JP2022513140A - がんを治療するための組成物および方法 - Google Patents
がんを治療するための組成物および方法 Download PDFInfo
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Abstract
Description
本明細書では、ユビキチン特異的プロテアーゼ6(USP6)遺伝子が、致死率の高い小児悪性腫瘍であるユーイング肉腫において、強力な抗腫瘍性を有することが示されている。ユーイング肉腫細胞のUSP6の高発現は、免疫賦活性サイトカインおよびケモカインの分泌を誘導し、腫瘍免疫の浸潤を強固にし、免疫細胞を抗腫瘍性の表現型に分化させる。USP6はまた、ナチュラルキラー細胞やCD8+Tリンパ球などの免疫エフェクター細胞による腫瘍細胞の認識と殺傷を促進する受容体の表面発現を増加させるきっかけとなる。具体的には、I型のIFNはプロ・アポトーシス・リガンドであるTRAILの相乗的な発現を誘導し、USP6+ユーイング肉腫細胞を選択的に殺傷する。IFNはまた、USP6+ユーイング肉腫細胞において、CXCL9/10/11やCCL5などの多数の抗腫瘍形成性ケモカインの発現の亢進を誘発する。これらの細胞からの馴化培地は、in vitroで初代単球および活性型CD4+/CD8+T細胞の遊走を促進する。さらに、USP6は、MHC Iの表面発現を増加させる。USP6+ ES細胞の異種移植を受けたマウスでは、無イベント生存期間および終末腫瘍塊までの時間が延長された。USP6+の腫瘍では、免疫の浸潤も劇的に亢進していた。最後に、初代ユーイング肉腫サンプルのトランスクリプトーム解析により、USP6の高い発現が生体内の免疫浸潤遺伝子シグネチャーと関連していることが明らかになった。
単数形の「a」、「an」および「the」は、文脈上明らかに他の意味を持たない限り、複数の参照対象を含む。
肉腫は、腫瘍学における重要な課題を表す多様なクラスの悪性腫瘍である。ユーイング肉腫は2番目に多い骨肉腫であり、通常、生後20年以内に個人に発症する (Biswas, et al. (2016) World J. Orthop., 7:527-38)。限局性の患者の5年生存率は75%であるが、転移性の患者の生存確率は約20%と悲惨な状況である。そのため、再発や治療効果を予測できるバイオマーカーを特定し、転移性疾患に対抗する戦略を立てることが急務となっている。
細胞株とCRISPRを用いたジーンターゲティング
RD-ESとTC-71は、それぞれ国立がん研究所(メリーランド州ベセスダ)とロサンゼルス小児病院、ケック医学校(カリフォルニア州ロサンゼルス)から入手した。CHLA-10およびSK-N-MCは、ペンシルベニア大学(ペンシルベニア州フィラデルフィア)のペレルマン医学部から入手した。ドキシサイクリンで誘導してUSP6を発現させた株を作成した (Ye, et al. (2010) Oncogene 29:3619-29)。 細胞は3~6ヶ月ごとにマイコプラズマの検査を行い、解凍後2週間はMycoplasma Removal薬剤(MP Biomedicals #09350044)で予防的に維持した。すべての実験で、解凍後20回以下の継代で維持された細胞を使用した。細胞株の同一性は、原稿提出の直前に短タンデムリピート解析で確認した。
ドキシサイクリンはClonTech社から入手した(#8634-1)。Jak Inhibitor I (CAS 457081-03-7; #420099)とPS-1145 (P6624)はSigma-Aldrich社から入手した。Lipofectamine 2000は、Life Technologies社から入手した。IFNα、IFNβ、IFNγは、それぞれPBL Assay Science社(#11410-2、#11200-1)、PeproTech社(#300-02)から入手した。ZVAD(FMK001)とIETD(FMK007)はRandD Systems社から入手した。TRAIL(カタログ番号752904)および抗TRAIL(カタログ番号308202)はBioLegend社から入手した。カスパーゼ-3/7(#G8090)とカスパーゼ-9(#G8210)の活性化キットはPromega社から購入し、Molecular Devices社のSpectroMaxでアッセイを行った。アネキシンV染色キットはeBioscience社から入手し(#88-8007-72)、サンプルはBD Biosciences社のAccuri C6およびLSR II機器で分析した。
細胞溶解は、記載されている通りに行った (Sanjana, et al. (2014) Nat. Methods 11:783-4)。Jak1(cs-3332),pSTAT1(cs-9167),pSTAT3(cs-9145),TRAIL(cs-3219),PARP(cs-9542),カスパーゼ-8(cs-9746),およびBid(cs-2002)は Cell Signaling Technology 社から入手した。HA(sc-805)、STAT1(sc-346)、STAT3(sc-482)、およびp65(sc-372)は、Santa Cruz Biotechnology社から入手した。Erk抗体はWeill Cornell Medical College(New York, NY)から入手した。定量化はImage Studio Liteを用いて行った。RNAの単離にはTRIzolを用い、SYBR Green(カタログ番号436765、Thermo Fisher Scientific社)を用いてqPCRを行った。Erk、STAT3、およびp65は、説明されているように、タンパク質負荷のコントロールとして使用された (Hwang, et al. (2005) J. Biol. Chem., 280:12758-65; Huang, et al. (2004) J. Biol. Chem., 279:13866-77; Banerjee, et al. (2010) Cancer Res., 70:1356-66; Chien, et al. (2011) Genes Dev., 25:2125-36)。示したように、これらのレベルはすべての条件で同程度であった。
ドキシサイクリンとIFNαを24時間処理した、または処理しなかったUSP6/RD-ES細胞からRNAを分離した。RNAシーケンス(RNA-seq)、アラインメント、処理、リポジトリへの登録は、ペンシルバニア大学次世代シーケンスコア(GSE107307)で行った。Affymetrix U133AおよびU133 Plus 2.0アレイのCDFファイルを編集し、USP32や他の遺伝子と交差反応するプローブをUSP6プローブセット(206405_x_at)から削除した。この洗練されたUSP6特異的プローブセットは、Probe 4、8、9、11から構成されている。公開されているユーイング肉腫のデータセット[GSE7007 (Tirode, et al. (2007) Cancer Cell 11:421-9) and GSE37371 U133A (Martignetti, et al. (2012) PLoS One, 7:e41770)]をUSP6の発現量でソートした。USP6レベルが最も高い患者と最も低い患者を比較した(各グループ5名)。生殖細胞腫瘍のデータセットGSE10615(Palmer, et al. (2008) Cancer Res., 68:4239-47)では、サンプルをセミノーマ(USP6high)と卵黄嚢腫瘍(USP6low)に分離した。遺伝子セットエンリッチメント解析(GSEA)は、「Hallmarks」分子シグネチャーデータベースを用いて、前述の方法で行った。結節性筋膜炎の遺伝子発現解析は、記述されているように、他のUSP6非発現の間葉系腫瘍と比較した (Quick, et al. (2016) Cancer Res., 76:5337-47)。
ユーイング肉腫においてUSP6がIFN応答を誘発することを、患者サンプルおよび培養細胞を用いて明らかにした
USP6が発がん因子ではない悪性細胞でどのように機能するかについては、ほとんど知られておらず、主にHeLaに限定した報告はわずかしかない (Madan, et al. (2016) Proc. Nat. Acad. Sci., 113:E2945-54; Masuda-Robens, et al. (2003) Mol. Cell Biol., 23:2151-61; Rueckert, et al. (2012) Biol. Cell., 104: 22-33; Li, et al. (2017) Mol. Cell. Biol., 38:e00320-17; Funakoshi, et al. (2014) J. Cell. Sci., 127:4750-61)。前述したように、新生物におけるUSP6の発現は、当初考えられていたよりもはるかに制限されている。幅広い原発性サンプルをスクリーニングしたところ、高発現は主にユーイング肉腫などの間葉系腫瘍に限られていた (Oliveira, et al. (2005) Oncogene 24:3419-26)。
USP6は、それ自体でIFN応答を引き起こすだけでなく、Jak1レベルの上昇により、RD-ESを外因性IFNに対して過敏にさせることができる。実際、USP6/RD-ES細胞におけるSTAT1/3活性化の劇的な増強と延長は、I型およびII型のIFN(それぞれIFNα/IFNβとIFNγ、図2)で観察された。親のRD-ES細胞をIFNαまたはIFNγで処理すると、STAT1とSTAT3のリン酸化が誘導され、30分以内にピークに達し、8時間後までに徐々に減少した。一方、USP6/RD-ESでは、STAT1およびSTAT3のリン酸化が増強され、8時間後には顕著な活性化が持続した(図2AおよびB)。興味深いことに、I型IFNはUSP6のダウンレギュレーションを誘導した(図2A)。
IFNは、細胞の種類によって、細胞表面の受容体にリガンドが結合することで起こる外因性アポトーシスや、ミトコンドリアの制御異常によって起こる内因性アポトーシスを引き起こすことができる。これらの経路は、異なるカスパーゼプロテアーゼを必要とすることで区別される。外因性アポトーシスでは、カスパーゼ-8が切断・活性化され、続いてカスパーゼ-3/7が活性化される。内因性アポトーシスでは、ミトコンドリアのタンパク質であるBidが切断され、カスパーゼ-9が活性化され、さらにカスパーゼ-3/7が活性化される。しかし、IFNによって誘導された外因性アポトーシスがミトコンドリアルートに流れ込み、Bidやカスパーゼ-9の切断・活性化を引き起こす状況もある。
IFNはプロアポトーシスのリガンドであるFasLとTRAILの発現を誘導する。RNA-seqデータによると、USP6/RD-ESでは、親細胞と比較して、FasではなくTRAILがIFNによって相乗的に誘導されることが示された。RT-qPCRにより、IFNがRD-ESのTRAIL発現にほとんど影響を及ぼさないことが確認された(図5A)。しかし、IFNβで処理したUSP6/RD-ESでは、TRAIL mRNAレベルが劇的に上昇していた。また、IFNαおよびIFNγでも、より程度は低いものの誘導が見られ(図5A)、それぞれで誘導された死の程度と相関していた(図3)。一方、FasLの発現はUSP6の影響を大きく受けなかった。5つのTRAIL受容体の発現も調べ、活性型(DR4/DR5)と不活性型デコイ(TNFRSF10C/DおよびOPG)の両方で、そのバランスがTRAIL誘発性アポトーシスに対するがん細胞の感作に重要な役割を果たすことが示されている (von Karstedt, et al. (2017) Nat. Rev. Cancer 17:352-66)。USP6は、死への感応と一致する方法で受容体の発現を変化させなかった。
上記のように、I型IFNはUSP6タンパク質のダウンレギュレーションを誘導する(図2、3、4)。TRAILはまた、時間および用量依存的にUSP6のダウンレギュレーションを引き起こした(図6AおよびB)。TRAILはより迅速に作用し、USP6のダウンレギュレーションが4時間以内に観察されたが、IFNβは12~18時間を必要とした(図2Aおよび6B)。カスパーゼはTRAILシグナル伝達において重要な役割を果たすため、USP6のダウンレギュレーションを媒介するかどうかをテストした。汎カスパーゼ阻害剤ZVADとカスパーゼ8阻害剤IETDの両方が、IFNβおよびTRAILによって誘導されるUSP6のダウンレギュレーションを完全にブロックした(それぞれ図4Aおよび6C)。総合すると、これらの結果は、USP6がTRAIL転写を誘導し、それがDR4を介してシグナルを送り、USP6のカスパーゼ依存性ダウンレギュレーションを引き起こすという負のフィードバックメカニズムを明らかにしている(モデルを参照、図6D)。注目すべきは、I型IFNとTRAILがUSP6を制御する第1の生理的なアゴニストであることである。
ユビキチン特異的ペプチダーゼ6(USP6)は、多くの免疫賦活因子の産生を促進する。USP6はヒトに特異的な遺伝子で、ほとんどの組織や器官で発現が制限されており、精巣でのみかなりの発現が検出されている。悪性腫瘍の中では、ユーイング肉腫を含むいくつかの肉腫で最も高発現しているが、他のがんでは高発現することはまれである (Oliveira, et al. (2014) Hum. Pathol., 45(1):1-11; Oliveira, et al. (2005) Oncogene 24(21):3419-26)。USP6は、動脈瘤性骨嚢胞(ABC)および結節性筋膜炎(NF)として知られる2つの良性骨軟部腫瘍の主要な病因となっている。NFとABCでは、USP6がプロモーターを交換する転座を起こし、その結果、野生型タンパク質が持続的に高発現する。NFの臨床経過は独特であり、急速な増殖とそれに続く数週間または数ヶ月の自然退縮が見られる(Erickson-Johnson, et al. (2011) Lab Invest., 91(10):1427-33)。NF病変は、CD163マクロファージ、CD8+およびCD4+T細胞を含む免疫細胞の豊富な浸潤を示すが、Tregは示さない。ABCおよびNFにおけるUSP6の役割が調査され、USP6がJak1キナーゼを直接脱ユビキチン化および安定化する適応性および自然免疫応答を仲介する重要なエフェクターであるという発見につながった(Quick et al. (2016) Cancer Res., 76(18):5337-47)。
図8Aに示すように、USP6発現が高い急性骨髄性白血病患者は、予後が有意に改善している。同様に、図8Bは、USP6の発現量が高いユーイング肉腫患者の予後が有意に改善していることを示している。
図12は、in vitro転写(IVT)mRNAのUSP6プラスミドマップの概略図を示している。HiScribeTM T7 ARCA(アンチリバースキャップアナログ)mRNAキット(ニューイングランドバイオラボ、マサチューセッツ州イプスウィッチ)などの市販のキットを使用して、キャップ付きおよびテール付きのmRNAを生成できる。In vitroで転写されたRNAは、細胞に投与できる(例えば、ナノ粒子、リポソーム、またはミセルを介して)。ここでは、市販の脂質キャリアであるLipofectamine MessengerMaxTM(Invitrogen, Carlsbad, CA)を用いてmRNAをカプセル化し、細胞に送達した。カプセル化とトランスフェクションは、メーカーの推奨する方法で行った。
USP6の3’UTRがタンパク質の発現に必要かどうかを、3種類のコンストラクトを用いて調べた。IVTのmRNAを合成するためには、まず、3’と5’の末端に対するプライマーを使って、作業可能な断片を作ることが必要である。ここでは、IVTのmRNAを合成するT7 RNAポリメラーゼの結合部位となるT7プロモーターを使用した。また、このコンストラクトは、USP6タンパク質の発現を検出するために、USP6コード領域の5’末端にHAタグを含んでいる。第1のコンストラクトは、USP6のコーディング領域(CDSと呼ぶ)の3’エンドで終了する。第2のコンストラクトは、さらにUSP6 3’UTRを含む。第3のコンストラクトは、USP6 3’UTR(UTRと呼ばれる)と、USP6 3’UTRのすぐ下流にあるSP6サイトをさらに含む。
Claims (30)
- それを必要とする対象のがんを治療する方法であって、ユビキチン特異的プロテアーゼ6(USP6)活性を増加させる薬剤を前記対象に投与することを含む、方法。
- 前記薬剤が、薬学的に許容される担体をさらに含む組成物として投与される、請求項1に記載の方法。
- 前記薬剤が、腫瘍内および/または腫瘍部位に投与される、請求項1に記載の方法。
- 前記薬剤が、USP6をコードする核酸分子である、請求項1に記載の方法。
- 前記USP6をコードする核酸分子がmRNAである、請求項4に記載の方法。
- 前記USP6をコードする核酸分子が、in vitroで転写されたUSP6 mRNAである、請求項5に記載の方法。
- 前記mRNAが5'キャップを含む、請求項5または6に記載の方法。
- 前記5’キャップがアンチリバースキャップアナログ(ARCA)である、請求項7に記載の方法。
- 前記mRNAがポリアデニル酸テールを含む、請求項5~8のいずれか1項に記載の方法。
- 前記ポリアデニル酸テールが100~150個のアデノシンを含む、請求項9に記載の方法。
- 前記mRNAが、少なくとも1つのシュードウリジンおよび/または5-メチルシチジンを含む、請求項5~10のいずれか1項に記載の方法。
- ウリジンの少なくとも40%がシュードウリジンで置換されており、シチジンの少なくとも40%が5-メチルシチジンで置換されている、請求項5~11のいずれか1項に記載の方法。
- 前記mRNAが、アンチリバースキャップアナログ(ARCA)および100~150個のアデノシンのポリアデニル酸テールを含み、ウリジンの少なくとも40%がシュードウリジンで置換され、シチジンの少なくとも40%が5-メチルシチジンで置換されている、請求項5に記載の方法。
- 前記薬剤がUSP6タンパク質である、請求項1に記載の方法。
- さらに、免疫療法を投与することを含む、請求項1に記載の方法。
- インターフェロン(IFN)を投与することをさらに含む、請求項15に記載の方法。
- 前記IFNがIFNβである、請求項15に記載の方法。
- 前記がんがユーイング肉腫である、請求項1に記載の方法。
- 前記がんが、膵臓がん、子宮頸部がん、肺がん、卵巣がん、または膀胱がんである、請求項1に記載の方法。
- 前記がんが急性骨髄性白血病である、請求項1に記載の方法。
- 前記薬剤が脂質ナノ粒子内に含まれている、請求項1に記載の方法。
- 前記脂質ナノ粒子が、ターゲティング部位またはナノボディを含む、請求項21に記載の方法。
- USP6をコードする核酸分子であって、前記核酸分子がmRNAであり、前記mRNAが少なくとも1つの改変塩基または非天然塩基を含む、核酸分子。
- 前記mRNAが少なくとも1つのシュードウリジンおよび/または5-メチルシチジンを含む、請求項23に記載のUSP6をコードする核酸分子。
- 前記mRNAが5’キャップを含む、請求項23に記載のUSP6をコードする核酸分子。
- 前記5’キャップがアンチリバースキャップアナログ(ARCA)である、請求項25に記載のUSP6をコードする核酸分子。
- 前記mRNAがポリアデニル酸テールを含む、請求項23に記載のUSP6をコードする核酸分子。
- 前記ポリアデニル酸テールが100~150個のアデノシンの長さである、請求項27に記載のUSP6をコードする核酸分子。
- ウリジンの少なくとも40%がシュードウリジンで置換されており、シチジンの少なくとも40%が5-メチルシチジンで置換されている、請求項23~28のいずれか1項に記載のUSP6をコードする核酸分子。
- 前記mRNAがアンチリバースキャップアナログ(ARCA)および100~140個のアデノシンのポリアデニル酸テールを含み、ウリジンの少なくとも40%がシュードウリジンで置換されており、シチジンの少なくとも40%が5-メチルシチジンで置換されている、請求項23に記載のUSP6をコードする核酸分子。
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