JP2019503672A - T細胞受容体の標的化破壊 - Google Patents
T細胞受容体の標的化破壊 Download PDFInfo
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Abstract
Description
本出願は、2015年12月18日に出願された米国仮出願第62/269,365号および2016年3月10日に出願された米国仮出願第62/306,500号の利益を主張し、これらの開示は、その全体が本明細書において参考として援用される。
本開示は、リンパ球および幹細胞を含むヒト細胞のゲノム改変の分野にある。
遺伝子治療は、ヒト治療学の新しい時代の莫大な潜在性を秘める。これらの方法論は、標準医療行為によって対処可能ではなかった状態のための処置を可能にする。遺伝子治療は、遺伝子座の破壊もしくは補正、および導入遺伝子に融合させた特異的外因性プロモーターによって、またはゲノムへの挿入部位で見出される内因性プロモーターによって調節することができる発現可能な導入遺伝子の挿入などの、ゲノム編集技術の多くの変形を含むことができる。
しかし養子細胞療法の欠点の1つは、移植された細胞の潜在的拒絶を回避するために細胞産物の供給源が患者特異的(自己)でなければならないことである。このことがこの拒絶を回避するために研究者に患者自身のT細胞を編集する方法を開発させた。例えば、患者のT細胞または造血幹細胞は、工学技術で作製されたCAR、ACTRおよび/またはT細胞受容体(TCR)の付加によりex vivoで操作することができ、次にPD1および/またはCTLA4などのT細胞チェックポイントインヒビターをノックアウトするために工学技術で作製されたヌクレアーゼによりさらに処置することができる(PCT公開WO2014/059173を参照)。より大きな患者集団へのこの技術の応用のために、細胞(同種)の汎用性集団を開発することは有利である。さらにTCRのノックアウトは、患者に導入されても移植片対宿主病(GVHD)応答を開始することができない細胞をもたらす。
したがって、T細胞でのTCR発現を改変(例えば、ノックアウト)するために使用することができる方法および組成物の必要性がまだある。
本明細書で、TCR遺伝子の部分的なまたは完全な不活性化または破壊のための組成物および方法、ならびに内因性TCRの破壊後もしくは破壊と同時のTリンパ球における外因性TCR導入遺伝子の導入および所望のレベルでの発現のための組成物および方法が開示される。さらに、本明細書で、TCRヌルT細胞、幹細胞、組織または生物全体、例えばその表面に1つまたは複数のT細胞受容体を発現しない細胞、を産生するためにTCR遺伝子を欠失させる(不活性化する)または抑制するための方法および組成物が提供される。ある特定の実施形態ではTCRヌル細胞または組織は、移植における使用のために有利であるヒト細胞または組織である。好ましい実施形態ではTCRヌルT細胞は、養子T細胞療法における使用のために調製される。
本明細書で、細胞表面上にTCRをもはや含まないようにTCR遺伝子の発現がモジュレートされている細胞を生成するための組成物および方法が開示される。この様式で改変された細胞は、TCR複合体の欠如がHLAベースの免疫応答を予防または低減することから治療剤、例えば移植片として使用することができる。さらに目的の他の遺伝子は、TCR遺伝子が操作されている細胞に挿入することができる、および/または目的の他の遺伝子をノックアウトすることができる。
本明細書に開示される方法の実施、ならびに組成物の調製および使用は、別途指示がない限り、分子生物学、生化学、クロマチン構造および分析、計算化学、細胞培養、組換えDNAおよび当技術分野の範囲内である関連分野における従来の技術を用いる。これらの技術は、文献において詳細に説明される。例えば、Sambrookら、MOLECULAR CLONING: A LABORATORY MANUAL、第2版、Cold Spring Harbor Laboratory Press、1989年および第3版、2001年;Ausubelら、CURRENT PROTOCOLS IN MOLECULAR BIOLOGY、John Wiley & Sons、New York、1987年および定期の最新版;シリーズMETHODS IN ENZYMOLOGY、Academic Press、San Diego;Wolffe、CHROMATIN STRUCTURE AND FUNCTION、第3版、Academic Press、San Diego、1998年;METHODS IN ENZYMOLOGY、第304巻、「Chromatin」(P.M. WassarmanおよびA. P. Wolffe編)、Academic Press、San Diego、1999年;およびMETHODS IN MOLECULAR BIOLOGY、第119巻、「Chromatin Protocols」(P.B. Becker編)、Humana Press、Totowa、1999年を参照のこと。
用語「核酸」、「ポリヌクレオチド」および「オリゴヌクレオチド」は互換的に使用され、直鎖状または環状の立体配座の、および一本鎖または二本鎖の形のデオキシリボヌクレオチドまたはリボヌクレオチドポリマーを指す。本開示のために、これらの用語は、ポリマーの長さに関して制限するものと解釈されるべきでない。これらの用語は、天然のヌクレオチドならびに塩基、糖および/またはリン酸部分(例えば、ホスホロチオエート骨格)が修飾されるヌクレオチドの公知の類似体を包含することができる。一般に、特定のヌクレオチドの類似体は、同じ塩基対合特異性を有する;すなわち、Aの類似体はTと塩基対合する。
核酸、主にDNA、ならびにヒストンおよび非ヒストン染色体タンパク質を含むタンパク質を含む。大多数の真核生物の細胞クロマチンはヌクレオソームの形で存在し、ここで、ヌクレオソームコアはヒストンH2A、H2B、H3およびH4の各々2つを含む八量体に会合した概ね150塩基対のDNAを含み;リンカーDNA(生物体によって様々な長さの)がヌクレオソームコアの間に延びる。ヒストンH1の分子は、リンカーDNAに一般的に会合している。本開示のために、用語「クロマチン」は、原核生物および真核生物の両方の、全てのタイプの細胞核タンパク質の包含を意味するものである。細胞クロマチンには、染色体およびエピソームの両方のクロマチンが含まれる。
(i)哺乳動物において、具体的にはそのような哺乳動物が状態になりやすい素因を有するが、それを有するとしてまだ診断されていない場合に、疾患または状態の出現を予防すること;
(ii)疾患または状態を抑制すること、すなわちその発症を抑止すること;
(iii)疾患もしくは状態を緩和すること、すなわち疾患もしくは状態の退縮をもたらすこと;または
(iv)疾患もしくは状態から生じる症状を緩和すること、すなわち根底にある疾患もしくは状態に対処すること無く疼痛を緩和すること
が含まれる。
本明細書で、HLA遺伝子またはHLA制御因子を含む任意の遺伝子中の標的部位に特異的に結合するDNA結合ドメインを含む組成物が記載される。任意のDNA結合ドメインは、本明細書で開示される組成物および方法において使用することができ、限定されずにジンクフィンガーDNA結合ドメイン、TALE DNA結合ドメイン、CRISPR/CasヌクレアーゼのDNA結合部分(sgRNA)またはメガヌクレアーゼ由来DNA結合ドメインが含まれる。DNA結合ドメインは、限定されずに、本明細書に開示される標的部位のいずれかに示す(配列番号8〜21および/または92〜103)12またはそれより多いヌクレオチドの標的配列を含む、遺伝子内の任意の標的配列に結合することができる。
本明細書に記載されるDNA結合ドメイン(例えば、ZFPまたはTALE、単一ガイドRNAなどのCRISPR/Cas構成成分)を含み異種制御(機能的)ドメイン(またはその機能性断片)と会合する融合分子も提供される。共通ドメインには、例えば、転写因子ドメイン(活性化因子、抑制因子、共活性化因子、共抑制因子)、サイレンサー、オンコジーン(例えば、myc、jun、fos、myb、max、mad、rel、ets、bcl、myb、mosファミリーメンバーなど);DNA修復酵素およびそれらの関連因子およびモディファイヤー;DNA再編成酵素およびそれらの関連因子およびモディファイヤー;クロマチン関連タンパク質およびそれらのモディファイヤー(例えばキナーゼ、アセチラーゼおよび脱アセチル化酵素);ならびにDNA改変酵素(例えば、メチル基転移酵素、トポイソメラーゼ、ヘリカーゼ、リガーゼ、キナーゼ、ホスファターゼ、ポリメラーゼ、エンドヌクレアーゼ)およびそれらの関連因子およびモディファイヤーが含まれる。そのような融合分子には、本明細書に記載されるDNA結合ドメインを含む転写因子および転写制御ドメインならびにDNA結合ドメインを含むヌクレアーゼおよび1つまたは複数のヌクレアーゼドメインが含まれる。
ある特定の実施形態では融合分子は、切断(ヌクレアーゼ)ドメインと会合しているDNA結合ドメインを含む。そのように遺伝子改変は、ヌクレアーゼ、例えば工学技術で作製されたヌクレアーゼを使用して達成することができる。工学技術で作製されるヌクレアーゼ技術は、天然に存在するDNA結合タンパク質の工学技術に基づいている。例えば、目的に合わせたDNA結合特異性を有するホーミングエンドヌクレアーゼの工学技術は記載されている。Chamesら(2005年)Nucleic Acids Res 33巻(20号):e178頁、Arnouldら(2006年)J. Mol. Biol. 355巻:443〜458頁。さらに、ZFPの工学技術も記載されている。例えば米国特許第6,534,261号、第6,607,882号、第6,824,978号、第6,979,539号、第6,933,113号、第7,163,824号および第7,013,219号を参照。
年)Nucleic Acids Res.31巻:418〜420頁を参照のこと。
送達
されたい)。
開示される組成物および方法は、限定されずに、TCRモジュレーションが望ましい治療用および研究用応用を含む、TCR発現および/または機能性をモジュレートすることが望ましい任意の応用のために使用することができる。例えば開示される組成物は、養子細胞療法のために1つもしくは複数の外因性CAR、外因性TCRまたは他のがん特異的受容体分子を発現し、それによりがんを処置および/または予防するように改変されたT細胞において、内因性TCRの発現を破壊するためにin vivoおよび/またはex vivo(細胞治療)で使用することができる。さらにそのような状況において、細胞内でのTCR発現の抑止は、健康な、非標的化組織との不必要な交差反応(すなわち移植片対宿主応答)の危険を除去または実質的に低減することができる。
TCR−特異的ヌクレアーゼの設計
TCR特異的ZFNをTCRα(TCRA)遺伝子での二本鎖切断の部位特異的導入を可能にするために構築した。ZFNをUrnovら(2005年)Nature 435巻(7042号):646〜651頁、Lombardoら(2007年)Nat Biotechnol. Nov;25巻(11号):1298〜306頁および米国特許出願公開第2008−0131962号、第2015−016495号、第2014−0120622号、第2014−0301990号および米国特許第8,956,828号に本質的に記載の通り設計した。ZFN対は、TCRA遺伝子の定常領域中の異なる部位を標的とした(図1を参照)。例示的ZFN対に対する認識ヘリックスならびに標的配列を下の表1に示す。TCRAジンクフィンガー設計の標的部位を第1カラムに示す。ZFP認識ヘリックスによって標的化される標的部位中のヌクレオチドを大文字で示し;非標的化ヌクレオチドを小文字で示す。FokIヌクレアーゼドメインとZFP DNA結合ドメインとを繋ぐために使用されるリンカーも示す(米国特許出願公開第20150132269号を参照)。例えばドメインリンカーL0のアミノ酸配列は、DNA結合ドメイン−QLVKS−FokIヌクレアーゼドメイン(配列番号5)である。同様にドメインリンカーN7aについてのアミノ酸配列は、FokIヌクレアーゼドメイン−SGTPHEVGVYTL−DNA結合ドメイン(配列番号6)であり、N7cはFokIヌクレアーゼドメイン−SGAIRCHDEFWF−DNA結合ドメイン(配列番号7)である。
in vitroヌクレアーゼ活性
表1に記載するZFNをK562細胞におけるヌクレアーゼ活性を検査するために使用した。切断活性を検査するために、上に記載のヒトTCRA特異的ZFNの対をコードするプラスミドをプラスミドまたはmRNAを用いてK562細胞にトランスフェクトした。K562細胞は、American Type Culture Collectionから得て、推奨の通り10%品質認定済みウシ胎児血清(FBS、Cyclone)を補充したRPMI培地(Invitrogen)中で成長させた。トランスフェクションのために、表1に列挙した活性ヌクレアーゼについてのORFを、5’および3’UTRならびに合成ポリAシグナルを有する、mRNA産物のために最適化した発現ベクターにクローニングした。mRNAを製造者の指示に従ってmMessage mMachine T7 Ultra kit(Ambion)を使用して生成した。ヌクレアーゼmRNAのin vitro合成は、T7プロモーター、適切なヌクレアーゼおよびin vitro転写反応に続くポリAテールの酵素的付加のためのポリAモチーフを含有するpVAXベースのベクター、またはT7プロモーター、5’UTR、適切なヌクレアーゼ、3’UTRおよび64bpポリAストレッチを含有するpGEMベースのベクター、またはT7プロモーター、5’UTR、適切なヌクレアーゼ、3’UTRおよび60bpポリAストレッチを含有するPCRアンプリコンのいずれかを使用した。K562細胞、100万個を250ngまたは500ngのZFNコードmRNAと混合した。細胞を、プログラムT−16を使用してAmaxa Nucleofector II(商標)においてトランスフェクトし、1.4mLの温かいRPMI培地+10%FBSに回収した。ヌクレアーゼ活性を、標準的プロトコールによりトランスフェクション3日後にディープシークエンシング(MiSeq、Illumina)によって評価した。結果を下の表3に提示する。
T細胞におけるTCRA特異的ZFN活性
標的化組み込みによるB2MおよびTCRAのダブルノックアウト
上に記載のヌクレアーゼおよび表5に記載されるB2M標的化ヌクレアーゼ(米国仮特許出願第62/269,410号、2015年12月18日出願;第62/305,097号および米国仮特許出願第62/329,439号も参照)をB2MおよびTCRAを不活性化し、標的化組み込みを介してドナー(導入遺伝子)をTCRAまたはB2M遺伝子座のいずれかに導入するために使用した。B2M特異的ZFNを下の表5に示す:
(a)群1(TCRAおよびB2M ZFNのみ、ドナーなし):TCRA 120ug/mL:B2Mのみ60ug/mL;
(b)群2(TCRAおよびB2M ZFNならびにTCRA相同アームを有するドナー):TCRA 120ug/mL;B2M 60ug/mLおよびAAV(TCRA−Site E−hPGK−eGFP−Clone E2)1E5vg/細胞;
(c)群3(TCRAおよびB2M ZFNならびにTCRA相同アームを有するドナー):TCRA 120ug/mL;B2M 60ug/mL;およびAAV(TCRA−Site E−hPGK−eGFP−Clone E2)3E4vg/細胞;
(d)群4(TCRAおよびB2M ZFNならびにB2M相同アームを有するドナー):TCRA 120ug/mL;B2M 60ug/mLおよびAAV(pAAV B2M−hPGK GFP)1E5vg/細胞
(e)群5(TCRAおよびB2M ZFNならびにB2M相同アームを有するドナー):TCRA 120ug/mL;B2M 60ug/mLおよびAAV(pAAV B2M−hPGK GFP)3E4vg/細胞。
全ての実験は、3e7細胞/mlの細胞密度で米国特許出願第15/347,182号に記載のプロトコール(超低温ショック(extreme cold shock))を使用して実施し、電気穿孔後に、30℃、一晩の低温ショックのために培養した。
TCR−特異的ヌクレアーゼの設計
TCR特異的ZFNをTCRα(TCRA)遺伝子での二本鎖切断の部位特異的導入を可能にするために構築した。ZFNをUrnovら(2005年)Nature 435巻(7042号):646〜651頁、Lombardoら(2007年)Nat Biotechnol. Nov;25巻(11号):1298〜306頁および米国特許出願公開第2008−0131962号、第2015−016495号、第2014−0120622号、第2014−0301990号および米国特許第8,956,828号に本質的に記載の通り設計した。ZFN対は、TCRA遺伝子の定常領域中の異なる部位を標的とした(図1を参照)。例示的ZFN対に対する認識ヘリックスならびに標的配列を下の表1に示す。TCRAジンクフィンガー設計の標的部位を第1カラムに示す。ZFP認識ヘリックスによって標的化される標的部位中のヌクレオチドを大文字で示し;非標的化ヌクレオチドを小文字で示す。FokIヌクレアーゼドメインとZFP DNA結合ドメインとを繋ぐために使用されるリンカーも示す(米国特許出願公開第20150132269号を参照)。例えばドメインリンカーL0のアミノ酸配列は、DNA結合ドメイン−QLVKS−FokIヌクレアーゼドメイン(配列番号5)である。同様にドメインリンカーN7aについてのアミノ酸配列は、FokIヌクレアーゼドメイン−SGTPHEVGVYTL−DNA結合ドメイン(配列番号6)であり、N7cはFokIヌクレアーゼドメイン−SGAIRCHDEFWF−DNA結合ドメイン(配列番号7)である。
Claims (13)
- T細胞受容体(TCR)遺伝子の発現がTCRA遺伝子のエクソンc1、c2またはc3の改変によってモジュレートされる、単離細胞。
- 配列番号8〜21および/または92〜103のいずれかに示す標的部位に結合するDNA結合ドメインならびに機能的(fumctional)ドメインを含む外因性融合分子を含む、請求項1に記載の細胞。
- 配列番号8〜21、92〜103、AACAGT、AGTGCT、CTCCT、TTGAAA、TGGACTTおよび/またはAATCCTCの1つまたは複数の中に挿入および/または欠失を含む、請求項1に記載の細胞。
- 不活性化ベータ2ミクログロブリン(B2M)、PD1および/またはCTLA4遺伝子をさらに含む、請求項1から3のいずれかに記載の細胞。
- キメラ抗原受容体(CAR)をコードする導入遺伝子、抗体結合T細胞受容体(ACTR)をコードする導入遺伝子および/または工学技術で作製されたTCRをコードする導入遺伝子をさらに含む、請求項1から4のいずれかに記載の細胞。
- リンパ系細胞、幹細胞または前駆細胞である、請求項1から5のいずれかに記載の細胞。
- T細胞、人工多能性幹細胞(iPSC)、胚性幹細胞、間葉系幹細胞(MSC)または造血幹細胞(HSC)である、請求項5に記載の細胞。
- 請求項1から7のいずれかに記載の細胞を含む、医薬組成物。
- TCR遺伝子のエクソンc1、c2またはc3に結合するDNA結合ドメインと、転写制御ドメインまたはヌクレアーゼドメインとを含む融合分子であって、該DNA結合ドメインが表1の1つの行に示すジンクフィンガータンパク質(ZFP)または表2の1つの行に示す単一ガイドRNA(sgRNA)を含む、融合分子。
- 請求項9に記載の前記融合分子をコードする、ポリヌクレオチド。
- ウイルスベクター、プラスミドまたはmRNAである、請求項10に記載のポリヌクレオチド。
- 請求項1から7のいずれかに記載の細胞または請求項8に記載の医薬組成物をがんを有する被験体に導入することを含む、がんを処置または予防する方法。
- 請求項1から7のいずれかに記載の細胞、請求項8に記載の医薬組成物または請求項9に記載の融合分子または請求項10に記載のポリヌクレオチドの、がんを有する被験体の処置のための使用。
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