JP2021521126A - エキソソームを用いたがん遺伝子に対する治療的な標的指向化の方法 - Google Patents
エキソソームを用いたがん遺伝子に対する治療的な標的指向化の方法 Download PDFInfo
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Abstract
Description
本願は、全内容が参照により本明細書に組み入れられる、2018年4月9日に出願された米国特許仮出願第62/655,036号の優先権恩典を主張する。
本願は、EFS-Web経由でASCIIフォーマットで提出されており、その全体が参照により本明細書に組み入れられる配列表を含む。このASCIIコピーは2019年4月2日に作成され、UTFC.P1365WO_ST25.txtと命名され、サイズは0.5キロバイトである。
本発明は全体として医学および腫瘍学の分野に関する。さらに詳細には、本発明は、がん遺伝子活性を阻害するために、カーゴを輸送するエキソソームを投与することによってがんを処置するための組成物およびがんを処置する方法に関する。
がんは遺伝子欠陥に関連し、ほとんどのがんは、c-Mycなどのがん遺伝子の転写レベルでの遺伝子増幅および/またはアップレギュレーションに関連する。いくつかの異なる研究から、がんの進行および転移はc-Myc発現に依存し、c-Myc発現によりc-Mycががんの「最重要指名手配(most wanted)」標的リストに載ることが分かっている。c-Mycの中心的な機能上の役割は多くの異なるタイプのがんについて証明されている。c-Mycにはがん生物学において、このような中心的な役割があるのにもかかわらず、c-Mycならびに他の多くのがん遺伝子を阻害する臨床で実行可能な薬物は現在存在しない。
従って、エキソソームを用いて、c-Mycなどのがん遺伝子を特異的に阻害するための組成物、およびがん遺伝子を特異的に阻害する方法が本明細書において提供される。一態様では、がん遺伝子を不活性化する治療用物質カーゴを含む脂質ベースナノ粒子を含む組成物が本明細書において提供される。一部の局面では、脂質ベースナノ粒子はその表面にCD47を含む。一部の局面では、脂質ベースナノ粒子はその表面に増殖因子を含む。一部の局面では、脂質ベースナノ粒子はリポソームまたはエキソソームである。
c-Mycに特異的なsiRNAを搭載したエキソソームはc-Myc発現を抑制し、がん細胞の増殖を阻害し、腫瘍成長を弱め、膵臓腫瘍および脳腫瘍があり、ヒト膵管腺がん(PDAC)およびグリア芽細胞腫(GBM)を模倣するマウスの全生存期間を延ばす。従って、がん細胞においてMycなどのがん遺伝子を標的にする方法が本明細書において提供される。
一部の態様では、脂質ベースナノ粒子は、リポソーム、エキソソーム、脂質調製物、または別の脂質ベースナノ粒子、例えば、脂質ベース小胞(例えば、DOTAP:コレステロール小胞)である。脂質ベースナノ粒子は正に荷電してもよく、負に荷電していてもよく、中性でもよい。脂質ベースナノ粒子は、転写および翻訳、シグナル伝達、走化性、または他の細胞機能を可能にするために必要な成分を含んでもよい。
「リポソーム」は、閉じた脂質二重層または凝集物を生じることで形成された様々な単一膜および多重膜の脂質ビヒクルを含む総称的な用語である。リポソームは、一般的にリン脂質を含む二重層膜がある小胞構造と、一般的に水性組成物を含む内部媒体とを有すると特徴決定されることがある。本明細書において提供されるリポソームには、単層リポソーム、多重膜リポソーム、および多胞体リポソーム(multivesicular liposome)が含まれる。本明細書において提供されるリポソームは正に荷電してもよく、負に荷電していてもよく、中性に荷電していてもよい。ある特定の態様では、リポソームは電荷が中性である。
本明細書で使用する「マイクロベシクル」および「エキソソーム」という用語は、直径(または粒子がスフェロイドでない場合は最大の寸法)が約10nm〜約5000nm、より典型的には30nm〜1000nm、最も典型的には約50nm〜750nmであり、エキソソームの膜の少なくとも一部が細胞から直接得られている膜状粒子を指す。最も一般的には、エキソソームのサイズ(平均直径)はドナー細胞のサイズの5%までである。従って、特に意図されるエキソソームには、細胞から脱落したエキソソームが含まれる。
翌日に細胞が約70%コンフルエントになるように、1日目に、10%FBSを含有する培地が入っているT225フラスコに、十分な数の細胞(例えば、約500万個の細胞)を播種する。2日目に、細胞上の培地を吸引し、細胞をPBSで2回洗浄し、次いで、25〜30mLの基本培地(すなわち、PenStrepもFBSも無い)を細胞に添加する。細胞を24〜48時間インキュベートする。48時間のインキュベーションが好ましいが、細胞株の中には無血清培地に対して感受性が高いものもあり、そのため、インキュベーション時間を24時間に短縮しなければならない。FBSは、NanoSight結果を強くゆがめるエキソソームを含有することに留意のこと。
最初に、血清試料を氷上で解凍する。次いで、250μLの無細胞血清試料を11mLのPBSで希釈する。0.2μm孔フィルターで濾過する。希釈した試料を150,000×gで4℃において一晩超遠心する。翌日、上清を注意深く捨て、11mL PBSでエキソソームペレットを洗浄する。150,000×gで4℃において2時間、2回目の超遠心を行う。最後に、上清を注意深く捨て、分析のために100μL PBSにエキソソームペレットを再懸濁する。
1×108個のエキソソーム(NanoSight分析によって測定した)または100nmリポソーム(例えば、Encapsula Nano Sciencesから購入した)と、1μgのsiRNA(Qiagen)またはshRNAを400μLの電気穿孔緩衝液(1.15mMリン酸カリウム, pH7.2、25mM塩化カリウム、21%Optiprep)に入れて混合する。4mmキュベットを用いてエキソソームまたはリポソームを電気穿孔する(例えば、Alvarez-Erviti et al., 2011; El-Andaloussi et al., 2012を参照されたい)。電気穿孔後に、エキソソームまたはリポソームをプロテアーゼフリーRNアーゼで処理し、その後に10×濃縮RNアーゼ阻害剤を添加する。最後に、前記のように超遠心法下でエキソソームまたはリポソームをPBSで洗浄する。
本発明のある特定の局面は、がん細胞において発がん活性を不活性化する治療用物質を発現するまたは含むエキソソームを用いて患者を処置することを提供する。本明細書で使用する「治療用物質」は、がんまたは他の状態の処置において有用な原子、分子、または化合物である。治療用物質の例には、薬物、化学療法剤、治療抗体および抗体断片、毒素、放射性同位体、酵素、ヌクレアーゼ、ホルモン、免疫調節剤、アンチセンスオリゴヌクレオチド、遺伝子編集システム、キレート剤、ホウ素化合物、光活性剤、および色素が含まれるが、これに限定されない。
多種多様な化学療法剤を本発明に従って使用することができる。「化学療法」という用語は、がんを処置するための薬物の使用を指す。「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意味するために用いられる。これらの剤または薬物は、細胞内での活性の様式、例えば、細胞周期に影響を及ぼすかどうか、またはどの段階で細胞周期に影響を及ぼすのかによって分類される。または、剤は、DNAを直接架橋する能力、DNAにインターカレートする能力、または核酸合成に影響を及ぼすことで染色体異常および有糸分裂異常を誘導する能力に基づいて特徴付けられることがある。
DNA損傷を引き起こし、かつ広範に用いられてきた他の要因には、γ線、X線、および/または腫瘍細胞への放射性同位体の特異的送達として一般に知られているものが含まれる。マイクロ波、陽子線照射(米国特許第5,760,395号および同第4,870,287号)、ならびにUV照射などの他の形態のDNA損傷因子も意図される。これらの要因が全て、DNA、DNA前駆体、DNAの複製および修復、ならびに染色体の集合および維持に対する広範な損傷に影響を及ぼす可能性が高い。X線の線量範囲は、長期の場合(3〜4週間)は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及ぶ。放射性同位体の線量範囲は多種多様であり、同位体の半減期、放出される放射線の強度およびタイプ、ならびに新生細胞による取り込みによって決まる。
当業者は、本発明の方法と組み合わせて、または本発明の方法と一緒に、さらなる免疫療法が用いられ得ることを理解する。がん治療の状況では、免疫療法は、一般的に、がん細胞を標的にするおよび破壊するために免疫エフェクター細胞および免疫エフェクター分子の使用に頼る。リツキシマブ(Rituxan(登録商標))は、このような例の1つである。免疫エフェクターは、例えば、腫瘍細胞表面上の何らかのマーカーに特異的な抗体でもよい。この抗体だけが療法のエフェクターとして働いてもよく、他の細胞を動員して細胞死滅に実際に影響を及ぼしてもよい。この抗体はまた、薬物または毒素(化学療法剤、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)に結合体化されてもよく、単に標的指向性物質として働いてもよい。または、エフェクターは、腫瘍細胞標的と直接的または間接的に相互作用する表面分子を有するリンパ球でもよい。様々なエフェクター細胞には細胞傷害性T細胞およびNK細胞が含まれる。
がんを有する人の約60%は、予防手術、診断、または進行度診断のための手術、根治的手術、および姑息的手術を含む何らかの種類の外科手術を受ける。根治的手術は、がん組織の全てまたは一部が物理的に除去、切除、および/または破壊される切除を含み、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、および/または代替療法などの他の療法と共に用いられてもよい。腫瘍切除とは、腫瘍の少なくとも一部の物理的除去を指す。腫瘍切除に加えて、外科手術による処置は、レーザー手術、凍結手術、電気手術、および顕微鏡的に管理される手術(microscopically-controlled surgery)(モース術)を含む。
処置の治療有効性を改善するために、本発明のある特定の局面と組み合わせて他の作用物質が用いられ得ることが意図される。これらのさらなる作用物質には、細胞表面受容体およびギャップ結合のアップレギュレーションに影響を及ぼす作用物質、細胞分裂停止物質および分化物質、細胞接着阻害剤、アポトーシス誘導物質に対する過剰増殖性細胞の感受性を高める作用物質、または他の生物学的作用物質が含まれる。ギャップ結合数を増やすことで細胞間シグナル伝達を増大させると、付近の過剰増殖性細胞集団に対する抗過剰増殖作用が増大する。他の態様では、処置の抗過剰増殖有効性を改善するために、細胞分裂停止物質または分化物質は本発明のある特定の局面と組み合わせて使用することができる。細胞接着阻害剤は本発明の有効性を改善することが意図される。細胞接着阻害剤の例は局所接着キナーゼ(FAK)阻害剤およびロバスタチンである。処置有効性を改善するために、アポトーシスに対する過剰増殖性細胞の感受性を高める他の作用物質、例えば、抗体c225を本発明のある特定の局面と併用できることがさらに意図される。
抗発がん物質を発現するまたは含むエキソソームは、腫瘍細胞増殖を阻害するために、最も好ましくは局所進行がんまたは転移がんを有するがん患者のがん細胞を死滅させるために全身投与または局所投与できることが意図される。CRISPRシステムを発現する、または含むエキソソームは静脈内投与、くも膜下腔内投与、および/または腹腔内投与することができる。CRISPRシステムを発現する、または含むエキソソームは単独で投与されてもよく、抗増殖性薬物と組み合わせて投与されてもよい。一態様では、CRISPRシステムを発現する、または含むエキソソームは外科手術または他の処置の前に患者のがん負荷(cancer load)を減らすために投与される。または、CRISPRシステムを発現する、または含むエキソソームは、残存しているがん(例えば、外科手術で除去されなかったがん)が生き残らないことを確かなものにするために外科手術後に投与することができる。
A.核酸およびベクター
本発明のある特定の局面では、治療用タンパク質または抗体をコードする核酸配列が開示され得る。どの発現系が用いられるかに応じて、核酸配列は従来の方法に基づいて選択することができる。例えば、それぞれの遺伝子またはその変種は、ある特定の系において発現するようにコドン最適化されてもよい。関心対象のタンパク質を発現するために様々なベクターも使用することができる。例示的なベクターには、プラスミドベクター、ウイルスベクター、トランスポゾン、またはリポソームベースのベクターが含まれるが、これに限定されない。
一部の態様は、例えば治療用抗体などの組換えタンパク質およびポリペプチドに関する。一部の態様において、治療抗体は、細胞内タンパク質に特異的または選択的に結合する抗体であってもよい。さらなる局面では、前記タンパク質またはポリペプチドは血清安定性を高めるように改変されてもよい。従って、本願が「改変されたタンパク質」または「改変されたポリペプチド」の機能または活性について言及している場合に、これは、例えば、改変されていないタンパク質またはポリペプチドと比べて、さらなる利点を有するタンパク質またはポリペプチドを含むと当業者に理解されるだろう。「改変されたタンパク質」に関する態様は「改変されたポリペプチド」に関して実施されることがあり、逆もまた同じであると特に意図される。
siRNA(例えば、siNA)は当技術分野において周知である。例えば、siRNAおよび二本鎖RNAは、米国特許第6,506,559号および同第6,573,099号ならびに米国特許出願第2003/0051263号、同第2003/0055020号、同第2004/0265839号、同第2002/0168707号、同第2003/0159161号、および同第2004/0064842号に記載されている。これらは全て、その全体が参照により本明細書に組み入れられる。
一般的に、「CRISPRシステム」とは、Cas遺伝子をコードする配列を含むCRISPR関連(「Cas」)遺伝子の発現または活性誘導に関与する転写物および他のエレメント、tracr(トランス活性化CRISPR)配列(例えば、tracrRNAもしくは活性のある部分的tracrRNA)、tracr-mate配列(内因性CRISPRシステムの文脈では「ダイレクトリピート」およびtracrRNAによってプロセシングされた部分的ダイレクトリピートを含む)、ガイド配列(内因性CRISPRシステムの文脈では「スペーサー」とも呼ばれる)、ならびに/またはCRISPR遺伝子座に由来する他の配列および転写物を総称して指す。
本発明の様々な局面では、エキソソームを体液または組織培養培地から精製するための必要な成分を含むキットが想定される。他の局面では、エキソソームを単離してエキソソームに治療用核酸、治療用タンパク質、または阻害RNAをトランスフェクトするための必要な成分を備えるキットが想定される。キットは、このような任意の成分を含む1つまたは複数の密封したバイアルを含んでもよい。一部の態様では、キットはまた、キットの成分と反応しない容器である適切な容器手段、例えば、エッペンドルフチューブ、アッセイプレート、注射器、瓶、またはチューブも備えてよい。容器は、プラスチックまたはガラスなどの滅菌可能な材料から作製されてもよい。キットは、本明細書において説明される方法の手順工程を概説する指示書をさらに備えてもよく、本明細書に記載のものと実質的に同じ手順に従うか、または当業者に公知である。コンピュータを用いて実行された場合に、試料からエキソソームを精製して治療用カーゴをエキソソームにトランスフェクトする、現実または仮想の手法を表示する、機械可読指示書を備える、コンピュータ可読媒体中に、指示書の情報は存在してもよい。
以下の実施例は、本発明の好ましい態様を証明するために含まれる。以下の実施例に開示される技法は、本発明者が発見した技法が本発明の実施において十分に機能することを示すこと、かつ、従って、本発明を実施するための好ましい態様を構成すると考えられ得ることが、当業者に理解されるはずである。しかしながら、本開示を考慮すれば、本発明の精神および範囲から逸脱することなく、開示された特定の態様において多くの変更を加えることができ、それでもなお、類似または同様の結果を得ることができると当業者に理解されるはずである。
c-Mycを標的にする5種類のsiRNAを、Panc-1細胞におけるノックダウン効率についてリポフェクタミントランスフェクションを用いて試験した(図1A)。次いで、ノックダウン効率が最も高いsiRNA(#26siRNA c-Myc、配列:
)のノックダウン効率を経時的に試験し、6時間で86%ノックダウン、48時間で93%ノックダウンをもたらすことが見出された(図1B)。
Panc-1同所性腫瘍を有するマウスを、plasmalyte(すなわち、希釈剤のみ;N=5)、非標的(スクランブルド)siRNAを含有するエキソソーム(N=10)、またはc-Mycを標的にするsiRNAを含有するエキソソーム(N=13)を用いてPanc-1細胞注射の28日後から開始して1日おきに処置した。対照群は両方とも、c-Mycを標的にするsiRNAを含有するエキソソームで処置したマウスと比較してがん細胞注射の112〜140日後に有意な死亡率を示した(図2A)。腫瘍組織の壊死を分析することで、c-Mycを標的にするsiRNAを含有するエキソソームで処置した、時間を一致させたマウスの壊死した腫瘍組織は、plasmalyteで処置したマウスまたは非標的(スクランブルド)siRNAを含有するエキソソームで処置したマウスよりも多いことが分かった(図2B)。また、c-Mycを標的にするsiRNAを含有するエキソソームで処置したマウスに由来する同所性腫瘍における免疫標識によってc-Myc発現低下も示された(図3D)。さらに、時間を一致させた肝臓分析(表1に示した)から、対照と比較して、c-Mycを標的にするエキソソームで処置したマウスにおけるマクロ転移の証拠が減少していることが分かった(表1ならびに図2CおよびE)。
ヌードマウスに、GFPとルシフェラーゼを発現するU87グリア芽細胞腫細胞を同所に(脳に)移植した。移植して28日後に、U87同所性腫瘍を有するマウスを、plasmalyte(すなわち、希釈剤のみ)、非標的(スクランブルド)siRNAを含有するエキソソーム、またはc-Mycを標的にするsiRNAを含有するエキソソームを用いて1日おきに処置した(図3A)。2人の無関係の研究者が、この実験を、c-Mycを標的にするsiRNAの2つの別個の供給元を用いて2回繰り返して行った。マウスの生存率ならびに生物発光画像化に基づいた腫瘍負荷をモニタリングした。さらに、蛍光顕微鏡を用いてU87腫瘍への(c-Mycを標的にする)標識siRNAの取り込みを評価した(図3F)。
Claims (40)
- がん遺伝子を不活性化する治療用物質カーゴを含む脂質ベースナノ粒子を含む、組成物。
- 前記脂質ベースナノ粒子がその表面にCD47を含む、請求項1に記載の組成物。
- 前記脂質ベースナノ粒子がその表面に増殖因子を含む、請求項1に記載の組成物。
- 前記脂質ベースナノ粒子がリポソームまたはエキソソームである、請求項1に記載の組成物。
- 前記治療用物質カーゴが、治療用タンパク質、抗体、阻害RNA、遺伝子編集システム、または低分子薬物である、請求項1に記載の組成物。
- 前記治療用タンパク質が、がんの細胞中の活性過剰である前記がん遺伝子のドミナントネガティブバージョンに対応する、請求項5に記載の組成物。
- 前記抗体が細胞内抗原に結合する、請求項5に記載の組成物。
- 前記抗体が、完全長抗体、scFv、Fab断片、(Fab)2、ダイアボディ、トリアボディ、またはミニボディである、請求項5に記載の組成物。
- 前記阻害RNAがsiRNA、shRNA、miRNA、またはプレmiRNAである、請求項5に記載の組成物。
- 前記siRNAが前記がん遺伝子の発現をノックダウンする、請求項9に記載の組成物。
- 前記遺伝子編集システムがCRISPRシステムである、請求項9に記載の組成物。
- 前記CRISPRシステムがエンドヌクレアーゼおよびガイドRNA(gRNA)を含む、請求項11に記載の組成物。
- 前記エンドヌクレアーゼおよびgRNAが、前記エキソソーム内の単一の核酸分子上にコードされている、請求項12に記載の組成物。
- 前記CRISPRシステムが発がん変異を標的にする、請求項11に記載の組成物。
- 前記発がん変異が1つまたは複数の点変異である、請求項14に記載の組成物。
- 前記発がん変異が遺伝子重複である、請求項14に記載の組成物。
- 前記がん遺伝子が、ABLI、BLC1、BCL6、CBFA1、CBL、CSFIR、ERBA、ERBB、EBRB2、ETS1、ETS1、ETV6、FGR、FOX、FYN、HCR、HRAS、JUN、KRAS、LCK、LYN、MDM2、MLL、MYB、MYC、MYCL1、MYCN、NRAS、PIM1、PML、RET、SRC、TAL1、TCL3、またはYESである、請求項1に記載の組成物。
- 前記がん遺伝子がc-Mycである、請求項1に記載の組成物。
- 前記治療用物質カーゴが、c-Mycを標的にするsiRNAである、請求項18に記載の組成物。
- 前記siRNAがSEQ ID NO:1の配列を有する、請求項19に記載の組成物。
- 請求項1〜20のいずれか一項に記載の脂質ベースナノ粒子ナノ粒子と、賦形剤とを含む、薬学的組成物。
- 非経口投与用に製剤化されている、請求項21に記載の組成物。
- 静脈内注射用、筋肉内注射用、皮下注射用、または腹腔内注射用に製剤化されている、請求項22に記載の組成物。
- 抗菌剤をさらに含む、請求項22に記載の組成物。
- 前記抗菌剤が、塩化ベンザルコニウム、塩化ベンゼトニウム、ベンジルアルコール、ブロノポール、セントリミド、塩化セチルピリジニウム、クロルヘキシジン、クロロブタノール、クロロクレゾール、クロロキシレノール、クレゾール、エチルアルコール、グリセリン、エキセチジン、イミド尿素、フェノール、フェノキシエタノール、フェニルエチルアルコール、硝酸フェニル水銀、プロピレングリコール、またはチメロサールである、請求項24に記載の組成物。
- その必要のある患者においてがんを処置する方法であって、請求項21〜25のいずれか一項に記載の組成物を該患者に投与し、それによって該患者において該がんを処置する工程を含む、該方法。
- 投与によって前記患者におけるがん細胞への前記治療用物質カーゴの送達がもたらされる、請求項26に記載の方法。
- 前記がんが、乳がん、肺がん、頭頸部がん、前立腺がん、食道がん、気管がん、脳がん、肝臓がん、膀胱がん、胃がん、膵臓がん、卵巣がん、子宮がん、子宮頸がん、精巣がん、結腸がん、直腸がん、または皮膚がんである、請求項26に記載の方法。
- 前記膵臓がんが膵管腺がんである、請求項28に記載の方法。
- 前記脳がんがグリア芽細胞腫である、請求項28に記載の方法。
- 前記がんが転移性である、請求項26に記載の方法。
- 前記投与が全身投与である、請求項26に記載の方法。
- 前記全身投与が静脈内投与である、請求項32に記載の方法。
- 少なくとも第2の療法を前記患者に実施する工程をさらに含む、請求項26に記載の方法。
- 前記第2の療法が、外科的療法、化学療法、放射線療法、寒冷療法、ホルモン療法、または免疫療法を含む、請求項34に記載の方法。
- 前記患者がヒトである、請求項26に記載の方法。
- 前記脂質ベースナノ粒子がエキソソームであり、該エキソソームが前記患者にとって自己由来である、請求項36に記載の方法。
- 前記エキソソームが、前記患者から得られた体液試料から得られる、請求項37に記載の方法。
- 前記体液試料が、血液、リンパ液、唾液、尿、脳脊髄液、骨髄吸引液、眼滲出物/涙、または血清である、請求項38に記載の方法。
- 前記がんの部位に増殖因子勾配を提供して該部位に前記エキソソームを誘引しかつ該部位に前記治療用物質を送達する工程をさらに含む、請求項26に記載の方法。
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JP2015529467A (ja) * | 2012-09-14 | 2015-10-08 | ダイセルナ ファーマシューティカルズ, インコーポレイテッドDicerna Pharmaceuticals, Inc. | 二本鎖rnaによるmycの特異的阻害に関する方法および組成物 |
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JP2016520056A (ja) * | 2013-05-07 | 2016-07-11 | フンダシオ プリバダ インスティトゥト ディンベスティガシオ オンコロジカ デ バル エブロンFundacio Privada Institut D’Investigacio Oncologica De Vall Hebron | 癌の治療方法および組成物 |
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CA2936100A1 (en) * | 2013-12-04 | 2015-06-11 | Board Of Regents, The University Of Texas System | Analysis of genomic dna, rna, and proteins in exosomes for diagnosis and theranosis |
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US20120107317A1 (en) * | 2010-10-27 | 2012-05-03 | The University Of Hong Kong | Use of cytoplasmic c-myc for regulating immune responses |
JP2015529467A (ja) * | 2012-09-14 | 2015-10-08 | ダイセルナ ファーマシューティカルズ, インコーポレイテッドDicerna Pharmaceuticals, Inc. | 二本鎖rnaによるmycの特異的阻害に関する方法および組成物 |
JP2016520056A (ja) * | 2013-05-07 | 2016-07-11 | フンダシオ プリバダ インスティトゥト ディンベスティガシオ オンコロジカ デ バル エブロンFundacio Privada Institut D’Investigacio Oncologica De Vall Hebron | 癌の治療方法および組成物 |
US20150306036A1 (en) * | 2014-04-08 | 2015-10-29 | Pablo E. Vivas-Mejia | Nanoliposomal c-MYC-siRNA Inhibits In Vivo Tumor Growth of Cisplatin-Resistant Ovarian Cancer |
WO2016201323A1 (en) * | 2015-06-10 | 2016-12-15 | Board Of Regents, The University Of Texas System | Use of exosomes for the treatment of disease |
WO2017161010A1 (en) * | 2016-03-15 | 2017-09-21 | Codiak Biosciences, Inc. | Therapeutic membrane vesicles |
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WO2019199803A1 (en) | 2019-10-17 |
KR20200143416A (ko) | 2020-12-23 |
EP3773492A1 (en) | 2021-02-17 |
US20210024936A1 (en) | 2021-01-28 |
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