JP2014504150A - 細胞特異的ターゲティングのためのペプチドに基づいたシステムの組成物 - Google Patents
細胞特異的ターゲティングのためのペプチドに基づいたシステムの組成物 Download PDFInfo
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Classifications
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- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- C12N15/09—Recombinant DNA-technology
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/035—Fusion polypeptide containing a localisation/targetting motif containing a signal for targeting to the external surface of a cell, e.g. to the outer membrane of Gram negative bacteria, GPI- anchored eukaryote proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/85—Fusion polypeptide containing an RNA binding domain
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2810/00—Vectors comprising a targeting moiety
- C12N2810/50—Vectors comprising as targeting moiety peptide derived from defined protein
- C12N2810/80—Vectors comprising as targeting moiety peptide derived from defined protein from vertebrates
- C12N2810/85—Vectors comprising as targeting moiety peptide derived from defined protein from vertebrates mammalian
- C12N2810/855—Vectors comprising as targeting moiety peptide derived from defined protein from vertebrates mammalian from receptors; from cell surface antigens; from cell surface determinants
- C12N2810/856—Vectors comprising as targeting moiety peptide derived from defined protein from vertebrates mammalian from receptors; from cell surface antigens; from cell surface determinants from integrins
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Abstract
Description
本出願は、その全体が参照によって本明細書に組み入れられる2010年11月1日に出願された米国仮特許出願第61/436、127号の利益を主張する。
しかしながら、これら必須のターゲティング因子は未だに達成されていない。従って、治療有効性を高めるための、細胞、特に癌細胞へのsiRNA(及び他の薬剤分子)の標的化送達のための試薬及び方法に対する当該技術におけるニーズが存在したままである。
記載されるナノ粒子システムのモジュール型の性質は、化学合成技術又は組換えDNA技術のいずれかによって異なった薬物結合ペプチドの又はターゲティングペプチドの配列を分子の構造に容易に導入することができるという点で、現在のリポソーム又はナノ粒子の薬剤送達システムに有利な柔軟性を提供する。非限定例では、ナノ粒子ポリペプチドを調製するのに使用されるプラスミドベクターに本発明に係るポリペプチドをコードする核酸をクローニングすることができ、特定のターゲティング配列をその特定の実施形態に導入することができる。別の利点は製造の簡素性であり、その際、組換えベクター又は発現構築物を適切な細胞種に導入することができ(たとえば、ナノ粒子ポリペプチド用のDNA配列を持つプラスミドを細菌細胞に導入する)、ポリペプチドが多量に産生され、特異的な結合、とりわけ、DNAアフィニティカラムを用いて精製される。
態様の1つでは、本発明は、核酸結合ドメイン(NBD)、集合ドメイン(AD)及び細胞ターゲティングドメイン(CTD)を含む単離されたポリペプチドを記載する。他の実施形態では、単離されたポリペプチドはさらに、薬剤結合ドメイン(DBD)を含む。特定の実施形態では、単離されたポリペプチドは以下の断片:AD、CTD、NBD及びDBDを含む。本発明のポリペプチドのドメインは当業者に容易に明らかなように、任意の順序であり得る。本発明はさらに、複数のAD、CTD、NBD及び/又はDBDを含む単一のポリペプチドを記載する。
本発明のポリペプチドは従来の生物学的技法によって調製することができる。態様の1つでは、本発明は、薬剤結合ドメイン(DBD)、集合ドメイン(AD)及び細胞ターゲティングドメイン(CTD)を含むポリペプチドをコードするヌクレオチド配列を有する単離されたポリヌクレオチドを記載する。
特定の実施形態では、ADはタンパク質に基づくポリマーである。他の実施形態では、ADはエラスチン様ポリペプチド(ELP)を含む。
特定の且つ有利な実施形態では、本発明のポリペプチドは1以上の細胞ターゲティングドメイン(CTD)を含む。組換えDNAを含む従来の遺伝子工学技法を用いて、様々な細胞ターゲティングドメインのヌクレオチド配列を包含して、ポリペプチド又はナノ粒子のターゲティングに対するその効果を判定することができる。
本発明の特定の態様では、ポリペプチドは薬剤結合ドメイン(DBD)を含む。DBDは薬剤を結合するポリペプチド配列を含むことができる。用語「剤」又は「薬剤」は、化合物、化合物の混合物、生体高分子、又は生体物質から作られる抽出物を示すのに本明細書で使用される。薬剤には、アルキル化剤、代謝拮抗物質、アントラサイクリン、植物アルカロイド、トポイソメラーゼ阻害剤及びその他の抗癌剤が挙げられる。他の薬剤には、アザシチジン、アザチオプリン、ブレオマイシン、ボルテゾニブ、カルボプラチン、カペシタビン、シスプラチン、クロラムブシル、サイクロホスファミド、シタラビン、ダウノルビシン、ドセタキセル、ドキシフルリジン、ドキソルビシン、エピルビシン、エポチロン、エトポシド、フルオロウラシル、ゲムシタビン、ヒドロキシウレア(カテゴリー化を必要とする)、イダルビシン、イマチニブ、メクロレタミン、メルカプトプリン、メソトレキセート、ミトキサントロン、オキサリプラチン、パクリタキセル、ペメトレキセド、テニポシド、チオグアニン、バルルビシン、ビンブラスチン、ビンクリスチン、ビンデシン及びビノレルビンが挙げられる。
本発明の特定の態様では、ポリペプチドは核酸結合ドメイン(NBD)を含む。特定の実施形態では、ポリペプチドはDBD及びNBDの双方を含む。一部の実施形態では、DBD及びNBDは双方とも核酸を結合することができる。特定の実施形態では、NBDはsiRNA結合ドメインを含む。特定の場合では、NBDは、たとえば、共有結合を介してELPに抱合することができる。ポリペプチドのNBD及び他のドメインはスペーサーペプチドによって分離することができる。一部の他の場合では、NBDを含むポリペプチドはNBD、AD及びCTDを含む融合タンパク質であり得る。
別の態様では、本発明は、集合ドメイン(AD)と細胞ターゲティングドメイン(CTD)に核酸結合ドメイン(NBD)及び/又は薬剤結合ドメイン(DBD)を加えて含む1以上のポリペプチドを含むナノ粒子を記載する。特定の実施形態では、ナノ粒子はさらに薬剤を含む。他の実施形態では、ナノ粒子はさらにsiRNA分子を含む。
mRNAレベル(qPCR)及びタンパク質レベル(ウエスタンブロット)でのその標的遺伝子を下方調節するsiRNAの能力もこれらの細胞株にて調べる。siRNAが負荷され、ヌクレアーゼ分解からそれを保護し、受容体が介在するエンドサイトーシスを介した卵巣癌細胞による取り込みを促進するELP含有のナノ粒子の能力は、以下の試験によって確認される。
ゲルシフトアッセイ及びスキャチャード型分析によって精製K8ELPポリペプチドへのsiRNAの静電凝集を確認した。細胞輸送試験のために、5’センス鎖にてDY547(Dharmacon)又は他の好適な蛍光標識によってsiRNAを標識する。標識したsiRNAを0.2〜2N/P(生体高分子のカチオン性リジンアミンとsiRNAのアニオン性リン酸基のモル比)で混合し、1Xトリス塩基、酢酸及びEDTA(TAE)、5%グルコースの緩衝液にて室温で30分間インキュベートした。Microcon−100スピン遠心分離によって生体高分子/siRNAナノ粒子をsiRNAから分離した。蛍光分析分光光度アッセイによって遊離のsiRNA及び凝集したsiRNAの濃度を定量した。ナノ粒子と結合したsiRNAを保持するが、遊離のsiRNAを流してしまうMicrocon−100を介した遠心分離に混合物を供した。蛍光分析分光光度計及びDY547 siRNA(Ex/Em547/574)の既知の濃度の検量線を用いて、遊離のsiRNA及び結合したsiRNAの濃度を決定した。siRNAに対する生体高分子の親和性定数(Kd)はスキャチャードプロット解析によって算出し、低いマイクロモル範囲が得られた。CTDを伴ったK8ELPポリペプチドすべてについてこの調製を行う。
LK8ELPのL1CAMの腫瘍細胞を結合する能力を免疫沈降アッセイによって調べる。CTDを含有する他のK8ELPペプチドもすべて評価する。プロテインGを事前に被覆したプロテインGMagnaBindビーズ(イリノイ州、ロックフォードのPierce、カタログ番号21356)は、各親和性標的の精製にすぐ使用できる手段を提供した。プロテインGと抗体との間の高い親和性の相互作用は、たとえば、SDS−PAGE用の試料負荷緩衝液又は8Mのグアニジン/HCl、pH1.5にて煮沸することのような非常に過酷な条件を除いて、効率的には解離しない。遠心分離又は重力法にて磁気ビーズを選択し、沈殿物へのナノ粒子の非特異的な包含を回避する。
動物全身の生物発光画像化(BLI)によって非侵襲性に腫瘍のサイズ及び局在をモニターする。一方は腫瘍特異的受容体(LK8ELP(1〜60))に対するリガンドを含有し、他方はこのペプチドK8ELP(1〜60)を欠く2つの異なったナノ粒子製剤を、蛍光標識(Dy677)を標識したsiRNAを含んで調製した。担癌マウスの群(n=3)は、3種の用量レベル(siRNAに関して1、3又は10mg)のうちの1つでの各ナノ粒子製剤の単回静脈注射を受けた。投与後の3つの時点(0.5、4及び24時間)にて、動物全身の生物発光画像化によって双方のK8ELP(1〜60)ナノ粒子の腫瘍局在化を測定した。
mRNA(qPCR)及びタンパク質(ウエスタンブロット)のレベルで標的遺伝子を下方調節するsiRNAの能力も表2に従って癌細胞にて調べる。RNA干渉の構成を5’RACE法によって測定する。原理の証明に使用されるsiRNAは癌遺伝子の転写因子EVI1のものである。剖検の際、マウスから腫瘍を切除し、イソチオシアン酸グアニジニウムTRIZol溶液にて保存し、凍結する。製造元の指示書に従ってTRIZol法(カリフォルニア州、カールスバットのInvitrogen)を用いてマウスの腫瘍から全RNAを単離する。ランダムプライマー及びAMV逆転写酵素を用いて逆転写に続いてPCRを行う。
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Claims (39)
- 集合ドメイン(AD)と、細胞ターゲティングドメイン(CTD)と、核酸結合ドメイン(NBD)を含む単離されたポリペプチド。
- さらに薬剤結合ドメイン(DBD)を含む請求項1に記載のポリペプチド。
- 核酸結合ドメイン(NBD)がsiRNAに結合する請求項1に記載のポリペプチド。
- 単離されたポリペプチドが配列番号56を含む請求項1に記載のポリペプチド。
- NBDがカチオン性ドメインを含む請求項1に記載のポリペプチド。
- NBDがオリゴリジンドメインを含み、前記オリゴリジンドメインがアミノ酸配列(Val−Gly−LysK−Gly)を含み、Kが1より大きい整数である請求項1に記載のポリペプチド。
- Kが8に等しい請求項6に記載のポリペプチド。
- NBDがオリゴアルギニンドメインを含み、前記オリゴアルギニンドメインがアミノ酸配列(Val−Gly−ArgR−Gly)を含み、Rが1より大きい整数である請求項1に記載のポリペプチド。
- Rが9に等しい請求項8に記載のポリペプチド。
- DBDが、従来の薬剤又は試験中の薬剤に結合する請求項2に記載のポリペプチド。
- ADがエラスチン様ポリペプチド(ELP)を含む請求項1に記載のポリペプチド。
- ELPがアミノ酸配列(Val−Pro−Gly−X−Gly)N(配列番号57)を含み、XがVal、Ala及びGlyを含むペプチドであり、Nが1以上の整数である請求項11に記載のポリペプチド。
- Nが60に等しい請求項12に記載のポリペプチド。
- Xが、約5:2:3の比率でVal、Ala及びGlyを含むペプチドである請求項12に記載のポリペプチド。
- CTDが、標的細胞の表面上に存在する生体分子と相互作用する請求項1に記載のポリペプチド。
- CTDが、標的細胞の外表面上に存在する生体分子と相互作用する請求項1に記載のポリペプチド。
- CTDが、標的細胞の内表面上に存在する生体分子と相互作用する請求項1に記載のポリペプチド。
- CTDが配列番号19を含む請求項1に記載のポリペプチド。
- 生体分子が細胞接着分子を含む請求項15に記載のポリペプチド。
- 生体分子が受容体分子を含む請求項15に記載のポリペプチド。
- 細胞接着分子がフィブロネクチン又はラミニンを含む請求項19に記載のポリペプチド。
- 請求項1に記載のポリペプチドをコードするヌクレオチド配列を有する単離されたポリヌクレオチド。
- 単離されたポリヌクレオチドが配列番号55を含む請求項22に記載の単離されたポリヌクレオチド。
- 請求項22に記載のポリヌクレオチドを含む組換え発現構築物。
- 請求項22に記載のポリヌクレオチドを含む宿主細胞。
- 請求項1に記載の1以上のポリペプチドを含むナノ粒子であって、溶液中で集合する前記ナノ粒子。
- 薬剤をさらに含む請求項26に記載のナノ粒子。
- 薬剤がsiRNA分子である請求項27に記載のナノ粒子。
- ポリペプチドが配列番号56を含む請求項26に記載のナノ粒子。
- 標的細胞に対して薬剤を向ける方法であって、
凝集ドメイン(AD)、ヌクレオチド結合ドメイン(NBD)、及び細胞ターゲティングドメイン(CTD)を含む1以上のポリペプチドを得ることと;
1以上のポリペプチドのNBDに薬剤を接触させることと;
1以上のポリペプチドのADを凝集させて集合ポリペプチドを生成することと;
集合ポリペプチドを標的細胞に接触させることと;
標的細胞の外側に存在する生体分子に集合ポリペプチドのCTDを接触させることを含む、前記方法。 - 標的細胞に対して薬剤を向ける方法であって、
凝集ドメイン(AD)、薬剤結合ドメイン(DBD)、及び細胞ターゲティングドメイン(CTD)を含む1以上のポリペプチドを得ることと;
1以上のポリペプチドのDBDに薬剤を接触させることと;
1以上のポリペプチドのADを凝集させて集合ポリペプチドを生成することと;
集合ポリペプチドを標的細胞に接触させることと;
標的細胞の外側に存在する生体分子に集合ポリペプチドのCTDを接触させることを含む、前記方法。 - 1以上のポリペプチドが配列番号56を含む請求項30に記載の方法。
- 生体分子が標的細胞の内側に存在する請求項30に記載の方法。
- 薬剤がsiRNA分子を含む請求項30に記載の方法。
- 細胞が腫瘍細胞を含む請求項30に記載の方法。
- 腫瘍細胞が、ヒト膀胱細胞、ヒト乳腺細胞、ヒト結腸細胞、ヒト肝臓細胞、ヒト肺細胞、ヒト神経芽腫細胞、ヒト卵巣細胞、ヒト膵臓細胞、ヒト前立腺細胞又はヒト皮膚細胞である請求項35に記載の方法。
- 生体分子が細胞接着分子を含む請求項30に記載の方法。
- 生体分子が受容体分子を含む請求項30に記載の方法。
- 細胞接着分子がフィブロネクチン又はラミニンを含む請求項37に記載の方法。
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