JP2016537020A - 腫瘍溶解性hsvベクター - Google Patents
腫瘍溶解性hsvベクター Download PDFInfo
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- JP2016537020A JP2016537020A JP2016552209A JP2016552209A JP2016537020A JP 2016537020 A JP2016537020 A JP 2016537020A JP 2016552209 A JP2016552209 A JP 2016552209A JP 2016552209 A JP2016552209 A JP 2016552209A JP 2016537020 A JP2016537020 A JP 2016537020A
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Abstract
Description
本特許出願は、2013年10月28日出願の米国仮特許出願第61/896,497号(その内容全体が参照により本明細書に組み込まれる)の優先権を主張する。
本発明は、国立衛生研究所により交付された、補助金番号CA119298、CA163205、CA175052、NS040923、及びDK044935における政府の支援によりなされた。本発明においては、政府が一定の権利を有する。
多形性膠芽腫(GBM)は、併用療法の適用・利用が可能にもかかわらず、一様に致死的な疾患である。前臨床試験は、腫瘍溶解性HSV(「oHSV」)ベクターを含む、複製可能なウイルスが、有望な代替治療手段の典型であるが、患者試験における治療の有効性は限られていることを示唆する。ベクターの安全性の達成は、腫瘍細胞における溶菌複製も無効にし得るベクター突然変異の抑制に依存している。
本発明は、ベクターの、腫瘍関連細胞表面受容体への再標的化(retargeting)と、正常な脳では高度に発現するが、腫瘍細胞中には実質的に存在しない、細胞のマイクロRNA(「miR」)によるベクター複製の阻害とを組み合わせることにより、減衰なく、腫瘍に選択的なベクター複製ができるoHSVを提供する。miR応答性エレメントは、インビトロ又は異種脳腫瘍モデルでの、原発性腫瘍細胞における溶解性のベクター複製を妨げることなく、ヌードマウスの脳においてベクターの病原性を抑える。この新しいベクターの設計は、より安全でより効果的なベクタープラットフォームを提供するはずであり、患者の腫瘍への適用のために、更に発展し得る。
本発明は、細胞(がん細胞等)の表面に存在する分子(タンパク質、脂質、又は炭水化物の決定基)に特異的な非HSVリガンド及び1以上のHSV遺伝子座、好ましくは、正常(即ち、非がん性)細胞におけるHSVの複製に必要な、1以上のHSV遺伝子(複数可)、に挿入された、1以上のマイクロRNA標的配列の、1以上のコピーを含む、組換えoHSVを提供する。本発明は、本発明のoHSVを含むストック及び医薬組成物並びに本発明のoHSVを用いる、腫瘍細胞を殺傷するための方法を更に提供する。
目的:多形性膠芽腫(GBM)は、有効な治療がない、浸潤性の脳腫瘍である。oHSVベクターは、ヒトGBMモデルの治療のために動物において設計されているが、患者の試験においては、有効性は不調と判明した。我々は、ベクターの減衰なく、高度に選択的な腫瘍溶解を実現する新しいoHSV設計の開発を模索してきた。
GBMは、効果的な治療が見つけにくいままの、最も悪性形態のがんの一つである。手術並びに放射線及び化学療法等の標準的な医療行為では、長期の臨床効果が限られることがわかっている。単純ヘルペスウイルス1型(oHSV−1)由来のものを含む腫瘍溶解性ベクターは、代替治療戦略の候補として、多くの研究室で開発中である(1)。oHSVベクターは、原発性GBMの動物モデルの治療に有望なことが示されているが、良好な安全性プロファイルを提供するのとは別に、初期の臨床試験からの結果は、有効な腫瘍殺傷、又は患者の生存における、一貫性のある改善を示していない(2)(3)。
miR−124応答エレメントの検証。ニューロンにおいて、GBM細胞よりも高レベルで発現する複数のmiRNAのうち、miR−124が最も量が多く、GBMでの発現は最少である(6)。我々は、異なる8ヌクレオチド(nt)のスペーサーによって分離された、成熟miR−124の逆相補配列の、タンデムの4コピーから成るmiR−124応答エレメント(T124)を設計した。この配列の機能性を評価するために、我々は、それをホタルルシフェラーゼ(fLuc)発現プラスミドの3’UTRに挿入し、ほとんど又は全くmiR−124を発現しないと報告されているU2OS骨肉腫細胞に対する共トランスフェクション実験を、特異的(pre−miR−124)又は非特異的(pre−miR−21)miRNA前駆体により行った(9)。正規化のために、ウミシイタケルシフェラーゼ(rLuc)発現プラスミドを含めた。結果(pfLuc−T124、図1)は、モックを共トランスフェクションした細胞又はpre−miR−21を共トランスフェクションした細胞と比較して、pre−miR−124と共トランスフェクションした細胞において、24時間での、fLuc活性の極端な低下を示した。対照的に、miR−21配列の4コピーを逆向きに含有するコントロールのfLucプラスミドをトランスフェクションした細胞(pfLuc−Ctrl、モック)と、pfLuc−Ctrlとpre−miR−21又はpre−miR−124のいずれかとを共トランスフェクションした細胞との間には、fLuc発現にほとんど差が観察されなかった(図1)。これらの結果は、miR−124媒介性の、遺伝子発現の制限のための効率的かつ特異的な標的としての、T124エレメントの機能性を実証する。
我々の目標は、完全なウイルス機能を発現するが、GBM−関連受容体を発現する細胞にのみ感染し得、且つ腫瘍中のみで高効率で複製し、正常な脳細胞ではしない腫瘍溶解性HSVベクターを設計することであった。腫瘍選択的感染及び溶解性ウイルスの増殖は、全面的なウイルス侵入再標的化(5)及び正常な脳組織におけるウイルス複製の、細胞性、miRNA媒介性制限との組み合わせに依存した。溶解性感染は、腫瘍表現型、標的受容体及び腫瘍特異的miRNA発現プロファイルの維持に重要な、標的細胞の2つの別個の特性を必要とするので、この、形質導入及び転写後の腫瘍標的化との組み合わせは、非常に安全且つ効果的なoHSVを提供する見込みがある。この一般的戦略は、異なるがんに合わせた標的化及びmiRNAの応答エレメントを用いて、広く適用可能であり、その適用は、同型の個々の腫瘍間で、特定の抗原及びmiRNA発現に差異がある可能性を考慮することによって、パーソナライズ治療に関して最適化し得る。
細胞培養。U2OS、HEK293T及びHEK293AD細胞は、ATCC(Manassas,VA)からのものであり、5〜10%(v/v)のウシ胎児血清(FBS;Sigma,St.Louis,MO)を添加したATCC推奨培地中、37℃で、5%CO2インキュベーター中で増殖させた。安定的にCreリコンビナーゼ(U2OS−Cre)を発現するU2OS細胞株は、レトロウイルス形質導入(Y.M.及びJ.C.G.、未発表の結果)によって作製された。患者由来のGBM30及びGli68の原発性神経膠腫スフェロイド株は、E.A.Chiocca(Harvard Medical School,MA)の好意により提供され、10ng/mLの組換えヒト上皮成長因子(rhEGF)及び10ng/mLの組換えヒト塩基性線維芽細胞成長因子(bFGF)(両方Shenandoah Biotechnology,Warwick,PAから)を加えた、2%(v/v)B27 w/o ビタミンA、2mg/mLアムホテリシンB(Lonza,Walkersville,MD)、100μg/mLゲンタマイシン(Lonza)、2mM L−グルタミン(Cellgro,Manassas,VA)を加えたニューロベイサル(Neurobasal)培地(Gibco/Invitrogen/Life Technologies,Carlsbad,CA)中で増殖させた。
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本実施例は、ベクター分布と殺傷活性の増進のための、マトリクスメタロプロテイナーゼ9による、腫瘍標的化1型oHSVの強化(arming)について説明する。
細胞株。ヒト神経膠芽腫SNB19、U251、U87(Dr.H Okada,University of Pittsburghの好意により提供)、J/A、J/C、J/EGFR[9]、アフリカミドリザル腎臓ベロ細胞及び7b[15]細胞を、標準的な方法により培養した。
MMP9を発現させる、再標的化したmiRにより制御されるベクターのコンストラクト及び特性解析
本研究のためのベクター改変及び設計は、図5Aに図解されており、すべてのウイルス溶解の機能を変化させることを避け、従って正常な脳におけるウイルス増殖を回避しながら、腫瘍細胞において複製及び溶解活性を最大にするよう意図される複数の修飾を含む。
細胞でのMMP−9発現上昇の、腫瘍細胞スフェロイドにおけるHSV伝播に対する影響を評価するために、GBM30及びGBM169細胞を、単一のスフェロイドとして培養し、KMMP9又はKGwウイルスに感染させた(図8A)。5dpiでは、KMMP9は、KGwに比べて、ベクター発現eGFPの分布を増強させることを示した。各スフェロイドにおけるeGFP陽性細胞の定量化は、KMMP9感染スフェロイドにおいて、KGw感染スフェロイドに対する、6dpiでの約1.5倍の増大を実証した(図8B;P=0.006)。
我々は以前、GBM30は、ヌードマウスにおいて、腫瘍細胞接種後20日以内に動物の死に至る、致死性の腫瘍を一貫して確立することを示した[9]。我々は、ヌードマウス[9]における、浸潤性の頭蓋内腫瘍を確立するために、患者由来の、球形成性GBM30細胞を用いた。動物を毎日観察し、罹患の徴候を示した時に安楽死させた。公表された我々の結果と同様に、腫瘍細胞接種後5日目にPBSを同じ定位座標に注入したマウスは、腫瘍細胞移植の数週間以内(中央値18日;図9)に死亡した。対照的に、MMP9を発現するウイルスであるKMMP9、又はコントロールウイルスKGwのいずれかを用いる、腫瘍の治療は、少なくとも35日間、半数の動物を防護し、これら2群についての生存期間中央値は、同等であった(それぞれ29日及び31.5日、P=0.61、ログランク検定)。これらの結果は、MMP9処理された動物の50%が、処理なしの18日と比較して、最大35日生存することを示した(図9)。
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Claims (39)
- (a)がん細胞の表面に存在する分子に特異的である、oHSVキャプシドの表面上に提示される非HSVリガンド、及び;
(b)正常(非がん性)細胞におけるHSV複製に必要なHSV遺伝子の遺伝子座に挿入された1以上のマイクロRNA標的配列の複数コピー
を含む、組換え腫瘍溶解性単純ヘルペスウイルス(oHSV)。 - リガンドが、HSVの表面に露出した糖タンパク質に組み込まれている、請求項1のoHSV。
- ウイルスのエンベロープタンパク質が、gD又はgCである、請求項1又は2のoHSV。
- リガンドが、gDの残基1〜25の間に組み込まれている、請求項1〜3のいずれかのoHSV。
- リガンドが、EGFR又はEGFRvIIIを特異的に結合させることができる、請求項1〜4のいずれかのoHSV。
- リガンドが、細胞受容体を結合させる、一本鎖抗体(scFv)又はペプチド性若しくは非ペプチド性のホルモン又は成長因子である、請求項1〜5のいずれかのoHSV。
- 前記マイクロRNA標的配列が、マイクロRNAの逆相補配列である、請求項1〜6のいずれかのoHSV。
- 前記HSV遺伝子の遺伝子座に挿入された、2以上(タンデムに2、3、4、5、又は6)の前記マイクロRNA標的配列を含む、請求項1〜7のいずれかのoHSV。
- 前記HSV遺伝子の遺伝子座に挿入された、前記マイクロRNA標的配列のタンデムの4コピーを含む、請求項8のoHSV。
- 前記マイクロRNA標的配列の多重コピーが、oHSVゲノム内の、4以上のヌクレオチドのスペーサーによって分離されている、請求項8又は9のoHSV。
- 前記マイクロRNA標的配列(複数可)が挿入されている前記HSV遺伝子が、ICP4である、請求項1〜10のいずれかのoHSV。
- 前記マイクロRNA標的配列(複数可)が、前記HSV遺伝子の3’非翻訳領域(3’UTR)に挿入されている、請求項1〜11のいずれかのoHSV。
- 前記マイクロRNAがmiR−124である、請求項1〜12のいずれかのoHSV。
- 前記マイクロRNAが、miR−122、miR−124、miR−128、miR−137及び/若しくはmiR−199、又はそれらの2以上の組み合わせである、請求項1〜12のいずれかのoHSV。
- (a)がん細胞の表面に存在するタンパク質に特異的な非HSVリガンドであって、EGFR又はEGFRvIIIを特異的に結合させるscFvであり、且つoHSVのgD糖タンパク質の残基1〜25の間に挿入されている、非HSVリガンド、及び
(b)マイクロRNA miR−124の逆相補配列の4コピーであり、それぞれが8ヌクレオチドのスペーサーによって分離され、oHSVゲノムのICP4の3’UTRに挿入された、前記コピー
を含む、組換えoHSV。 - ICP47遺伝子についてのプロモーターと共にディプロイド遺伝子ICP0、ICP34.5、LAT及びICP4の各1コピーを含む内部反復(接合部)領域を欠失している、請求項1〜15のいずれかのoHSV。
- 非カノニカルな受容体を介したベクター侵入を促進するgB遺伝子又はgH遺伝子の突然変異を更に含む、請求項1〜16のいずれかのoHSV。
- 導入遺伝子を更に含む、請求項1〜17のいずれかのoHSV
- 導入遺伝子が、腫瘍溶解性因子をコードする、請求項18のoHSV。
- 導入遺伝子が、oHSVの水平伝播を増強するタンパク質又はポリペプチドをコードする、請求項18のoHSV。
- 導入遺伝子が、メタロプロテイナーゼ9(「MMP9」)をコードする、請求項20のoHSV。
- 導入遺伝子が、がんに対する患者の免疫応答を誘導するタンパク質又はポリペプチドをコードする、請求項18のoHSV。
- 導入遺伝子が、プロドラッグの変換を触媒するタンパク質又はポリペプチドをコードする、請求項18のoHSV。
- 導入遺伝子が、シトシンデアミナーゼ又はチミジンキナーゼをコードする、請求項22のoHSV。
- 導入遺伝子が、プリンヌクレオシドホスホリラーゼ(PNP)をコードする、請求項18のoHSV。
- KGE−4:T124である、請求項1のoHSV。
- 請求項1〜25のいずれかのoHSVをコードする、核酸。
- 細菌人工染色体(BAC)である、請求項26の核酸。
- 請求項1〜25のいずれかのoHSVベクターを含む、ウイルスストック。
- 請求項1〜25のいずれかのoHSV及び医薬的に許容可能な担体を含む、組成物。
- 請求項28のウイルスストック及び医薬的に許容可能な担体を含む、組成物。
- 請求項1〜25のいずれかのoHSV、請求項28のストック、又は請求項29若しくは30の組成物に、前記oHSVが前記がん性細胞に感染するのに十分な条件下で細胞を曝露することを含む、がん性細胞を殺傷する方法であって、それによってがん性細胞内でのoHSVの複製が細胞死をもたらす、方法。
- 細胞がインビボのである、請求項31の方法。
- 細胞が腫瘍内にある、請求項31又は32の方法。
- 腫瘍が多形性膠芽腫である、請求項33の方法。
- 細胞がヒトのである、請求項31〜34のいずれかの方法。
- 腫瘍が動物の脳内にある、請求項33又は34の方法。
- oHSVが、前記oHSV、ストック、又は組成物を動物に頭蓋内注入することによって細胞に曝露される、請求項36の方法。
- 動物がヒトである、請求項37の方法。
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