異的なリポソーム組込型アンチセンスオリゴヌクレオチド(オリゴ)であるBP1001は、Grb2発現を遮断するために開発された。Grb2の連続cDNA配列を配列番号2に提供し、Grb2のタンパク質配列を配列番号3に提供する。
A.ラットでの薬物動態研究
静脈内(i.v.)投与後のラットでBP1001の薬物動態研究が行われた(Tari,2007)。Lewisラット(n=5、400gm)の右大腿動脈及び左大腿静脈にカニューレを挿入し、放射標識(32P)BP1001を体重1kgあたり10mgのオリゴヌクレオチドの用量で静脈内注射した。注射から5、10、20、30、60、90、120、180及び240分後に血液(0.3mL)を右大腿動脈から採取した。各採血の後にはカテーテルをヘパリンナトリウム1:1000(単位/mL)で洗い流した。全血試料を抽出し、以前に記載されているような液体シンチレーション(Tari,1998、Gutierrez−Puente,1999)によって32P放射性について検査した。薬物動態パラメータを非線形回帰解析(Rstrip;Micro Math,Inc.,Salt Lake City,UT)によって決定した。全血の薬物濃度データは2−コンパートメントモデルで最もよく近似された。血液からのBP1001のクリアランスは2−コンパートメント数学的モデルで緊密に近似されることが分かった(相関r2>0.98)。初期の分布相は注射後の最初の6分間にわたって起こった(t1/2α=5.16±0.3分)。終末相の半減期(t1/2β)は225.6±13.2分であった。すぐに分かる分布容積(36.42±1.88mL)はこの大きさのラットの総血液体積よりも高かった。濃度曲線下面積(AUC)が5.4±0.9mg/mL×分であった一方、滞留時間は309.6±21.5分であった。この試験で認められたBP1001の薬物動態分布及び高い分布容積は、以前に研究された他のリポソーム組込型P−エトキシオリゴヌクレオチドについて報告されたそれと類似していた(Tari,1998、Gutierrez−Puente,1999)。
静脈内投与後のマウスでBP1001の組織分布試験を行った。20匹のマウス(5匹/群)を3つの試験項目群と1つの対照群とに分けた。試験項目群には尾静脈を介して放射標識(32P)BP1001を体重1kgあたり20mgのオリゴヌクレオチドの用量で静脈内注射した。注射したマウスを臓器採取のために注射から4、24及び48時間後にCO2吸入によって安楽死させた。対照動物は非注射動物であった。脾臓、肝臓、腎臓、心臓、胃、肺及び骨髄組織を全ての動物から採取し、各臓器から組織試料(50〜100mg)を計り取って加工した。シンチレーション計数器で32P放射性の計数を行った。結果は平均μgのBP1001/g組織として表した。予想されるように、対照動物では放射性は検出されなかった。BP1001の組織分布は、以前に研究された他のリポソーム組込型P−エトキシオリゴヌクレオチドについて報告されたそれと類似していた。BP1001は全ての組織で蓄積し、脾臓、肝臓及び腎臓組織において最も多く蓄積していた。注射から4時間後の組織1gあたりの平均BP1001組織濃度は、64μg(脾臓)、50μg(肝臓)、34μg(腎臓)であり、他の組織では12〜34μgの範囲であった。組織半減期は、脾臓、肝臓、腎臓、心臓及び胃ではおよそ24時間であり、肺では48時間であった。骨髄では最小量のBP1001(2つの大腿部で約0.4μg)が検出され、濃度は72時間にわたって比較的一定にとどまった。
1.マウスでの単回用量毒性試験
BP1001の単回用量毒性試験では15匹の雄のICRマウス(5匹/群)を、非注射対照群(I群)と、単回注射として尾静脈を介して15及び30mgオリゴ/kgを静脈内に受ける2つの処置群(II群及びIII群)とに割り当てた。15匹の雌のICRマウス(5匹/群)を、非注射対照群(IV群)と、単回注射として尾静脈を介してそれぞれ20及び40mgオリゴ/kgを静脈内に受ける2つの処置群(V群及びVI群)とに割り当てた。動物を毎日観察し、血液学評価及び臨床化学評価のために注射から2及び6週間後に血液を採取した。注射から6週間後の採血の後に動物を屠殺し、臓器毒性の巨視的及び微視的評価のために組織を採取した。罹患または死亡の兆候は観察されなかった。15〜40mg/kgのBP1001の単回静注は、調べた臓器において薬物関連の病変を生じさせなかった。30及び40mgオリゴ/kgの注射から2週間後にWBC計数の減少が認められた。WBC計数の回復は30mgオリゴ/kgでの注射から6週間後に認められた。群の平均WBC計数は、40mgオリゴ/kgを受けている動物では6週目に完全には回復しなかったが、対照に比べて統計的差異はなかった(Tari,2007)。
マウスでのBP1001の多回投薬毒性試験では、24匹のICRマウス(Institute for Cancer Researchからのマウスの非近交系統;雌5匹/群、雄3匹/群)を、非注射対照群(群I)と、連続して5日間毎日尾静脈を介して15及び25mgオリゴ/kgを静脈内に受ける2つの処置群(II〜III群)とに割り当てた。動物を毎日観察し、血液学評価及び臨床化学評価のために注射から2及び6週間後に血液を採取した。注射から6週間後の採血の後に動物を屠殺し、臓器毒性の巨視的及び微視的評価のために組織を採取した。罹患または死亡の兆候は観察されなかった。15〜25mg/kgのBP1001の多回静注は、調べた臓器において薬物関連の病変を生じさせなかった。処置群では注射から2週間後にWBC計数の減少が認められたが、これは注射から6週間後において持続していた。差分WBC計数は、処置動物のWBCの特定集団が対照とは異なっていないことを示した(Tari,2007)。
ダッチベルトウサギにBP1001を週に2回静脈内(低速ボーラス)投与することの潜在的毒性を行った。BP1001を28日間の期間にわたって投与し、その後、2週間の回復期を設けた。試験デザインを表2に示す。
エームス変異原性試験でBP1001を試験した。5mgのGrb2オリゴヌクレオチドを含有するBP1001のバイアルに塩化ナトリウム(0.9%)を加えた。S−9酵素活性化系の存在下及び非存在下で試料を様々な濃度の5つのサルモネラ系統に対して試験した。試料は試験した系統に対して変異原性を有していなかった。
アロクロール誘導S9活性化系の存在下と非存在下との両方においてCHO細胞を使用して染色体異常アッセイでBP1001を試験した。染色体異常アッセイの用量範囲を設定するために予備毒性試験を実施した。染色体異常アッセイを用いてBP1001のクラストゲン潜在能を評価した。この試験の知見に基づけば、BP1001は非活性化試験系及びS9活性化試験系のどちらにおいてもCHO細胞の構造的及び数的染色体異常の誘導について陰性であると結論付けられた。
BP1001第I相試験を2パートで行った:(A)BP1001用量漸増、及び(B)同時発生的な低用量シタラビン(LDAC)を伴うBP1001の用量拡張。用量漸増(パートA)については、血液悪性腫瘍を有する3名以上の患者の連続コホートを5〜135mg/m2の漸増用量のBP1001で最大耐量(MTD)が同定されるまで処置する標準的な「3+3」デザインを用いた。試験の用量拡張パート(パートB)については、安全性及び生物学的作用をさらに特性評価するためならびに第2相推奨用量を同定するために、AMLを有する患者の2つの連続サブセットを、固定用量のLDACと組み合わせたMTD(または最高試験用量[HTD])及びMTD(またはHTD)よりも1つ低いレベルのBP1001によって処置した。試験のどちらのパートも、安全性、忍容性及び毒性、薬物動態(PK)、腫瘍応答ならびに抗白血病活性を評価するために非盲検逐次用量漸増デザインを採用した。試験では合計39名の患者を処置した:AML(n=30)、CML−BP(n=5)及びMDS(n=4)。39名の患者のうち、27名は評価可能であり、12名は疾患進行のためにサイクル全体を完遂することができずプロトコールに従って元の所へ返された。5mg/m2を受けている1名の患者だけは、増殖性CML−BPのための高用量ヒドロキシ尿素を受けている間、グレード3の粘膜炎及び手足症候群の用量制限毒性(DLT)を被った。試験医薬を原因因子として除外することができなかったため、この事象はDLTとして報告した。患者を6名に増やしたところ、DLTに発展する患者は他にはいなかった。他の薬物関連毒性は、処置したどの患者においても認められなかった。MTDは同定されなかった。BP1001のHTDは90mg/m2である。
フローサイトメトリーを用いて、BP1001単剤療法を受けている患者の循環白血病細胞中のGrb2及びpErkタンパク質のレベルを決定し、中央蛍光強度(MFI)として報告した。処置中のGrb2及びpErkのMFIをベースラインでのそれらと比較した。最後(処置の最後またはサイクル1の22日目)に測定した試料では、試料12個中10個においてBP1001はGrb2レベルを25%以上低下させ、試料12個中7個においてpErkレベルを25%以上低下させた。低下の平均は、Grb2レベルについては49%であり(範囲:28〜91%)、pErkレベルについては52%であった(範囲:27〜91%)。
BP1001(60mg/m2)+LDACまたはBP1001(90mg/m2)+LDACを受けている、AMLと診断された難治性/再発性の患者から採取した血漿試料に対して薬物動態(PK)分析を実施した。両方のコホートにおいて、Tmaxは投与の1時間後であった。両方の用量のCmaxは82ng/mLであった。しかしながら、BP1001の血漿半減期は60mg/m2用量の方が90mg/m2用量よりも長かった(29.6±8.1時間対11.8±5.4時間)。BP1001のクリアランス速度は60mg/m2用量の方が90mg/m2用量よりも低かった(133±24L/時対205±70L/時)。これらの結果は、60mg/m2BP1001用量の方が90mg/m2用量よりも好ましい可能性があることを示唆している。
本明細書において「リポソーム」は、アンチセンスオリゴヌクレオチドを捕捉または組み込むことができる、脂質二重層を有する脂質含有小胞、及びその他の脂質担体粒子を意味して使用される。このように、リポソームは、封入された脂質二重層または凝集体の生成によって形成される様々な単層、多層及び多重小胞脂質ビヒクルを包含する包括的用語である。さらに、リポソームは、定義されない層状構造を有してもよい。リポソームは、リン脂質二重膜と内部の水性媒体とを備えた小胞構造を有するものとして特徴付けられ得る。多層リポソームは、水性媒体によって隔てられた多重脂質層を有する。それらは、リン脂質を過剰の水溶液中に懸濁させると自発的に形成される。脂質成分は閉鎖構造を形成する前に自己再配置を受け、脂質二重層間に水と溶解した溶質とを捕捉する(Ghosh and Bachhawat,1991)。しかしながら、本発明は、水溶液中で通常の小胞構造とは異なる構造を有する構成物も包含する。例えば、脂質はミセル構造をとっていてもよいし、または単に脂質分子の非一様な凝集体として存在していてもよい。
脂質は、天然に存在するかまたは合成のものであり得る脂肪性物質である。例えば、脂質としては、細胞質中に天然に存在する脂肪滴ならびに、脂肪酸、アルコール、アミン、アミノアルコール及びアルデヒドなどの長鎖脂肪族炭化水素及びそれらの誘導体を含有する当業者によく知られている類の化合物が挙げられる。一例は、脂質1,2−ジオレオイル−sn−グリセロ−3−ホスホコリン(DOPC)である。
「中性のリポソームまたは脂質構成物」または「非荷電のリポソームまたは脂質構成物」は、本明細書中で使用される場合、本質的に中性の正味の電荷を生む(実質的に非荷電である)1つ以上の脂質を有するリポソームまたは脂質構成物として定義される。特定の実施形態では、中性のリポソームまたは脂質構成物は、大部分において、自体が中性である脂質及び/またはリン脂質を含み得る。特定の実施形態では、中性のリポソームまたは脂質構成物を生み出すために両親媒性脂質を組み込むまたは使用することがある。例えば、電荷が互いに実質的に相殺されてそれによって本質的に中性の正味電荷がもたらされるように、正または負に帯電した脂質を組み合わせることによって、中性リポソームが生み出され得る。「本質的に中性」または「本質的に非荷電」とは、他成分の反対電荷によって相殺されない電荷を含む脂質は所与の集団(例えばリポソームの集団)中に存在するとしてもわずかであること(例えば、成分の10%未満、より好ましくは5%未満、最も好ましくは1%未満が非相殺電荷を含むこと)を意味する。本発明の特定の実施形態では、構成物の脂質成分が本質的に中性であるがリポソームの形態でない、構成物が調製され得る。
阻害性オリゴヌクレオチドは、細胞における遺伝子の転写または翻訳を阻害することができる。オリゴヌクレオチドは、長さが5〜50ヌクレオチド以上であり得、特定の実施形態では長さが7〜30ヌクレオチドであり得る。特定の実施形態では、オリゴヌクレオチドは長さが7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29または30ヌクレオチドであり得る。オリゴヌクレオチドは核酸及び/または核酸類縁体を含み得る。典型的には、阻害性オリゴヌクレオチドは細胞内での単一の遺伝子の翻訳を阻害することになるが、特定の実施形態では、阻害性オリゴヌクレオチドは細胞内での2つ以上の遺伝子の翻訳を阻害し得る。
本発明は、中性リポソームによってオリゴヌクレオチドを送達するための方法及び組成物を提供する。オリゴヌクレオチドは核酸からなるため、核酸に関係する方法(例えば、核酸の生成、核酸の修飾など)をオリゴヌクレオチドに関して用いてもよい。
本明細書中で使用する場合、「核酸塩基」は、複素環式塩基、例えば、天然に存在する少なくとも1つの核酸(すなわちDNA及びRNA)中にみられる天然に存在する核酸塩基(すなわち、A、T、G、CまたはU)ならびに、それらの核酸塩基の天然に存在するまたは天然に存在しない誘導体(複数可)及び類縁体などを指す。核酸塩基は通常、天然に起こる核酸塩基対合(例えば、AとT、GとC、及びAとUの水素結合)を置き換え得るように、少なくとも1つの天然に存在する核酸塩基と1つ以上の水素結合を形成(つまり「アニールする」または「ハイブリダイズ」)することができる。核酸塩基は、本明細書中に記載されているかまたは当業者に知られている任意の化学または天然の合成方法を用いてヌクレオシドまたはヌクレオチドの中に含み込められ得る。
本明細書中で使用する場合、「ヌクレオシド」は、核酸塩基リンカー部分に共有結合した核酸塩基を含んでいる個々の化学単位を指す。「核酸塩基リンカー部分」の非限定的な例は、5−炭素原子を含む糖(すなわち「5−炭素糖」)であり、限定されないが、デオキシリボース、リボース、アラビノース、または5−炭素糖の誘導体もしくは類縁体を含む。5−炭素糖の誘導体または類縁体の非限定的な例としては、2’−フルオロ−2’−デオキシリボース、または糖環において炭素が酸素原子で置き換わった炭素環糖が挙げられる。本明細書中で使用する場合、「部分」は通常、大きい化学または分子構造体の、小さい化学または分子成分を指す。
本明細書中で使用する場合、「ヌクレオチド」は、「主鎖結合」をさらに含んでいるヌクレオシドを指す。主鎖結合は通常、ヌクレオチドを、ヌクレオチドを含んでいる別の分子、または別のヌクレオチドに共有結合させて核酸を形成している。天然に存在するヌクレオチドの「主鎖結合」は典型的にはリン酸部分(例えば、ホスホジエステル主鎖結合)を含んでいるが、これは5−炭素糖と共有結合している。主鎖部分の結合は典型的には5−炭素糖の3’位または5’位で起こる。しかしながら、他のタイプの結合は、とりわけ天然に存在する5−炭素糖またはリン酸部分の誘導体または類縁体をヌクレオチドが含む場合に、当技術分野で知られている。
核酸は、核酸塩基の誘導体もしくは類縁体、核酸塩基リンカー部分、及び/または天然に存在する核酸に存在し得る主鎖結合を含む、または完全にそれらからなるものであり得る。本明細書中で使用する場合、「誘導体」は、化学修飾されているかまたは改変された形態の天然に存在する分子を指す一方、「模倣体」または「類縁体」は、天然に存在する分子または部分と構造的に類似しているものであってもなくてもよいが同様の機能を有している分子を指す。核酸塩基、ヌクレオシド及びヌクレオチドの類縁体または誘導体は当技術分野でよく知られている。
核酸は、当業者に知られている任意の技術、例えば、化学合成、酵素的生産または生物学的生産によって作られ得る。合成核酸(例えば合成オリゴヌクレオチド)の非限定的な例としては、ホスホトリエステル、亜リン酸エステルもしくはホスホロアミダイト化学及び固相技術、例えば参照により本明細書に援用されるEP266,032に記載されているものを使用して試験管内での化学合成によって作られるか、または参照により各々が本明細書に援用されるFroehler et al.(1986)及び米国特許第5,705,629号により記載されているようなデオキシヌクレオシドH−リン酸中間体によって作られる、核酸が挙げられる。本発明の方法では、1つ以上の種類のオリゴヌクレオチドを使用してもよい。オリゴヌクレオチド合成の様々な機構が例えば米国特許第4,659,774号、第4,816,571号、第5,141,813号、第5,264,566号、第4,959,463号、第5,428,148号、第5,554,744号、第5,574,146号、第5,602,244号に開示されているが、参照によりこれらの各々を本明細書に援用する。
核酸はポリアクリルアミドゲル、塩化セシウム遠心分離勾配または当業者に知られている他の任意の手段(例えば、参照により本明細書に援用されるSambrook et al.(2001)を参照のこと)で精製され得る。
本明細書中で使用する場合、「ハイブリダイゼーション」、「ハイブリダイズする」または「ハイブリダイズすることができる」は、二本鎖もしくは三本鎖分子、または部分的な二本鎖もしくは三本鎖の性質を有する分子を形成することを意味すると理解される。本明細書中で使用される「アニールする」という用語は「ハイブリダイズする」と同義である。
標的mRNAの特定領域に対して相補的であるアンチセンスオリゴヌクレオチド(オリゴ)を使用して内因性遺伝子の発現が阻害された。アンチセンスオリゴヌクレオチドが標的mRNAと結合するとき、DNA−RNAハイブリッドが形成される。このハイブリッド形成はmRNAの翻訳、したがってコードされるタンパク質の発現を阻害する。タンパク質が細胞の生存にとって必須である場合、その発現の阻害は細胞死につながり得る。したがって、アンチセンスオリゴヌクレオチドは抗がん及び抗ウイルス療法において有用なツールとなり得る。
リポソームP−エトキシアンチセンス薬製品は2つのcGMP製品からなるが、これらは両方とも、FDA承認済みの発売告知基準でのFDAによって義務付けられた分析証を有する。原材料、溶媒及び最終薬製品は本明細書中に記載されている。製造されたときの薬製品は凍結乾燥された琥珀色または白色の結晶または粉末であり、以下の材料を含む:オリゴヌクレオチド(例えば、P−エトキシアンチセンス薬物質)、中性脂質(例えばDOPC)及び界面活性剤(例えばポリソルベート20)。患者への投与のために調合するときは生理食塩水をバイアルに加えるが、この時に、P−エトキシアンチセンスを内部に組み込んだリポソームが形成される。
完成品の固有の物理的特質(例えば溶解性及び疎水性であるが、これらは後に生理食塩水への薬製品の溶解性、リポソーム中へのオリゴの組込み、及びリポソーム粒径に影響を与える)は、P−エトキシアンチセンス薬物質の生産中に所定のP−エトキシとホスホジエステルアミダイトとの原材料混合物を使用して定義することができる。オリゴヌクレオチド製造中にP−エトキシ主鎖基の逸失がランダムに起こり、結果としてそれらの結合がホスホジエステル結合になるが、その逸失はオリゴヌクレオチド中でのP−エトキシ:ホスホジエステル主鎖結合の好ましい比をもたらさないことがある。この場合には、P−エトキシとホスホジエステルアミダイト原材料との混合物でP−エトキシ主鎖欠失の予想される値を補い、かくして所望の比を有するオリゴヌクレオチドが生成する。オリゴヌクレオチドの主鎖中のP−エトキシ分子の数を増加させることは、分子の疎水性をより大きくし(この結果、リポソーム粒子はより大きくなる;表1)、極性を小さくし、溶解性を小さくする(表2)。中性電荷の疎水性P−エトキシ薬物質を試験する方法としては、例えば、オリゴヌクレオチド長の分布を決定する質量分析、及び薬物質の溶解性を決定するアッセイ(溶解性のための実用目的では、生理食塩水で再構成した薬製品の目視検査である)が挙げられる。P−エトキシ主鎖結合の数が大きくなるにつれてオリゴヌクレオチドの溶解性は低下するため、再構成された溶液は白くなってゆき、ついには疎水性が高くなり過ぎたために微粒子が形成される。
1グラム(1g)のpEオリゴをDMSO中に、DMSO1mLあたりオリゴヌクレオチド10mgの比率で溶解させる。次に、DOPCをtert−ブチルアルコールに、tert−ブチルアルコール1719mLあたりDOPC1gの比率で添加する。オリゴとDOPCとを、DOPC2.67gあたりオリゴヌクレオチド1gの比率で合わせて混合する。その後、0.835%(v/v)のポリソルベート20の溶液20mLを混合物に添加し、結果として0.039mg/mLの終濃度を得る。溶液を無菌フィルタに通し、その後、凍結乾燥のためにガラスバイアル内に分注する。
凍結乾燥製剤を生理食塩水(0.9%/10mMのNaCl)で10〜5000μMの終オリゴ濃度に水和させた。リポソーム−P−エトキシオリゴを手による振盪によって混合した。
製造された薬製品の目視検査:製造後、薬製品を含有する試料バイアルを選択して目視検査をする。液体が存在しないことは必須であり、バイアルの底に琥珀色結晶があるのは許容範囲内であり、許容性は、最良の結果としての白色の凝集した粉末または外観に向かうにつれて向上する。白色の外観は、乾燥プロセスがより良好であるとともに表面積対質量の比率が高いことを示唆しているが、このことは、使用のために再構成する上で大いに役に立つ。
本発明の特定の態様は、Grb2を標的とするヌクレアーゼ耐性阻害性オリゴを含有するオリゴヌクレオチド−脂質複合体(例えば、中性リポソーム中に組み込まれたオリゴヌクレオチド)でがん患者を処置する方法を提供する。詳しくは、オリゴヌクレオチドは、Grb2の翻訳開始部位においてヒトヌクレオチド配列と塩基対合することを可能にする配列を有し得、かくして、Grb2の発現を阻害し得る。いくつかの態様では、方法はさらに、最前線の治療薬、例えば、チロシンキナーゼ阻害薬(例えば、イマニチブ、ダサニチブ、ニロチニブ、ボスチニブ、ポナチニブまたはバフェチニブ)またはシチジン類縁体(例えば、デシタビン、アザシチジンまたはシタラビン)を患者に投与することを含む。
リポソームを含む医薬組成物は通常、滅菌された薬学的に許容できる担体または希釈剤、例えば水または生理食塩水溶液を含むであろう。
特定の実施形態では、本発明の方法は、阻害性オリゴヌクレオチド、または遺伝子発現の阻害薬を発現することができるオリゴヌクレオチドを第2または付加的療法と組み合わせて投与することを伴う。併用療法を含む方法及び組成物は治療的もしくは保護的効果を強化し、及び/または別の抗癌もしくは抗過剰増殖療法の治療的効果を増大させる。治療的及び予防的な方法及び組成物は、がん細胞の殺傷及び/または細胞過剰増殖の阻害などの所望の効果を得るのに有効な組み合わせの量で提供され得る。このプロセスは、遺伝子発現の阻害薬と第2療法、例えばチロシンキナーゼ阻害薬(例えば、イマチニブ、ニロチニブ、ダサチニブ、ボスチニブ、ポナチニブまたはバフェチニブ)またはシチジン類縁体(例えば、デシタビン、シタラビンまたはアザシチジン)との両方に細胞を接触させることを伴い得る。薬剤(すなわち、遺伝子発現の阻害薬または抗がん剤)のうちの1つ以上を含む1つ以上の組成物もしくは薬理製剤(複数可)を組織、腫瘍もしくは細胞に接触させることができ、または、2つ以上の別個の組成物もしくは製剤を組織、腫瘍及び/または細胞に接触させることができ、ここで、1つの組成物は、1)阻害性オリゴヌクレオチド;2)抗がん剤、または3)阻害性オリゴヌクレオチドと抗がん剤との両方を提供する。また、そのような併用療法を化学療法、放射線療法、外科的療法または免疫療法と併せて用いることもできる。
A/B/A B/A/B B/B/A A/A/B A/B/B
B/A/A A/B/B/B B/A/B/B B/B/B/A
B/B/A/B A/A/B/B A/B/A/B A/B/B/A
B/B/A/A B/A/B/A B/A/A/B A/A/A/B
B/A/A/A A/B/A/A A/A/B/A。
広範な化学療法剤が本実施形態に従って使用され得る。「化学療法」という用語は、がんを処置する薬物の使用を指す。「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含意して使用される。これらの薬剤または薬物は、細胞内でのそれらの活性様式、例えば、それらが細胞周期に影響を及ぼすか否か及びそれがどの段階で起こるかによって分類される。あるいは、薬剤は、DNAと直接架橋する、DNA中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って染色体及び有糸分裂の異常を誘発するその能力に基づいて、特徴付けられ得る。
DNA損傷を引き起こす、幅広く使用されてきた他の因子としては、例えば、γ線、X線、及び/または放射線同位体の腫瘍細胞への指向的送達として一般に知られるものが挙げられる。他の形態のDNA損傷因子、例えば、マイクロ波、プロトンビーム照射(米国特許第5,760,395号及び第4,870,287号)及びUV照射も想定される。これらの因子は全て、DNA、DNAの前駆体、DNAの複製及び修復、ならびに染色体の集合及び維持に対して広範な損傷を与える可能性が最も高い。X線の線量範囲は、長期間(3〜4週間)にわたる50〜200レントゲンの1日線量から2000〜6000レントゲンの単回線量までの範囲である。放射線同位体の場合の線量範囲は広く様々であり、同位体の半減期、放出される放射線の強さ及び種類、ならびに新生物細胞による取込みに依存する。
がん処置に関して免疫療法薬は概して、免疫エフェクター細胞ならびに、がん細胞を指向及び破壊する分子の使用に依拠する。トラスツズマブ(ハーセプチン(商標))はそのような一例である。免疫エフェクターは例えば、腫瘍細胞の表面のいくつかのマーカーに対して特異的であり得る。抗体は単独で治療のエフェクターとしての役割を果たすものであってもよいし、またはそれは他の細胞を動員して実際は細胞殺傷に影響を与えるものであってもよい。抗体はまた、薬物または毒素(化学療法薬、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)と結合しており単に標的指向性薬剤としての役割を果たすものであってもよい。あるいは、エフェクターは、直接的あるいは間接的に腫瘍細胞標的と相互作用する表面分子を保有するリンパ球であってもよい。様々なエフェクター細胞には、細胞傷害性T細胞及びNK細胞が含まれる。治療様式の組み合わせ、すなわち、直接的な細胞傷害活性と、ErbB2の阻害または低減は、ErbB2過剰発現がんの処置に治療的利益をもたらすであろう。
がんを有する人々のうちのおよそ60%は何らかの種類の外科手術を受けることになるが、これには、防止、診断または病気判定、治癒及び緩和のための外科手術が含まれる。治癒的外科手術は、他の療法、例えば、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、免疫療法及び/または代替療法と併せて用いられるがん処置である。
他の薬剤を本実施形態の特定の態様と組み合わせて用いて処置の治療的有効性を向上させ得ることが想定される。これらの付加的薬剤としては、例えば、細胞表面受容体及びギャップ結合の上方制御に影響を与える薬剤、細胞増殖抑制剤及び分化剤、細胞接着阻害薬、アポトーシス誘導薬に対する過剰増殖細胞の感受性を増大させる薬剤、または他の生物学的薬剤が挙げられる。ギャップ結合の数を多くすることによって細胞間シグナル伝達を増加させることは、隣接する過剰増殖細胞集団に対する抗過剰増殖作用を増加させるであろう。他の実施形態では、細胞増殖抑制剤または分化剤を本実施形態の特定の態様と併せて使用して処置の抗過剰増殖有効性を向上させることができる。本実施形態の有効性を向上させるためには細胞接着を阻害することが考えられる。細胞接着阻害薬の例は焦点接着斑キナーゼ(FAK)阻害薬及びロバスタチンである。さらに、アポトーシスに対する過剰増殖細胞の感受性を増大させる他の薬剤、例えば抗体c225を本実施形態の特定の態様と併せて使用して処置有効性を向上させることができることが考えられる。
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。当業者であれば、以下の実施例で開示されている技術が、本発明の実施において十分に機能する本発明者によって発見された技術を表すこと、したがってその実施のための好ましい形態を構成するとみなすことができることを認識するはずである。しかしながら、本開示に鑑みて、開示される具体的実施形態に多くの変更を加えてなおも同様の、または類似した結果を本発明の趣旨及び範囲から逸脱することなく得ることができることは、当業者であれば認識するはずである。
成長因子受容体結合タンパク質2(Grb2)は、がん細胞シグナル伝達に必須であり、がん化チロシンキナーゼによって利用されてRas及びERKを活性化させる。BP1001は、Grb2発現を阻害する、リポソームに組み込まれたアンチセンスである。試験のねらいは、血液悪性腫瘍を有する患者におけるBP1001の安全性、最大耐量(MTD)、薬物動態及び抗白血病活性を画定することであった。
BP1001の臨床的活性を移行期または芽球期のCML患者で研究することになる。移行期及び芽球期の患者へのイマチニブの奏効は乏しいかまたは短期的である。これらの患者は他のチロシンキナーゼ阻害薬、例えば、ダサチニブ、ニロチニブ、ボスチニブ及びポナチニブで処置されることが多い。ここでは、BP1001がダサチニブ、ニロチニブ、ボスチニブ及びポナチニブのCML細胞における阻害効果を強化することができるか否かを判定した。
試験の原理的説明。第Ib期試験には、移行期または芽球期のPh+ CMLを有する参加者が登録されることになる。参加者はBP1001に加えてDasを受けることになる。これは非盲検シングルアーム治験である。第Ib相試験で処置を受けるのに適格な参加者は、BP1001(コホート1では60mg/m2、またはコホート2では90mg/m2)及び同じ用量レベルのDas(140mg)を受けることになる。第IIa相のための用量が同定された時点で、第IIa相での処置を受けるのに適格な全ての参加者はBP1001とDasとについて同じ用量レベルを受けることになる。この試験では無作為化を行わないこととする。
1.18歳以上の成人
2.女性は、出産潜在能を有さない者、外科的に不稔である者、閉経後である者、または適切な避妊方法を試験中及び試験薬もしくはDasの最終投薬後30日間に実施する者でなければならない
3.男性は、適切な避妊方法を試験中及び試験薬もしくはDasの最終投薬後少なくとも30日間に用いることに同意せねばならない
4.組織学的証拠によって支持されている、移行期または芽球期のPh+ CMLの診断。芽球期は、末梢血中または骨髄中の芽球が30%以上であること、または肝臓もしくは脾臓におけるものを除く髄外性疾患の存在として定義される。移行期CMLの基準を満たすには以下のパラメータのうちの1つが必要とされる:
a.末梢血中または骨髄中の芽球≧15%
b.末梢血中または骨髄中の前骨髄球及び芽球≧30%
c.PBまたはBM好塩基球≧20%
d.療法に起因しない血小板減少症<100×103/ml
e.細胞遺伝学的
5.以下によって定義される十分な肝及び腎機能:
a.アスパラギン酸アミノ基転移酵素(AST)及びアラニンアミノ基転移酵素(ALT)≦基準範囲上限(ULN)の2.5倍;かつ
b.総ビリルビン≦1.5ULN;かつ
c.少なくとも50ml/分の推定糸球体濾過量(eGFR)。血中尿素窒素(BUN)及びクレアチニンの試験をベースラインで実施するときにCockcroft−Gault式を利用してeGFRを決定することになる。安全性保証のためにeGFR血清クレアチニンとBUNとの組み合わせを使用して患者の腎機能を評価することになる。
(i)Cockcroft−Gault式:推定クレアチニンクリアランス=[(140−年齢)×総体重]/(血清クレアチニン×72)
(ii)女性の場合は0.85を掛ける
6.証拠によって支持されている米国東海岸がん臨床試験グループ(ECOG)の全身状態が0、1または2(表9)であること
7.以前のいかなる外科手術、放射線療法または抗新生物薬処置の影響(脱毛症を除く)から回復していること
8.書面でインフォームドコンセントを提供することに意欲的でありそれができること。
1.T315I突然変異を有する患者は排除されないが個別に奏効が分析されることになる
2.過去2年間におけるCML以外の別の原発性悪性腫瘍(非メラノーマ皮膚癌または子宮頸部上皮内癌は除く)
3.クモ膜下腔内療法を必要とする既知の活動性軟髄膜白血病。注:CNS疾患の病歴を有する患者は、スクリーニング前に少なくとも2回連続して陰性の髄液評価が証拠によって支持されていることに基づいて、参加が容認され得る。
4.白血病についての骨髄基準も満たすことなく単離される髄外性白血病
5.BP1001開始から14日以内に、ヒドロキシ尿素もしくはアナグレリドまたはTKI(2日以内)を除く何らかの抗がん療法を受けていること
6.制御されず活動性で未処置または進行性である感染症
7.BP1001開始から14日以内または5半減期以内に何らかの研究薬剤を受けていること
8.妊娠している、妊娠試験陽性である、もしくはスクリーニング期間中に授乳中である、または試験の過程中もしくは試験薬の最終投薬後30日以内に妊娠することもしくは授乳することを意図している、女性
9.以前におけるBP1001への曝露
10.Dasに対する不耐性の過去を有する、またはDasが適さない可能性がある、患者
11.参加者の試験完遂能力に干渉するであろう重篤な併発性の医学的病気または精神病
12.活動性/慢性B型肝炎感染症(陽性表面抗原[HBsAg]に基づく)、C型肝炎感染症(陽性抗体[HCV Ab]に基づく)、またはヒト免疫不全ウイルス(HIV−1またはHIV−2、陽性抗体に基づく)
13.試験処置を忍容する参加者の能力を損なうおそれ、または試験遂行もしくは結果解釈の何らかの側面に干渉するおそれがある同時進行的症状の存在。これには、限定されないが、不安定狭心症もしくは制御されない狭心症、ニューヨーク心臓協会(NYHA)のクラスIIIもしくはIVの鬱血性心不全、制御されず持続している高血圧、臨床的に重大な不整脈、または臨床的に重大なECG異常(例えば、QTcF>470msec)が含まれる。
14.過去6ヶ月間に以下のいずれかがあった:胸膜滲出、心筋梗塞、不安定狭心症、冠動脈/末梢動脈バイパス移植、脳血管事故、または一過性脳虚血性発作
15.制御されない発作障害(すなわち過去2ヶ月間の発作)
16.何らかの理由で、研究者との意思疎通ができない、もしくは意欲的でない、または協力をしない、あるいはプロトコールに従わない
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Claims (58)
- がんの処置を、それを必要とする患者に施す方法であって、
前記患者においてGrb2核酸とハイブリダイズするヌクレアーゼ耐性ポリヌクレオチドを含む有効量の第1薬物療法、及び
Bcr−Ablチロシンキナーゼ阻害薬を含む第2薬物療法
を前記患者に投与することを含む、前記方法。 - 前記ポリヌクレオチドがGrb2核酸の翻訳開始部位とハイブリダイズする、請求項1に記載の方法。
- 前記ポリヌクレオチドが、8〜50塩基の長さを有するオリゴヌクレオチドである、請求項1か請求項2かのどちらかに記載の方法。
- 前記ポリヌクレオチドが、配列番号1で示される配列を有する、請求項1〜3のいずれか1項に記載の方法。
- 前記ポリヌクレオチドがP−エトキシ主鎖結合を含む、請求項1〜4のいずれか1項に記載の方法。
- 前記ポリヌクレオチドがリポソーム中に封入されている、請求項1〜5のいずれか1項に記載の方法。
- 前記第1薬物療法がさらに中性脂質を含む、請求項1に記載の方法。
- 前記第1薬物療法が全身投与される、請求項1に記載の方法。
- 前記第1薬物療法が動脈内または静脈内への投与のために製剤化される、請求項1に記載の方法。
- 前記第1薬物療法が約60mg/m2〜約90mg/m2の投薬量で投与される、請求項7に記載の方法。
- 前記第1薬物療法が週に2〜4回投与される、請求項7に記載の方法。
- 前記Bcr−Ablチロシンキナーゼ阻害薬がダサチニブ、イマチニブ、ニロチニブ、ボスチニブ、ポナチニブまたはバフェチニブである、請求項1に記載の方法。
- 前記Bcr−Ablチロシンキナーゼ阻害薬がダサチニブである、請求項1に記載の方法。
- 前記ダサチニブが約140mgの投薬量で投与される、請求項13に記載の方法。
- 前記ダサチニブが1日1回投与される、請求項13に記載の方法。
- 前記第2薬物療法が全身投与される、請求項1に記載の方法。
- 前記第2薬物療法が、経口、動脈内または静脈内投与される、請求項16に記載の方法。
- 前記第1薬物療法が、前記第2薬物療法の投与に先立って投与される、請求項1に記載の方法。
- 前記第1薬物療法及び前記第2薬物療法が同時発生的に投与される、請求項1に記載の方法。
- 前記第1薬物療法及び前記第2薬物療法が別個の経路で投与される、請求項1に記載の方法。
- 前記患者がヒトである、請求項1に記載の方法。
- 前記がんが、大腸癌、神経芽腫、乳癌、膵臓癌、脳癌、肺癌、胃癌、血液癌、皮膚癌、精巣癌、前立腺癌、卵巣癌、肝臓癌または食道癌、子宮頸癌、頭頸部癌、非メラノーマ性皮膚癌または神経膠芽腫である、請求項1に記載の方法。
- 前記がんが血液癌である、請求項1に記載の方法。
- 前記血液癌が、慢性骨髄性白血病(CML)、急性骨髄性白血病(AML)または骨髄異形成症候群(MDS)である、請求項23に記載の方法。
- 前記CMLが移行期CMLまたは芽球期CMLである、請求項24に記載の方法。
- 前記CMLまたはAMLがBcr−Abl陽性CMLまたはBcr−Abl陽性AMLである、請求項24に記載の方法。
- 前記Bcr−Abl陽性CMLまたはBcr−Abl陽性AMLがT315I Bcr−Abl突然変異について陽性である、請求項26に記載の方法。
- 前記CMLまたはAMLがフィラデルフィア染色体陽性CMLまたはフィラデルフィア染色体陽性AMLである、請求項24に記載の方法。
- 前記患者が、以前にイマチニブによる処置が失敗した者である、請求項1に記載の方法。
- がんまたは骨髄異形成症候群(MDS)の処置を、それを必要とする患者に施す方法であって、
Grb2核酸とハイブリダイズするヌクレアーゼ耐性ポリヌクレオチドを含む有効量の第1薬物療法、及び
シチジン類縁体を含む第2薬物療法
を前記患者に投与することを含む、前記方法。 - 前記ポリヌクレオチドがGrb2核酸の翻訳開始部位とハイブリダイズする、請求項30に記載の方法。
- 前記ポリヌクレオチドが、8〜50塩基の長さを有するオリゴヌクレオチドである、請求項30か請求項31かのどちらかに記載の方法。
- 前記ポリヌクレオチドが、配列番号1で示される配列を有する、請求項30〜32のいずれか1項に記載の方法。
- 前記ポリヌクレオチドがP−エトキシ主鎖結合を含む、請求項30〜33のいずれか1項に記載の方法。
- 前記ポリヌクレオチドがリポソーム中に封入されている、請求項30〜34のいずれか1項に記載の方法。
- 前記第1薬物療法がさらに中性脂質を含む、請求項30に記載の方法。
- 前記第1薬物療法が全身投与される、請求項30に記載の方法。
- 前記第1薬物療法が動脈内または静脈内への投与のために製剤化される、請求項30に記載の方法。
- 前記第1薬物療法が約60mg/m2〜約90mg/m2の投薬量で投与される、請求項36に記載の方法。
- 前記第1薬物療法が週に2〜4回投与される、請求項36に記載の方法。
- 前記シチジン類縁体がデシタビン、シタラビンまたはアザシチジンである、請求項1に記載の方法。
- 前記シチジン類縁体がデシタビンである、請求項41に記載の方法。
- 前記シチジン類縁体がシタラビンである、請求項41に記載の方法。
- 前記シタラビンが約20mgの投薬量で投与される、請求項43に記載の方法。
- 前記シタラビンが1日2回投与される、請求項43に記載の方法。
- 前記シタラビンが皮下投与される、請求項43に記載の方法。
- 前記第1薬物療法が、前記第2薬物療法の投与に先立って投与される、請求項30に記載の方法。
- 前記第1薬物療法及び前記第2薬物療法が同時発生的に投与される、請求項30に記載の方法。
- 前記第2薬物療法が、前記第1薬物療法の投与に先立って投与される、請求項30に記載の方法。
- 前記第1薬物療法及び前記第2薬物療法が別個の経路で投与される、請求項30に記載の方法。
- 前記患者がヒトである、請求項30に記載の方法。
- 前記がんが、大腸癌、神経芽腫、乳癌、膵臓癌、脳癌、肺癌、胃癌、血液癌、皮膚癌、精巣癌、前立腺癌、卵巣癌、肝臓癌または食道癌、子宮頸癌、頭頸部癌、非メラノーマ性皮膚癌または神経膠芽腫である、請求項30に記載の方法。
- 前記がんが血液癌である、請求項52に記載の方法。
- 前記血液癌が、慢性骨髄性白血病(CML)、急性骨髄性白血病(AML)または骨髄異形成症候群(MDS)である、請求項53に記載の方法。
- 前記CMLが移行期CMLまたは芽球期CMLである、請求項54に記載の方法。
- 前記CMLまたはAMLがBcr−Abl陽性CMLまたはBcr−Abl陽性AMLである、請求項54に記載の方法。
- 前記Bcr−Abl陽性CMLまたはBcr−Abl陽性AMLがT315I Bcr−Abl突然変異について陽性である、請求項56に記載の方法。
- 前記CMLまたはAMLがフィラデルフィア染色体陽性CMLまたはフィラデルフィア染色体陽性AMLである、請求項54に記載の方法。
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EP3512525B1 (en) | 2022-07-27 |
CA3034637A1 (en) | 2018-03-22 |
EP3512525A1 (en) | 2019-07-24 |
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