JP6253160B2 - 腫瘍上の機能化ナノチューブの標的とする自己組織化 - Google Patents
腫瘍上の機能化ナノチューブの標的とする自己組織化 Download PDFInfo
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Description
この国際出願は、米国仮特許出願第61/581,228号に対して、特許法第119条(e)項の下で、優先権の利益を主張するものであり、この全体は引用によって本明細書に組み込まれる。
本発明は、国立衛生研究所によって与えられた助成金PO1 CA33049、RO1 CA55349、R21 CA128406、および、GM07739、ならびに、米国エネルギー省によって与えられた助成金DE−SC0002456の下、政府の支援で行われた。政府は本発明において一定の権利を有している。
ナノ医学の急速に拡大しつつある分野は、操作された薬物のナノ粒子の第一世代で臨床的な成功を収めるようになった(1−2)。ナノ医学は、薬物の送達または効能を改善するために、材料の大きさ、形状、および電荷を利用することを目標とする、合成のナノスケール粒子の使用を含んでいる。加えて、ナノ材料の固有の特性のなかには、独特の物理化学的な性質をもたらすものもある。カーボンナノチューブは生物医学研究の広範な用途で見られ(3)、これは部分的には、小分子(4)、ペプチド(5−6)、オリゴヌクレオチド(7)、放射性同位体(8)、モノクローナル抗体(9−10)、および、標的部分とする部分を含む、多様なリガンド群を添える可能性があるためである。
(方法と材料)
(SWNTの修飾)
高純度(>90%)単層カーボンナノチューブNanoLab社(マサチューセッツ州ウォルサム)から入手した。これらの、アーク放電により生成された単層カーボンナノチューブを、記載されたプロトコル(33)に従って反応させてSWNT−NH2を得た。SWNT−NH2生成物を適用によってC18 Seppak(Waters)で精製し、20%のアセトニトリルと0.1Mトリエチルのアミン酢酸中で洗浄した。精製された生成物を50%アセトニトリルと水で溶出させた。その後、この溶液を凍結乾燥させて暗褐色のSWNT−NH2固体を得るか、あるいは、炭酸水素塩バッファー(0.1M Na HC03,pH9)に直接入れて希釈した。SWNT−NH2に、0.6mmol/gのPEG4/PFB(Solulink)長鎖架橋剤を加えた。この反応を室温で2時間進めた。その後、反応混合物を使い捨てのbenchtop 10−DGサイズ排除カラム(Biorad)上で精製させ、SWNT−4FB−NH2生成物を有するアルデヒドおよびアミンを、0.1M MES、0.15MのNaCl、pH 5.5バッファーに溶出させた。
モルホリノオリゴヌクレオチド(MORF、配列:TCTTCTACTTCACAACTA、SEQ ID No:1)cMORF、配列:TAGTTGTGAAGTAGAAGA、SEQ ID No: 2)を、カスタム合成し(Gene Tools社)、3’末端に一級アミンを含ませた。抗体またはナノチューブにそれぞれ共役するために、アルデヒドまたはヒドラジンの部分のいずれかで一級アミンをキャッピングした。20%アセトニトリルを含む0.1M 炭酸水素ナトリウムバッファー中の20倍の過剰なサクシニミジル 4−ホルミル安息香酸(Thermo Scientific)またはサクシニミジルヒドラジノニコチンアミド(Thermo Scientific)と、MORF−NH2/cMORF−NH2を反応させた。遊離リンカー(free linker)を、10−DGカラム(Bio−Rad)のゲル濾過クロマトグラフィーによって除去し、モルホリノを精製して、0.1M MES、0.15M NaCl、pH 5.5のバッファーにする。
SWNT−cMORF−NH2を、Chelex 100レジン(Bio−rad)で事前に処理した0.1Mの炭酸水素ナトリウムのバッファーに溶解させて、バッファーに二価金属を含ませないようにした。この溶液に、10mmol/gのアミン反応性2−(4−イソチオシアナトベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−四酢酸(DOTA−SCN、Macrocyclics)の割合で加えられた。この反応を2時間室温で維持し、その後、25mMのDTPAで事前に処理された10−DGゲル濾過カラムで精製し、マトリックス金属が含まないようにした。生成物を、金属を含まない蒸留させたH2Oに溶出し、凍結乾燥させて固体のSWNT−cMORF−DOTA生成物を得た。50°Cで0.5時間、20%アセトニトリルを含有する酢酸アンモニウムバッファ(1M)、pH5に放射性同位体を加えることによって、この生成物を111InCl3(MDS Nordion)を用いて放射標識した。標識混合物を50mMのDTPAを加えることでクエンチし、10−DGゲル濾過カラムで精製してPBSに入れた。10mMのEDTAと0.9%のNaCL/10 mMのNaOHの移動相を使用して、即時の薄層クロマトグラフィーによって放射化学的純度を測定した(8)。ITLCストリップを、System400 Imaging Scanner(Bioscan社)を用いて計測した。5度の標識化反応の繰り返しの間、放射化学的純度は>90%であり、
HPLCでの放射線検出によって確認された。
すべての高性能液体クロマトグラフィーを、インラインγ−Ramモデル3放射能検出器(IN/US)が装備された、System Gold Bioessential 125/168ダイオードアレイ検出器具(Beckman Coulter)で行った。分析は、32カラット・クロマトグラフィ・ソフトウェア(Beckman Coulter)と、Prismグラフおよび分析ソフトウェア(Graphpad)の両方を使用して行なった。ゲル濾過クロマトグラフィーは、20mMの酢酸ナトリウム、0.15Mの塩化ナトリウム、pH6.5の均一濃度の移動相中で、Superdex 200カラムで行なわれた。逆相HPLCは、100%アセトニトリルに対して0.1MのTEAA中の20%アセトニトリルの勾配で、Gemini C18カラム(Phenomenex)で行なわれた。抗体ナノチューブハイブリダイゼーションアッセイについては、特に明記しない限り、HPLCカラムへの注入の5分前に、150μLの全容量のリン酸塩緩衝食塩水にサンプルを混合した。
LS174T細胞を、50,000の細胞/mLで24時間、組織培養物で処理された、ポリリジンをコーティングされた、複数のウェルの区画があるスライド(Nunc)に播種した。スライドを、37°Cで4時間、抗−A33−MORF、抗A33、または、対照の抗−CD19−MORFの10nMの抗体の1つで処理した。その後、非結合の抗体を洗い流し、細胞を、培地のみ、7.5μg/mLのSWNT−cMORF−AF647共役を含有する培地、100nMの蛍光標識したcMORF−AF647を含有する培地で処理した。その後、細胞を4時間以内37°Cインキュベートした。指定された時点(30分、1時間、4時間)で、細胞をPBSで洗浄し、4%の中性のバッファーしたパラホルムアルデヒドで固定した。抗A33抗体を視覚化するために、0.5%のBSAおよび0.2%のトリトン−Xを含有しているPBSのバッファーで細胞を透過性にし、その後、Alexa Fluor 488標識された抗ヒトIgG(Invitrogen)の1:500希釈液で染色した。染色後、細胞を洗浄し、DAPI核染色(Invitrogen)を含むProlong Gold培地に乗せた。SWNT−cMORFおよびcMORFは、添加されたAF647フルオロフォアによって直接視覚化することができる。撮像はレーザースキャニング共焦点画像解析(Leica)で行い、設定は様々な細胞処理条件の視覚化の間、維持される。
Daudi B細胞リンパ腫、LS174T結腸腺癌、および、HL60前骨髄性白血病細胞株をATCCから入手し、5%CO2中、37°Cで、10%FBSを含有しているRPMI内で培養した。GFPトランスフェクトDaudiを、先に記載されたように、レトロウイルストランスフェクションで精製した(9)。フローサイトメトリーアッセイの前に、ブロッキング剤として、2%ヒト血清、指定がある場合は100%ヒト血清を含有する氷冷リン酸塩緩衝食塩水(PBS)中に細胞を懸濁させた。懸濁培養物を遠心分離と再懸濁によって洗浄し、その間、付着細胞を、EDTA(Gibco)を含有する0.05%トリプシンでトリプシン処理し、その後、洗浄した。懸濁液中の細胞を、氷上で、または、37°Cで、1時間、10nMのmAb−MORFと最初に結合させた。mAb−MORF処置後、細胞を結合バッファーで洗浄して、その後、最大で10g/mLの広範な濃度で、SWNT−cMORF−AF647共役と結合させた。細胞を遠心分離/再懸濁によって洗浄し、Accuri C6フローサイトメーター(Accuri社)で読み取った。Flojo分析ソフトウェア(TreeStar社)を用いてデータを処理した。
すべてのマウスが生後4−6週のメスのNCI nu/nuであり、動物研究はすべて研究機関の動物実験委員会(Institutional Animal Care and Use Committee)の承認のもとで行われた。Daudiリンパ腫モデルについては、Daudi細胞を懸濁液で培養し、その後、0.9%NaCl(Hospira社)中の冷たいPBSと再懸濁液で洗浄した。その後、マウスに、マウス一匹当たり2000万個の細胞を注入した。6時間後、マウスを、Daudi特異的な抗CD20リツキシマブ(抗CD20−MORF)またはアイソタイプ対照抗CD33 HuM195(抗CD33−MORF)のいずれかの3μgのモルホリノ共役で処理した。16時間後、2μgのSWNT−cMORF−AF647をマウスに腹腔内から注入した。SWNT−cMORF−AF647を4時間循環させて標的化させ、その後、マウスを屠殺し、よく冷えたPBSで腹腔内空洞を洗浄することによって、リンパ腫細胞を集めた。この細胞懸濁液をPBSで洗浄し、破片を取り除くために細胞濾過機(cell strainer)に通し、Accuri C6フローサイトメーターにかけた。FL1経路内でDaudi−GFP細胞について細胞懸濁液をゲート選別(gating)し、その後、FL4経路内でSWNT−cMORF−AF647の蛍光を測定した。FloJoフローサイトメトリーソフトウェア(TreeStar社)でデータを分析した。
SWNT−cMORF−DOTAを、以前に記載したように、99.7%の放射化学的純度で111Inで標識化した。生後4−6週の30BALB/cマウス(NCI Labs)を、各郡5匹ずつの6つの群に無作為化した。それぞれのマウスに、無菌の生理食塩水200uL中の3200nCiのSWNT−cMORF−111In(DOTA)を腹腔内注入した。マウスを、1、4、8、12、および24時間後に屠殺した。排泄された尿および糞便を含むケージからの寝具を定量化のために集めた。腎臓、肺、筋肉、心臓、血液、肝臓、脾臓、腸、および骨を屠殺したマウスから採取し、以前に記載したように、各臓器の%注入量を定量化した。
SWNT−cMORF−DOTAを98.4%の放射化学的純度の225Acで標識化した。45 のBALB/cマウス(NCl Labs)は生後4−6週である。マウスを5匹の9つの群に無作為に分けて、表1に示されるような単回注入を受けさせた。
SWCNT−cMORF−DOTAを、96%の放射化学的純度で、225Acで標識化した。モルホリノのタグをつけたリツキシマブ(1つの抗体当たり3.5のMORF)を、以前に詳述したように生成した。HL60細胞とモルホリノタグを付けたHum195(1つの抗体当たり3.74MORF)を有する交雑種の対照(cross control)におけるレポーターとして、111In標識化したSWCNT−cMORF−DOTAを用いて、試薬の結合選択性をインビトロで確認した。生後4−6週のCB17SC−FSCIDマウス(Taconic Labs)に、200uLのPBS中の2000万のホタルルシフェラーゼ発現Daudiリンパ腫細胞を腹腔内に注入した。1週間後に、マウスを撮像して、IVIS200 Imaging System(Caliper Sciences)を用いる治療実験で使用されるすべてのマウスの腫瘍の成長を確認した。撮像は、5mg/mLのルシフェリン200μLの腹腔内注入の5分後に行った。
(SWNTのオリゴヌクレオチド修飾および放射能標識)
本明細書で使用されるアミンで機能化した単層カーボンナノチューブ(図1A,1)を、記載されたように、アゾメチンイリドの共有結合的な環化付加によって、高純度のアーク生成単層カーボンナノチューブまたはHiPCO SWNTから調製した(27−28)。この反応は、二官能性放射性金属キレート、フルオロフォア、または、修飾抗体(cMORF)に相補的なモルホリノオリゴヌクレオチドへの付着部位として機能するために一級アミンで終端し得る単層カーボンナノチューブの側壁に、親水性の鎖を付着させた。そのようにして調製された単層カーボンナノチューブ構成物は、約100乃至約300nmまでの長さに及ぶこともある。調製された構成物は、DLSおよびTEMによって平均長さは350nmであり、2.5オングストローム当たり12の炭素原子を与える、約1.2nmの直径を備えていた。
(SWNT−cMORFは、インビトロでの、および、37°の血清存在下で複数の異なるmAb−MORFとハイブリッド形成する)
SWNT−cMORF共役への抗体−MORFのハイブリダイゼーションは、HPLCによってモニタすることができる(図2A−2D)。HPLCサイズ排除カラム(Superdex 200)におけるSWNT−cMORF共役の均一濃度の水性の移動相の溶出は、後の広い帯域として生じた。溶出の遅れは、単層カーボンナノチューブの高い分子量にもかかわらず、SWNTの高異方性の形状に起因しており、これは一般的なゲル濾過マトリックスにおいて伸長した高分子を非常に遅らせることで知られている(9と33)。このピークはSWNTと一致するスペクトル特徴を有していた。mAb−MORF共役だけが、溶出時間が約18分であり、これはタンパク質基準に基づいて〜150,000Daの分子量と一致していた。
(SWNT−cMORFは、高親和性を備えた特異的なmAb−MORF構成物であらかじめ標的化された細胞上自己組織化可能である)
SWNT−cMORFは、相補的なオリゴヌクレオチド配列を含有するmAb−MORFによって特異的に結合した腫瘍細胞表面上で自己組織化された。それぞれ抗CD20(リツキシマブ)、抗CD33(Hum195)、および、抗A33モノクローナル抗体によって標的化された3つの異なる癌細胞株、Daudi(B細胞リンパ腫)、HL60(前骨髄性白血病)、および、LS174T(結腸腺癌)を使用した。抗体はすべてヒトIgG1アイソタイプであった。細胞を特異的なまたはアイソタイプ対照の抗体−MORFでインキュベートし、その後、蛍光標識したSWNT−cMORF(図1A、4)により処理した。対照として、特異的なmAb−MORF共役で標的化した細胞を、SWNT−cMORFの追加前に過剰なcMORFでブロックした。蛍光標識した単層カーボンナノチューブの結合を、フローサイトメトリーによって測定されるような中央の蛍光強度の変化として定量化した。
(抗体によって標的化された腫瘍細胞でのSWNT−cMORFの自己組織化は、標的抗原のキャッピングと自己組織化した複合体の内在化につながる)
腫瘍細胞上でのSWNT−cMORFの自己組織化を実証した後、細胞表面の自己組織化したSWNT−(cMORF−(mAB−MORF))複合体の運命が決定された。LS174T細胞に結合した後の抗A33抗体および抗A33/単層カーボンナノチューブ複合体を追跡するために、一連の共焦点顕微法研究が行なわれた。蒔かれた細胞を抗A33または抗−A33−MORFで処理し、洗浄し、最大24時間、培地で37°Cでインキュベートした。
(SWNT−cMORFは、インビボのあらかじめし標的化した腫瘍で選択的に自己組織化できる)
SWNT−cMORFがインビトロの特定の癌細胞上で自己組織化ことができることを実証したため、次はこの活性を生きたマウスで評価した。これはまず、細胞当たりxのレベルのCD20を発現するDaudiリンパ腫モデルの腹腔内(i.p.)で行われた。エキソビボのフローサイトメトリーによって標的細胞を定量化することができるようにすべく、GFPトランスフェクトしたDaudi B細胞リンパ腫、Daudi−GFPを用いた(9)。マウスにDaudi−GFP細胞を腹腔内に注入し、24時間後、特異的な抗CD20−MORFまたは抗CD33−MORFアイソタイプ対照のいずれかを注入した。その後、マウスを蛍光標識したSWNT−cMORFで処理し、6時間後にマウスを屠殺し、リンパ腫細胞を採取した。その後、細胞懸濁液をフローサイトメトリーで分析した。緑の陽性細胞についてゲート選別することによってDaudi−GFP細胞を追跡し、その後、FL4経路内のSWNT−cMORF−Alexa Fluor647の蛍光について分析した。ゲート選別されたDaudi細胞の中央の蛍光強度の20倍の増加が、抗CD20 mAb−MORF処理された動物からのFL4経路(図5A−5B)で観察され、採取された細胞中の標的への特異的な結合が確認された。アイソタイプ対照抗体で処理された動物は、結合または自己組織化を証明しなかった。
(225Acの送達ビヒクルとしてのSWNT−cMORF−DOTAの使用は、放射性同位体の毒性を和らげ、リンパ腫の効果的な治療をもたらす)
固形および播種性の悪性腫瘍の両方を標的化する能力を実証したため、我々は、SWNT−cMORF構成物が、ヒトのリンパ腫の治療モデルで有効な担体であることを証明しようとした。放射免疫療法のための任意のあらかじめ標的化したビヒクルの重要な特性は、第2の薬剤の迅速なクリアランスが、細胞毒性のエフェクターの循環時間の減少により、治療指数の改善をもたらすということである。多くの研究がかつて行われ、共有結合的に機能化したSWNTが、18−merのオリゴヌクレオチドを追加した後でさえ、この迅速なクリアランスを有していることを実証した(35)。本明細書に記載の構成物を用いて行われた同様の生体内分布実験は、同様のクリアランス特性を実証した。生体内分布は、注入の1、4、8、12、および24時間後に、全放射および%注入量の両方として評価された(補足情報を参照)。予想されたように、総注入量のほとんど(〜77%ID)が24時間で排泄(大部分は尿で)された。残りの大部分の放射線は腎臓(2.96% ID)に局在化された。
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Claims (4)
- 癌細胞への治療用の放射性核種の内在化のための自己組織化単層ナノチューブ系であって、癌細胞に選択的なモノクローナル抗体に連結された配列番号1で示される配列からなるモルホリノオリゴヌクレオチドを有する第1の構成成分、および、
それぞれ配列番号2で示される配列からなり、それぞれ単層ナノチューブに連結された複数の相補的なモルホリノオリゴヌクレオチド及び複数の相補的モルホリノオリゴヌクレオチドとは独立に、二官能性キレート剤を介して単層ナノチューブにそれぞれ連結された複数の治療用アクチニウム−225分子を含む第2の構成成分からなる自己組織化単層ナノチューブ系。 - モノクローナル抗体は、抗CD20、抗CD33、または、抗A33のモノクローナル抗体、あるいは、その一本鎖可変領域断片(scFv)または断片抗原結合(Fab)断片である、請求項1に記載の自己組織化単層ナノチューブ系。
- 癌細胞は、リンパ腫癌細胞、白血病癌細胞、または結腸癌細胞である、請求項1に記載の自己組織化単層ナノチューブ系。
- 二官能性キレート剤は、(4−イソチオシアナトベンジル)−1,4,7,10−テトラアザシクロドデカン−1,4,7,10−四酢酸(DOTA)またはジエチレントリアミンペンタ酢酸(DTPA)である、請求項1に記載の自己組織化単層ナノチューブ系。
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