JP2020530981A - T細胞の機能を調節するためのアンチセンスオリゴヌクレオチド - Google Patents
T細胞の機能を調節するためのアンチセンスオリゴヌクレオチド Download PDFInfo
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Abstract
Description
本発明は、特定の実施形態に関して及び特定の図面を参照して説明されているが、本発明はそれらに限定されず、特許請求の範囲によってのみ限定される。特許請求の範囲での参照符号は、範囲を限定すると解釈されるべきではない。説明されている図面は概略にすぎず、非限定的である。図面では、要素の一部のサイズが誇張されている場合があり、例示の目的のために縮尺通りに描かれていない。用語「含む」が本明細書及び特許請求の範囲で使用される場合、この用語は他の要素又は工程を除外しない。単数の名詞への言及時に不定冠詞又は定冠詞(例えば、「a」又は「an」、「the」)が使用される場合には、これは、他のことが具体的に述べられていない限り、その名詞の複数形を含む。さらに、本明細書及び特許請求の範囲における用語第1、第2、第3等は、類似の要素を区別するために使用され、必ずしも順番又は時系列を説明するためではない。そのように使用される用語は適切な状況下で交換可能であること、及び本明細書で説明されている本発明の実施形態は、本明細書で説明されているか又は例示されているものとは別の順序で作動可能であることを理解されたい。
ASOは、HBV特異的TCR再指向型初代T細胞に効率的に導入され得る。
初代T細胞の特異性を改変するために、本発明者らは、[9]のように、エレクトロポレーション法を使用して、HBVのエンベロープタンパク質中のペプチド(S183-191)を認識するTCRのVアルファ/ベータ鎖をコードするmRNAで初代T細胞をトランスフェクトした。このペプチドは通常、抗原提示細胞(APC)の表面上に又はHBV感染肝細胞上に、MHC-Iを介して提示される。従って、T細胞の表面上のS183-191特異的TCRの発現により、T細胞は、HBVの存在を認識し得るようになり、最終的にはTCR活性化を受けるようになる。T細胞の表面上でのHBV特異的TCRの発現は、MHC多量体による単純な表面染色とフローサイトメトリー分析とを使用して評価し得る。MHC多量体は、抗原特異的T細胞を特定するように設計された、MHC分子の標識されたオリゴマー形態であり、MHC多量体は特定の特異性のT細胞レセプターに直接結合することができ、この特異性は、MHC分子とこのMHC分子上に提示されるペプチドとの組み合わせにより決定される。同様に、本発明者らは、RNAエレクトポレーションを使用してT細胞の機能を改変し、望ましくない遺伝子の様々なエクソンを標的とするアンチセンスオリゴヌクレオチド(ASO)を導入した。
初代T細胞において、ASOにより遺伝子発現が調節され得る。
(HBV特異的TCRを伴う又は伴わない)初代活性化T細胞中でのASOのトランスフェクションの実行可能性を証明した後、本発明者らは、標的遺伝子のスプライシングに干渉するオリゴヌクレオチドの能力を試験することへと進んだ。概念実証のために、本発明者らは、インターフェロン-γ(IFN-γ)プレ-mRNAのエクソン2を標的とするASOを設計することを選択し、なぜならば、実験室で、そのようなサイトカインの存在及び活性を評価するために様々なツールを利用し得るからである。本発明者らは、トランスフェクトされた細胞のcDNAに対してシンプルなPCRを実施して完全長及び短い(エクソンがスキップされた)アイソフォームの両方を増幅させるPCR産物を得るために、(IFN-γ)のエクソン2を囲むプライマーを設計した[11]。この技術の特異性を評価するためのコントロールは、非ターゲティング/スクランブル化配列で初代細胞をトランスフェクトして実施する。図2.AはPCRの結果を示し、ASOがプレ-mRNAのスプライシングを用量依存的に妨げ、最終mRNAからエクソン2が排除されることが明らかである。500ピコモルのIFN-γターゲティングASOでトランスフェクトされたT細胞の8%だけがmRNAレベルで効果を示すところ、同一のオリゴマーの3倍の量でトランスフェクトされたT細胞は、完全長転写産物の92%の減少を示す。スクランブル化ASOで処理されたT細胞は、IFN-γ転写産物のいかなる改変も示さない。しかしながら、図2.Aで明らかなように、本発明者らが予想したようにエクソンがスキップされたmRNAをナンセンス媒介性RNA崩壊により除去することは達成できなかった。免疫関連タンパク質のバイオインフォマティクス検索の後、本発明者らは、多くのスプライスバリアントが生理的条件下で通常存在するが、機能的に特徴付けられていないことが多いことを理解した。
初代T細胞において、ASOにより細胞傷害性が調節され得る。
序論で述べたように、HCCのような悪性腫瘍の治療のための養子T細胞移入の使用の1つの考えられる欠点は、実質的に全肝臓がエフェクターT細胞の標的となる可能性があり、深刻な結果がもたらされうる、肝臓細胞傷害性である。このリスクを制限し治療の安全性を改善するために採用される1つの手段は、エレクトロポレーションにより誘導されるT細胞レセプター発現の一過性であるが、本発明者らは、アンチセンス技術を使用して、TCR再指向型T細胞の細胞傷害性機能も改変することができるかどうかを問うた。同一の設定を使用して、本発明者らは、グランザイムB(ASO #266及び#267)、並びにパーフォリン(ASO #268及び#269)のプレmRNAのそれぞれエクソン3及びエクソン2を標的とするASOを導入した。パーフォリン及びグランザイムは、細胞間細胞傷害性で作用する2種の主なエフェクターである。
図9は、AONが、典型的には、トランスフェクトされたT細胞の生存率に影響を及ぼさず、且つTCR発現を妨げないことを示す。図9(a)は、エレクトロポレートされていない細胞と比較した、HBV特異的TCR、AON、又はその両方を伴うT細胞EPの生存率を示す。図9(b)は、TCR又はTCR+AONを伴う、活性化された又は静止中のT細胞EPでのTCR発現を示す(フローサイトメトリーにおけるMHC多量体染色により測定した)。
Claims (48)
- T細胞の機能を調節するためのアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは、
T細胞の増殖、T細胞の殺傷能力もしくは抗ウイルス性サイトカインを産生する能力
のうちの1つ又は複数を調節する、請求項1に記載のアンチセンスオリゴヌクレオチド。 - 前記アンチセンスオリゴヌクレオチドは、T細胞により発現される免疫関連遺伝子又は免疫調節遺伝子の活性又は発現のレベルのうちの1つ又は複数を調節し、但し、前記遺伝子はCTLA4遺伝子ではない、請求項1又は2に記載のアンチセンスオリゴヌクレオチド。
- 前記発現のレベルは、前記免疫関連遺伝子又は免疫調節遺伝子のアイソフォーム発現を改変するスプラシング調節である、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは、免疫チェックポイント分子をブロックすることによりT細胞の機能を調節する、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記免疫チェックポイント分子はPD-1である、請求項5に記載のアンチセンスオリゴヌクレオチド。
- 前記発現のレベルは、前記免疫関連遺伝子又は免疫調節遺伝子の直接的な又は選択的な下方制御のうちの1つである、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、前記免疫関連遺伝子又は免疫調節遺伝子のプレmRNA又は成熟mRNAの標的領域に特異的にハイブリダイズする、請求項7に記載のアンチセンスオリゴヌクレオチド。
- 前記遺伝子は、IFN-γ、グランザイム、パーフォリン1、PD-1、PRDM1、PD-L1、CD40LG、NDFIP1、PDCD1LG2、REL、BTLA、CD80、CD160、CD244、LAG3、TIGIT. ADORA2A、及びTIM-3を含む群から選択されるいずれか1つである、請求項8に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、IFN-γ RNAのエクソン、イントロン、又はエクソン-イントロン境界の標的領域に特異的にハイブリダイズし、前記標的領域は、エクソン1及びエクソン2を含む群から選択されるいずれか1つである、請求項9に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、パーフォリンのエクソン、イントロン、又はエクソン-イントロン境界の標的領域に特異的にハイブリダイズし、前記標的領域はエクソン2bである、請求項9に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、グランザイムRNAのエクソン、イントロン、又はエクソン-イントロン境界の標的領域に特異的にハイブリダイズし、前記標的領域はエクソン3である、請求項9に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、PD-1 RNAのエクソン、イントロン、又はエクソン-イントロン境界の標的領域に特異的にハイブリダイズし、前記標的領域はエクソン2である、請求項9に記載のアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは、配列番号6508、69648、2565、7274、15372、63352、67190、66260、25333、25599、25676、43942、45170、45445、61632、及び53882のいずれか1つから選択される配列を含む、請求項1〜13のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは修飾ポリヌクレオチド骨格を含む、請求項1〜14のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾ポリヌクレオチド骨格は、ポリヌクレオチドの少なくとも1個の糖の代わりに修飾部分を含む、請求項15に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾部分は、ホスホロジアミデートモルホリノオリゴマー(PMO)、ペプチド結合ホスホロジアミデートモルホリノオリゴマー(PPMO)、及び非ペプチドデンドリマーオクタグアニジン部分タグ化モルホリノオリゴマーからなる群から選択される、請求項16に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾ポリヌクレオチド骨格は、少なくとも1個の修飾ヌクレオチド間連結を含む、請求項15〜17のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾ヌクレオチド間連結は修飾ホスフェートを含む、請求項18に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾ホスフェートは、硫黄原子を置換する非架橋酸素原子、ホスホネート、ホスホロチオエート、ホスホジエステル、ホスホロモルホリデート、ホスホロピペラジデート、及びホスホロアミデートを含む群から選択される、請求項19に記載のアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは、リボ核酸、デオキシリボ核酸、DNAホスホロチオエート、RNAホスホロチオエート、2’-O-メチル-オリゴリボヌクレオチド及び2’-O-メチル-オリゴデオキシリボヌクレオチド、2’-O-ヒドロカルビルリボ核酸、2’-O-ヒドロカルビルDNA、2’-O-ヒドロカルビルRNAホスホロチオエート、2’-O-ヒドロカルビルDNAホスホロチオエート、2’-F-ホスホロチオエート、2’-F-ホスホジエステル、2’-メトキシエチルホスホロチオエート、2-メトキシエチルホスホジエステル、デオキシメチレン(メチルイミノ)(デオキシMMI)、2’-O-ヒドロカルビルMMI、デオキシ-メチルホスホネート、2’-O-ヒドロカルビルメチルホスホネート、モルホリノ、4’-チオDNA、4’-チオRNA、ペプチド核酸、3’-アミデート、デオキシ3’-アミデート、2’-O-ヒドロカルビル3’-アミデート、ロックド核酸、シクロヘキサン核酸、三環式DNA、2’フルオロ-アラビノ核酸、N3’-P5’ホスホロアミデート、カルバメート連結、ホスホトリエステル連結、ナイロン骨格修飾、及び上述の骨格の混合物を含む群から選択される骨格を含む、請求項1〜20のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、前記アンチセンスオリゴヌクレオチドの活性、細胞分布、又は細胞取り込みを増強する1個又は複数個のコンジュゲートに化学的に連結されている、請求項1〜21のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 患者の癌又は自己免疫疾患の処置における使用のための請求項1〜22のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 前記疾患は癌であり、前記患者は、さらなる抗がん剤又は処置が施される患者である、請求項23に記載のアンチセンスオリゴヌクレオチド。
- 前記癌は、HBV誘発性HCC、EBV誘発性非ホジキンリンパ腫を含む群から選択されるいずれか1つである、請求項23又は24に記載のアンチセンスオリゴヌクレオチド。
- 請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチドと、薬学的に許容される担体とを含む医薬組成物。
- T細胞レセプター遺伝子をコードする核酸分子をさらに含む請求項26に記載の組成物。
- 前記核酸分子はmRNAである、請求項27に記載の組成物。
- 前記組成物は、裸で又は送達剤との複合体で、患者への非経口投与に適している、請求項26〜28のいずれか一項に記載の組成物。
- 前記担体は、ナノ粒子、例えば、ポリマーナノ粒子;リポソーム、例えば、pH感受性リポソーム、抗体結合リポソーム;ウイルスベクター、カチオン性脂質、ポリマー、UsnRNA、例えば、U7 snRNA、及び細胞膜透過ペプチドを含む群から選択される、請求項29に記載の組成物。
- 前記アンチセンスオリゴヌクレオチドが、経口投与、又は直腸投与、又は経粘膜投与、又は腸内投与、又は筋肉内投与、又は皮下投与、又は髄内投与、又は髄腔内投与、又は直接脳室内投与、又は静脈内投与、又は硝子体内投与、又は腹腔内投与、又は鼻腔内投与、又は眼内投与される、請求項26〜30のいずれか一項に記載の組成物。
- 患者の疾患を処置する方法であって、請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチド、又は請求項26〜31のいずれか一項に記載の組成物の薬学的有効量を投与することを含む方法。
- 前記アンチセンスオリゴヌクレオチドはT細胞にトランスフェクトされており、前記方法は、前記患者への前記トランスフェクトされたT細胞を投与することを含む、請求項32に記載の方法。
- 前記アンチセンスオリゴヌクレオチドは、ソノフォレーシス、電気パルス、エレクトロポレーション、浸透圧ショック、リン酸カルシウム沈殿、及びDEAEデキストラントランスフェクション、脂質媒介送達、及び受動送達を含む群から選択されるいずれか1つにより、T細胞にトランスフェクトされているか、又は導入されている、請求項33に記載の方法。
- 前記担体は、ナノ粒子、例えば、ポリマーナノ粒子;リポソーム、例えば、pH感受性リポソーム、抗体結合リポソーム;ウイルスベクター、カチオン性脂質、ポリマー、UsnRNA、例えば、U7 snRNA、及び細胞透過性ペプチドからなる群から選択される、請求項32〜34のいずれか一項に記載の方法。
- 前記アンチセンスオリゴヌクレオチド又は組成物が、経口投与、又は直腸投与、又は経粘膜投与、又は腸内投与、又は筋肉内投与、又は皮下投与、又は髄内投与、又は髄腔内投与、又は直接脳室内投与、又は静脈内投与、又は硝子体内投与、又は腹腔内投与、又は鼻腔内投与、又は眼内投与される、請求項32〜35のいずれか一項に記載の方法。
- 前記疾患は、HBV誘発性HCC、EBV誘発性非ホジキンリンパ腫を含む群から選択される癌である、請求項32〜36のいずれか一項に記載の方法。
- 医薬品における請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチドの使用。
- T細胞により発現される免疫関連遺伝子又は免疫調節遺伝子のプレmRNAのエクソンスキッピングを誘発する方法であって、請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチド又は請求項26〜31のいずれか一項に記載の組成物を細胞に送達することを含む方法。
- 前記細胞はヒト細胞である、請求項39に記載の方法。
- T細胞の機能を調節する方法であって、請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチドを前記T細胞に投与することを含む方法。
- 前記方法は、T細胞レセプター遺伝子をコードする核酸分子を前記T細胞に投与することにより前記T細胞の特異性を調節することをさらに含む、請求項41に記載の方法。
- T細胞レセプター遺伝子をコードする前記核酸分子を、ソノフォレーシス、電気パルス、エレクトロポレーション、浸透圧ショック、リン酸カルシウム沈殿、及びDEAEデキストラントランスフェクション、脂質媒介送達、及び受動送達を含む群から選択されるいずれか1つにより、前記T細胞にトランスフェクトさせるか、又は導入する、請求項42に記載の方法。
- 請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチドで形質転換されたか又はトランスフェクトされたT細胞。
- 前記アンチセンスオリゴヌクレオチドは、エレクトロポレーションにより前記T細胞にトランスフェクトされているか、又は導入されている、請求項44に記載のT細胞。
- T細胞レセプター遺伝子をコードする核酸分子をさらに含む請求項44又は45に記載のT細胞。
- 前記核酸分子はmRNAである、請求項46に記載のT細胞。
- 任意選択で容器中の、請求項1〜25のいずれか一項に記載のアンチセンスオリゴヌクレオチドと、パッケージ挿入物、パッケージラベル、説明書、又は他のラベリングとを含むキット。
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CN109477073B (zh) * | 2016-03-31 | 2024-04-12 | 来恩生物医药私人有限公司 | 表达外源病毒特异性t细胞受体(tcr)的非活化t细胞 |
US11312963B2 (en) * | 2018-10-18 | 2022-04-26 | Synerk Inc. | Compositions and methods for inhibiting TIGIT gene expression |
CA3132178A1 (en) | 2019-04-02 | 2020-10-08 | Aliye Seda Yilmaz-Elis | Antisense oligonucleotides for immunotherapy |
CN109988842B (zh) * | 2019-04-19 | 2022-12-06 | 上海吉玛制药技术有限公司 | 一种寡核苷酸标记探针原位检测pdl1的试剂组与应用 |
WO2020219977A1 (en) * | 2019-04-26 | 2020-10-29 | Stoke Therapeutics, Inc. | Methods and compositions for modulating splicing of alternative introns |
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US20230036569A1 (en) * | 2019-12-17 | 2023-02-02 | The General Hospital Corporation | Engineered immune cells with reduced toxicity and uses thereof |
WO2021173812A1 (en) * | 2020-02-28 | 2021-09-02 | Aligos Therapeutics, Inc. | Methods and compositions for targeting pd-l1 |
US20230183708A1 (en) * | 2020-04-30 | 2023-06-15 | Secarna Pharmaceuticals Gmbh & Co. Kg | PD-1-specific antisense oligonucleotide and its use in therapy |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010505741A (ja) * | 2006-05-10 | 2010-02-25 | エイブイアイ バイオファーマ, インコーポレイテッド | カチオン性のサブユニット間結合を有するオリゴヌクレオチドアナログ |
JP2017513485A (ja) * | 2014-04-18 | 2017-06-01 | エディタス・メディシン,インコーポレイテッド | がん免疫療法のためのcrispr−cas関連方法、組成物および構成要素 |
WO2017093969A1 (en) * | 2015-12-04 | 2017-06-08 | Novartis Ag | Compositions and methods for immunooncology |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6566132B1 (en) * | 2001-04-26 | 2003-05-20 | Isis Pharmaceuticals, Inc. | Antisense modulation of Interferon gamma receptor 1 expression |
US8501704B2 (en) * | 2005-11-08 | 2013-08-06 | Sarepta Therapeutics, Inc. | Immunosuppression compound and treatment method |
CA2628093A1 (en) * | 2005-11-08 | 2007-05-18 | Avi Biopharma, Inc. | Antisense oligonucleotide analog compounds targeting proprocessed ctla-4 mrna |
EP2295543A1 (en) * | 2009-09-11 | 2011-03-16 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Method for the preparation of an influenza virus |
WO2011120101A1 (en) * | 2010-04-01 | 2011-10-06 | The University Of Queensland | Small rna molecules and methods of use |
EP2825665B1 (en) * | 2012-03-14 | 2017-09-06 | Ruprecht-Karls-Universität Heidelberg | Epigenetic signatures as marker for cardiomyopathies and myocardial insufficiencies |
US20150017136A1 (en) * | 2013-07-15 | 2015-01-15 | Cellectis | Methods for engineering allogeneic and highly active t cell for immunotherapy |
WO2014078749A1 (en) * | 2012-11-15 | 2014-05-22 | The Regents Of The University Of California | Splice modulating oligonucleotides that inhibit cancer |
WO2014090985A1 (en) * | 2012-12-13 | 2014-06-19 | Universität Leipzig | T-cell modulation by exon skipping |
CN103820454B (zh) * | 2014-03-04 | 2016-03-30 | 上海金卫生物技术有限公司 | CRISPR-Cas9特异性敲除人PD1基因的方法以及用于特异性靶向PD1基因的sgRNA |
US9828601B2 (en) * | 2015-02-27 | 2017-11-28 | Idera Pharmaceuticals, Inc. | Compositions for inhibiting checkpoint gene expression and uses thereof |
IL254734B2 (en) * | 2015-03-27 | 2023-09-01 | Harvard College | Modified t cells and methods for their preparation and use |
JP6949728B2 (ja) * | 2015-05-29 | 2021-10-13 | ジュノー セラピューティクス インコーポレイテッド | 遺伝子操作された細胞における阻害相互作用を調節するための組成物および方法 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010505741A (ja) * | 2006-05-10 | 2010-02-25 | エイブイアイ バイオファーマ, インコーポレイテッド | カチオン性のサブユニット間結合を有するオリゴヌクレオチドアナログ |
JP2017513485A (ja) * | 2014-04-18 | 2017-06-01 | エディタス・メディシン,インコーポレイテッド | がん免疫療法のためのcrispr−cas関連方法、組成物および構成要素 |
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