JP2020517259A - 操作された抗原受容体を発現する免疫細胞 - Google Patents
操作された抗原受容体を発現する免疫細胞 Download PDFInfo
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Abstract
Description
2KB(Microsoft Windowsで測定した場合)であり、2018年4月18日に作成された「UTFCP1321WO_ST25.txt」の名称のファイルに含まれる配列表は、電子提出によって本明細書と共に出願され、本明細書に参考として組み込まれる。
本発明は、一般的に、免疫学および医学の分野に関する。より特定的には、本発明は、同じ細胞型において、抗原性受容体、例えば、キメラ抗原受容体およびT細胞受容体を発現する免疫細胞に関する。
癌と診断された患者が利用可能な診断および治療の選択肢における技術的進歩にもかかわらず、予後は依然として良くないことが多く、多くの患者は、治癒が不可能である。免疫療法は、種々の腫瘍と診断された患者に対する、正常組織に損傷を引き起こすことなく悪性腫瘍細胞を根絶する可能性を用いた、強力ではあるが、まだ標的化されていない治療を与える将来性を保持している。理論的に、免疫系のT細胞は、腫瘍細胞に特異的なタンパク質パターンを認識することができ、種々のエフェクター機能によるタンパク質パターンの破壊に介在する。養子T細胞療法は、患者自身のT細胞が腫瘍を根絶する能力を利用し、増幅させ、次いで、健康な組織に損傷を与えることなく、残った腫瘍を効果的になくすような状態で、これらのエフェクターを患者に戻す試みである。この手法は、腫瘍免疫学の分野で新しいものではないが、養子T細胞療法の臨床的使用における多くの欠点が、癌治療におけるこの手法の完全な使用を妨げている。
本開示は、免疫療法、癌および自己免疫障害を含む免疫関連疾患、および限定されないが、ウイルス(例えば、CMV、EBVおよびHIV)を含む感染の治療のための免疫療法のための抗原特異的免疫細胞(例えば、T細胞およびNK細胞)を提供することによる現在の技術に関連する問題を克服する。一実施形態では、本開示は、1個以上のT細胞受容体(TCR)を発現するNK細胞を提供する。従来の抗体が指向する標的抗原とは対照的に、TCRによって認識される抗原は、潜在的な細胞内タンパク質の全アレイを含んでいてもよく、これが処理され、ペプチド/MHC複合体として細胞表面に送達される。NK細胞は、内因性TCRを発現しないため、NK細胞への高アフィニティTCRの導入によって、外因性TCRおよび内因性TCRを発現するT細胞でみられるような混合ダイマーを生成するリスクなく、その抗原特異性を変える。NK細胞中で最適に機能する、より強力な受容体を作成するために、受容体は、共刺激ドメイン(限定されないが、CD28、41BBリガンド、DAP12、DAP10、またはこれらの任意の組み合わせを含む)、およびCD3ζシグナル伝達ドメインをベクター中に有していてもよい(図7D)。したがって、本開示はまた、通常はT細胞によってのみ認識される腫瘍および病原由来の標的抗原に対してNK細胞免疫療法を適用する方法を提供する。さらに、T細胞とは異なり、同種異系源に由来するNK細胞は、移植片対宿主病を誘発するリスクを増やさない。したがって、TCRを有する同種異系NK細胞を使用すると、養子治療のためのTCR操作されたNK細胞の潜在的な供給源を与える。
本明細書で使用される場合、具体的な構成要素に関して「本質的に含まない」は、具体的な構成要素が、組成物に意図的に配合されていないか、および/または混入物質として、または痕跡量のみが存在することを意味するために本明細書で使用される。したがって、ある組成物の意図しない混入から生じる具体的な構成要素の合計量は、0.05%より十分に低く、好ましくは、0.01%より低い。最も好ましいのは、具体的な構成要素が標準的な分析方法を用いて分析不可能である組成物である。
本開示の特定の実施形態は、キメラ抗原受容体(CAR)および/またはT細胞受容体(TCR)を発現する免疫細胞に関する。免疫細胞は、T細胞(例えば、制御性T細胞、CD4+T細胞、CD8+T細胞、またはガンマデルタT細胞)、NK細胞、インバリアントNK細胞、NKT細胞、幹細胞(例えば、間葉系幹細胞(MSC)または人工多能性幹(iPSC)細胞)であってもよい。いくつかの実施形態では、細胞は、単球または顆粒球、例えば、骨髄系細胞、マクロファージ、好中球、樹状細胞、マスト細胞、好酸球および/または好塩基球である。免疫細胞を製造し、操作する方法、養子細胞療法のために細胞を使用し、投与する方法も本明細書で提供され、どの場合でも、細胞は、自己由来であってもよく、または同種異系であってもよい。したがって、免疫細胞は、免疫療法として、例えば、癌細胞を標的化するために使用されてもよい。
いくつかの実施形態では、免疫細胞は、T細胞である。機能性抗腫瘍エフェクター細胞の誘導体化、活性化および増殖のためのいくつかの基本的な手法は、過去数十年間に記載されてきた。これらの細胞としては、自己由来細胞、例えば、腫瘍浸潤リンパ球(TIL);自己由来DC、リンパ球、人工の抗原提示細胞(APC)、またはT細胞リガンドおよび活性化抗体でコーティングされたビーズ、または標的細胞膜を捕捉するという観点で単離された細胞を用いてex−vivoで活性化されたT細胞;抗宿主腫瘍TCRを天然で発現する同種異系細胞;および「Tボディ」として知られる抗体に似た腫瘍認識能力を示す腫瘍反応性TCRまたはキメラTCR分子を発現するように遺伝的に再プログラム化または「再指令された」、腫瘍特異的ではない自己由来または同種異系細胞が挙げられる。これらの手法は、本明細書に記載の方法で使用可能なT細胞調製および免疫化のための多くのプロトコルを生じる。
いくつかの実施形態では、免疫細胞は、NK細胞である。NK細胞は骨髄および胸腺における種々の腫瘍細胞、ウイルス感染した細胞、およびいくつかの正常細胞に対し、自発的な細胞傷害性を有する、リンパ球の部分集合である。NK細胞は、形質変換され、ウイルス感染した細胞に対する初期の自然免疫応答の重要なエフェクターである。NK細胞は、ヒト末梢血中のリンパ球の約10%を構成する。リンパ球がIL−2存在下で培養される場合、強い細胞毒性の反応性が生じる。NK細胞は、サイズが大きいこと、その細胞質に特徴的なアズール顆粒が存在するため、大顆粒リンパ球として知られるエフェクター細胞である。NK細胞は、分化し、骨髄、リンパ節、脾臓、扁桃腺および胸腺で成熟する。NK細胞は、特定の表面マーカー、例えば、ヒトにおけるCD16、CD56およびCD8によって検出することができる。NK細胞は、T細胞抗原受容体、pan TマーカーCD3、または表面免疫グロブリンB細胞受容体を発現しない。
いくつかの実施形態では、本開示の免疫細胞は、幹細胞、例えば、人工多能性幹細胞(PSC)、間葉系幹細胞(MSC)または造血幹細胞(HSC)であってもよい。
免疫細胞(例えば、自己由来または同種異系T細胞(例えば、制御性T細胞、CD4+T細胞、CD8+T細胞、またはガンマデルタT細胞)、NK細胞、インバリアントNK細胞、NKT細胞、幹細胞(例えば、MSCまたはiPS細胞)は、操作されたTCRおよび/またはCARなどの抗原受容体を発現するように遺伝的に操作されていてもよい。例えば、宿主細胞(例えば、自己由来または同種異系のT細胞)は、癌抗原に対する抗原特異性を有するTCRを発現するように改変されている。特定の実施形態では、NK細胞は、TCRを発現するように操作されている。NK細胞は、CARを発現するようにさらに操作されていてもよい。複数のCARおよび/またはTCR(例えば、異なる抗原に対するもの)は、単一の細胞型(例えば、T細胞またはNK細胞)に加えられてもよい。
いくつかの実施形態では、CARは、(a)細胞内シグナル伝達ドメインと、(b)膜貫通ドメインと、(c)抗原結合領域を含む細胞外ドメインとを含む。
いくつかの実施形態では、遺伝的に操作された抗原受容体は、組換えTCRおよび/または天然に存在するT細胞からクローン化されたTCRを含む。「T細胞受容体」または「TCR」は、可変鎖およびβ鎖(それぞれTCRαおよびTCRβとしても知られる)または可変γ鎖およびδ鎖(これもそれぞれTCRγおよびTCRδとして知られる)を含み、MHC受容体に結合した抗原ペプチドに特異的に結合することが可能な分子を指す。いくつかの実施形態では、TCRは、αβ形態である。
抗原提示細胞は、マクロファージ、Bリンパ球および樹状細胞を含み、特定のMHC分子のこれらの発現とは区別される。APCは、抗原を内在化し、その外側細胞膜上のMHC分子と共に、その抗原の一部を再び発現する。MHCは、多重遺伝子座との大きな遺伝的複合体である。MHC遺伝子座は、クラスIおよびクラスII MHCと呼ばれる2つの主要なクラスのMHC膜分子をコードする。Tヘルパーリンパ球は、一般的に、MHCクラスII分子と会合する抗原を認識し、T細胞傷害性リンパ球は、MHCクラスI分子と会合する抗原を認識する。ヒトにおいて、MHCは、HLA複合体と呼ばれ、マウスにおいて、H−2複合体と呼ばれる。
インターロイキン−15(IL−15)は、組織制限されており、病的な状態でのみ、血清中または全身に任意のレベルで観察される。IL−15は、養子治療にとって望ましいいくつかの属性を有する。IL−15は、ナチュラルキラー細胞の成長および細胞増殖を誘発し、耐腫瘍性の細胞の機能的抑制を軽減することによって、確立された腫瘍の根絶を促進し、AICDを阻害する恒常性サイトカインである。
遺伝的に操作された抗原受容体によって標的とされる抗原は、特に、養子細胞治療によって標的とされる疾患、状態または細胞型の観点で表されるものである。特に、疾患および状態は、増殖性、新生物性および悪性の疾患および障害であり、癌および腫瘍を含み、血液癌、免疫系の癌、例えば、リンパ腫、白血病および/または骨髄腫、例えば、B、Tおよび骨髄性白血病、リンパ腫および多発性骨髄腫を含む。いくつかの実施形態では、抗原は、正常細胞または標的とされていない細胞または組織と比較して、疾患または状態の細胞、例えば、腫瘍または病原体細胞で選択的に発現するか、または過剰発現する。他の実施形態では、抗原は、正常細胞で発現するか、および/または操作された細胞で発現する。
本開示の免疫細胞のCARおよび/またはTCRは、1つ以上の自殺遺伝子を含んでいてもよい。「自殺遺伝子」との用語は、本明細書で使用される場合、プロドラッグを投与すると、その宿主細胞を死滅させる化合物への遺伝子産物の移動を行う遺伝子であると定義される。使用可能な自殺遺伝子/プロドラッグの組み合わせの例は、ヘルペス単純ウイルス−チミジンキナーゼ(HSV−tk)およびガンシクロビル、アシクロビル、またはFIAU;酸化還元酵素およびシクロヘキシミド;シトシンデアミナーゼおよび5−フルオロシトシン;チミジンキナーゼチミジレートキナーゼ(Tdk::Tmk)およびAZT;およびデオキシシチジンキナーゼおよびシトシンアラビノシドである。
当業者は、本開示の抗原受容体を発現するために、標準的な組換え技術によって、ベクターを構築する準備が十分にできているだろう(例えば、Sambrooket al.,2001およびAusubelet al.,1996、両方とも本明細書に参考として組み込まれる)。ベクターとしては、限定されないが、プラスミド、コスミド、ウイルス(バクテリオファージ、動物ウイルスおよび植物ウイルス)、および人工の染色体(例えば、YAC)、例えば、レトロウイルスベクター(例えばモロニーマウス白血病ウイルスベクター(MoMLV)、MSCV、SFFV、MPSV、SNVなどに由来するもの)、レンチウイルスベクター(例えばHIV−1、HIV−2、SIV、BIV、FIVなどに由来するもの)、複製能を有するもの、複製欠損およびその能力の低い形態を含む、アデノウイルス(Ad)ベクター、アデノ随伴ウイルス(AAV)ベクター、シミアンウイルス40(SV−40)ベクター、ウシパピローマウイルスベクター、Epstein−Barrウイルスベクター、ヘルペスウイルスベクター、ワクシニアウイルスベクター、ハーベイマウス肉腫ウイルスベクター、マウス乳腺腫瘍ウイルスベクター、ラウス肉腫ウイルスベクター、パルボウイルスベクター、ポリオウイルスベクター、水胞性口炎ウイルスベクター、マラバウイルスベクターおよびグループBアデノウイルスエナデノツシレブベクターが挙げられる。
抗原受容体をコードするウイルスベクターは、本開示の特定の態様で与えられてもよい。組換えウイルスベクターを作成する際に、必須ではない遺伝子は、典型的には、異種(または非ネイティブ)タンパク質の遺伝子またはコード配列と置き換えられる。ウイルスベクターは、核酸および場合によりタンパク質を細胞に導入するためにウイルス配列を利用する発現構築物の一種である。特定のウイルスが、受容体が介在するエンドサイトーシスを介して細胞を感染させ、または細胞に入り込む能力、宿主細胞ゲノムに組み込み、外来核酸を細胞(例えば、哺乳動物細胞)に移動するための魅力的な候補物にするウイルス遺伝子を安定にかつ効率的に発現する能力。本発明の特定の態様の核酸を送達するために使用可能なウイルスベクターの非限定例を以下に記載する。
本開示で有用なベクターに含まれる発現カセットは、特に、(5’から3’方向に)タンパク質コード配列、介在する配列を含むスプライスシグナルおよび転写停止/ポリアデニルか配列に作動可能に連結する真核生物転写プロモーターを含む。真核生物細胞においてタンパク質コード遺伝子の転写を制御するプロモーターおよびエンハンサーは、複数の遺伝子要素で構成される。細胞機構は、各要素によって運ばれてきた制御情報を集め、統合することができ、異なる遺伝子に、別個の、多くは複雑な転写制御パターンを発生させることができる。本開示の観点で私用されるプロモーターは、構成プロモーター、誘発性プロモーターおよび組織特異的プロモーターを含む。
本明細書で提供される発現構築物は、抗原受容体の発現を行わせるためのプロモーターを含む。プロモーターは、一般的に、RNA合成のための開始部位を位置決めするための機能を有する配列を含む。この最も良く知られた例は、TATAボックスであるが、TATAボックスを欠いたいくつかのプロモーター、例えば、哺乳動物ターミナルデオキシヌクレオチジルトランスフェラーゼ遺伝子のためのプロモーターおよびSV40後期遺伝子のためのプロモーターでは、開始部位自体の上にある別個の要素が、開始場所を固定するのに役立つ。さらなるプロモーター要素は、転写開始の頻度を制御する。典型的には、開始部位の領域から30110bp上流に位置しているが、多くのプロモーターは、同様に開始部位の下流の機能的要素を含有することが示されている。コード配列をプロモーターの「制御下」におくために、1つは、選択したプロモーターの(すなわち、3’の)「下流」にある転写リーディングフレームの転写開始部位の5’末端に置かれる。「上流」プロモーターは、DNAの転写を刺激し、コードRNAの発現を促進する。
特定の開始シグナルを、コード配列の効率的な翻訳のために、本開示で提供される発現構築物に使用してもよい。これらのシグナルとしては、ATG開始コドンまたは隣接配列が含まれる。ATG開始コドンを含む外因性翻訳制御シグナルが提供されることが必要な場合がある。当業者は、これを決定し、必要なシグナルを提供することが容易に可能であろう。全挿入物の翻訳を確実にするために、所望なコード配列のリーディングフレームと共に、開始コドンは、「フレーム内」になければならないことがよく知られている。外因性翻訳制御シグナルおよび開始コドンは、天然または合成のいずれかであってもよい。発現効率は、適切な転写エンハンサー要素を含むことによって高められるだろう。
宿主細胞中でベクターを増殖させるために、1つ以上の複製起点部位(多くは「ori」と呼ばれる)を含んでいてもよい(例えば、複製が開始される特定の核酸配列である、上述のようにEBVのoriP、またはプログラム化において同様の機能または向上した機能を有する遺伝的に操作されたoriPに対応する核酸配列)。または、上述の他の染色体外で複製するウイルスの複製起点または自己複製配列(ARS)を使用してもよい。
いくつかの実施形態では、本開示の構築物を含む細胞は、発現ベクターにマーカーを含ませることによって、in vitroまたはin vivoで特定されてもよい。このようなマーカーは、発現ベクターを含有する細胞の容易な特定を可能にする、細胞に対して特定可能な変化を与えるだろう。一般的に、選択マーカーは、選択を可能にする特性を与えるマーカーである。陽性選択マーカーは、マーカーの存在によって、その選択が可能になるマーカーであり、一方、陰性選択マーカーは、その存在が、その選択を妨げるマーカーである。陽性選択マーカーの一例は、薬物耐性マーカーである。
抗原受容体をコードする核酸のウイルス送達に加え、以下は、所与の宿主細胞に対する組換え遺伝子送達のさらなる方法であり、したがって、これも本開示で考慮される。
いくつかの実施形態では、本開示の免疫細胞は、グルココルチコイド受容体、TGFβ受容体(例えば、TGFβ−RII)および/またはCISHなどの特定の遺伝子の発現を変化させるように改変されている。一実施形態では、免疫細胞は、内因性TGFβを枯渇させるためのサイトカインシンクとして機能し得るドミナントネガティブTGFβ受容体II(TGFβRIIDN)を発現するように改変されてもよい。
いくつかの実施形態では、DNA標的化分子は、DNA結合タンパク質、例えば、エンドヌクレアーゼなどのエフェクタータンパク質に融合した、1つ以上のジンクフィンガータンパク質(ZFP)または転写アクチベーター様タンパク質(TAL)を含む。例としては、ZFN、TALEおよびTALENが挙げられる。
いくつかの実施形態では、DNA標的化分子は、天然に存在するか、または操作された(天然に存在しない)転写アクチベーター様タンパク質(TAL)DNA結合ドメイン、例えば、転写アクチベーター様タンパク質エフェクター(TALE)タンパク質を含む。例えば、本明細書に参考として組み込まれる米国特許公開第2011/0301073号を参照。
いくつかの実施形態では、変化は、1つ以上のDNA結合核酸を用いて行われ、例えば、RNA誘導型エンドヌクレアーゼ(RGEN)を介した変化である。例えば、変化は、クラスター化され、規則的に配置された短い回文反復(CRISPR)およびCRISPR関連(Cas)タンパク質を用いて行うことができる。一般的に、「CRISPRシステム」は、集合的に、Cas遺伝子をコードする配列、tracr(トランスで活性化するCRISPR)配列(例えば、tracrRNAまたは活性な部分的なtracrRNA)、tracr−mate配列(内因性CRISPRシステムの観点で、「直接反復」およびtracrRNAで処理された部分直接反復を包含する)、ガイド配列(内因性CRISPRシステムの観点で、「スペーサー」とも呼ばれる)および/またはCRISPR遺伝子座からの他の配列および転写体を含め、CRISPR関連(「Cas」)遺伝子の発現または活性の指令に関与する転写体および他の要素を指す。
が挙げられる。TGF−β受容体2のための例示的なgRNA配列としては、
が挙げられる。T7プロモーター、標的配列およびオーバーラップ配列は、配列
を有していてもよい。
いくつかの実施形態では、本開示は、本開示の免疫細胞の有効量を投与することを含む、免疫療法のための方法を提供する。一実施形態では、医学的な疾患または障害は、免疫応答を誘発する免疫細胞集合の移動によって治療される。本開示の特定の実施形態では、癌または感染は、免疫応答を誘発する免疫細胞集合の移動によって治療される。個人に、有効量の抗原特異的細胞療法を投与することを含む、前記個人において癌を治療するか、または癌の進行を遅らせる方法が本明細書で提供される。本発明の方法は、免疫障害、固形癌、血液癌およびウイルス感染の治療に適用されてもよい。
免疫細胞(例えば、T細胞またはNK細胞)と、医薬的に許容される担体とを含む医薬組成物および製剤も本明細書で提供される。
特定の実施形態では、本発明の実施形態の組成物および方法は、少なくとも1つのさらなる治療と組み合わせて、免疫細胞の集合を含む。さらなる治療は、放射線療法、外科手術(例えば、腫瘍摘出手術および乳腺切除)、化学療法、遺伝子療法、DNA療法、ウイルス療法、RNA療法、免疫療法、骨髄移植、ナノ治療、モノクローナル抗体療法、または上述のものの組み合わせであってもよい。さらなる治療は、補助療法または術前補助療法の形態であってもよい。
多種多様な化学療法剤を、本発明の実施形態にしたがって使用してもよい。「化学療法」との用語は、癌を治療するための薬物の使用を指す。「化学療法剤」は、癌の治療において投与される化合物または組成物を暗示するために使用される。これらの剤または薬物は、例えば、細胞周期に影響を与える段階で、細胞内のこれらの活性態様に分類される。または、ある剤は、DNAを直接的に架橋する能力、DNAにインターカレーションする能力、または核酸合成を行うことによって染色体および有糸分裂の異常を誘発する能力に基づいて特徴付けられてもよい。
DNA損傷を引き起こし、広範囲に使用されてきた他の因子としては、γ線、X腺として一般的に知られているもの、および/または腫瘍細胞への放射線同位体の指向性送達が挙げられる。マイクロ波、プロトンビーム照射(米国特許第5,760,395号および同第4,870,287号)、およびUV照射など、DNA損傷因子の他の形態も想定される。これらの因子の全てが、DNAに対し、DNAの前駆体に対し、DNAの複製および修復に対し、染色体のアセンブリおよび管理に対し、広範囲の損傷を与える可能性が最も高い。X線の投薬範囲は、長期間にわたって(3〜4週間)1日線量が50〜200レントゲンから、1回の線量2000〜6000レントゲンまでの範囲である。放射線同位体の投薬範囲は、非常にさまざまであり、同位体の半減期、発せられる放射線の強度および種類、新生物性細胞による取り込みに依存する。
当業者は、さらなる免疫療法を、本実施形態の方法と組み合わせて、または本実施形態の方法と共に使用してもよいことを理解するだろう。癌治療の観点で、免疫療法は、一般的に、癌細胞を標的とし、破壊するための免疫エフェクター細胞および分子の使用に依存する。リツキシマブ(RITUXAN(登録商標))は、このような一例である。免疫エフェクターは、例えば、腫瘍細胞表面にあるいくつかのマーカーに特異的な抗体であってもよい。抗体のみが、治療のエフェクターとして役立ってもよく、または細胞の死滅に実際に影響を与える様に、他の細胞を動員してもよい。抗体はまた、薬物または毒素(化学療法薬、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)に抱合され、標的化剤として役立ってもよい。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保有するリンパ球であってもよい。種々のエフェクター細胞は、細胞傷害性T細胞およびNK細胞を含む。
癌を有するヒトの約60%が、ある種の外科手術を受けており、予防手術、診断手術、または病気診断、治療、緩和の手術が含まれる。治療の外科手術は、癌組織の全てまたは一部を物理的に除去し、切除し、および/または破壊する切除術を含み、他の治療、例えば、本発明の実施形態の治療、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と組み合わせて使用されてもよい。腫瘍切除は、腫瘍の少なくとも一部の物理的な除去を指す。腫瘍切除に加え、外科手術による治療としては、レーザー手術、凍結手術、電気手術、および顕微鏡下手術(モース手術)が挙げられる。
他の剤を、治療の治療効能を高めるために、本発明の実施形態の特定の態様と組み合わせて使用してもよいことが想定される。これらのさらなる剤としては、細胞表面受容体およびGAP接合部のアップレギュレーションに影響を与える剤、細胞増殖抑制剤および分化剤、細胞接着阻害剤、アポトーシス誘発剤に対する過剰増殖性細胞の感度を高める剤、または他の生物学的剤が挙げられる。GAP接合部の数を増やすことによる、細胞内シグナル伝達の増加は、隣接する過剰増殖する細胞集合に対する抗過剰増殖効果を高めるだろう。他の実施形態では、治療の抗過剰増殖効能を高めるために、細胞増殖抑制剤および分化剤を、本発明の実施形態の特定の態様と組み合わせて使用してもよい。細胞接着の阻害剤は、本発明の実施形態の効能を高めると考えられる。細胞接着阻害剤の例は、焦点接着キナーゼ(FAK)阻害剤およびロバスタチンである。過剰増殖性細胞のアポトーシスに対する感度を高める他の剤、例えば、抗体c225を、治療効能を向上させるために、本発明の実施形態の特定の態様と組み合わせて使用してもよいことがさらに想定される。
免疫細胞を含む製造物品またはキットも本明細書で提供される。製造物品またはキットは、さらに、個人において癌を治療するか、または癌の進行を遅らせるために、または癌を有する個人の免疫機能を高めるために免疫細胞を用いるための指示を含む添付文書を含んでいてもよい。本明細書に記載する任意の抗原特異的免疫細胞は、製造物品またはキットに含まれていてもよい。適切な容器としては、例えば、瓶、バイアル、袋およびシリンジが挙げられる。容器は、種々の材料、例えば、ガラス、プラスチック(例えば、ポリ塩化ビニルまたはポリオレフィン)、または金属アロイ(例えば、ステンレス鋼またはハステロイ)から作られていてもよい。いくつかの実施形態では、容器は、製剤を保持し、ラベルが付けられているか、または関連して、容器は、使用のための指示を示していてもよい。製造物品またはキットは、他のバッファー、希釈剤、フィルター、ニードルおよびシリンジと、使用指示を含む添付文書を含め、商業的およびユーザの観点から望ましい他の材料をさらに含んでいてもよい。いくつかの実施形態では、製造物品は、別の剤(例えば、化学療法剤および抗新生物剤)のうち1つ以上をさらに含む。1つ以上の剤に適した容器としては、例えば、瓶、バイアル、袋およびシリンジが挙げられる。
以下の実施例は、本発明の好ましい実施形態を示すために含まれている。以下の実施例に開示される技術は、本発明の実施において十分に機能するように本願発明者によって開発された技術を表し、そのため、その実施のための好ましい態様を構成すると考えることができることが、当業者によって理解されるべきである。しかし、当業者は、本開示の観点で、開示される具体的な実施形態において、本発明の精神および範囲から逸脱することなく、同じまたは同様の結果が依然として得られる多くの変更をなし得ることを理解するべきである。
NK細胞は、臍帯血に由来し、その特異性は、移植片対宿主病(GVHD)のリスクを高めることなく、その抗腫瘍活性を高めることが可能な腫瘍特異的なキメラ抗原受容体(CAR)を発現するように遺伝的に操作し、そのため、治療(例えば、標的を発現する任意の癌の免疫療法)のための「既製品の」細胞源を与えることによって再変更された。遺伝子改変のために、CB−NK細胞を、レトロウイルス構築物(iC9/CAR.CS1/IL−15)を用いて形質導入し、腫瘍抗原CS1および標的骨髄腫を認識するように、その特異性を再変更させた。レトロウイルスベクターを用いて形質導入されたCB−NK細胞の形質導入効率をモニタリングし、導入遺伝子の発現が安定していることがわかった。2人の異なるドナー由来のNK細胞におけるCAR発現の形質導入効率を図1Aに示す。形質導入されたNK細胞を、CS1を発現する骨髄腫細胞株の優れた死滅性を発揮し(図1A)、CS1を発現する骨髄腫細胞株に応答して、より多くのエフェクターサイトカインを産生する(図1C)ことを観察した。
耐ステロイド性免疫細胞を製造するために、CRISPR−CAS9システムを使用し、gRNAの配列番号1〜2を用い、造血細胞中のグルココルチコイド受容体をノックアウトした。グルココルチコイド受容体ノックアウトのPCRによるスクリーニングは、T細胞およびNK細胞における効果的なノックダウンを示した(図3)。
次に、CRISPR−CAS9を使用し、CAR NK細胞においてTGFβをノックアウトし、CAR NK細胞を、外因性TGFβの免疫抑制効果に対して耐性にした。(図6A)TGFβ−RIIのノックアウトの成功は、CRISPR/CAS9技術を用いて達成された(配列番号3〜4のgRNAを用い、TGFβ−RIIのエキソン3のCas9およびgRNA標的化)(図6A)。野生型およびTGF−β−RIIノックアウトNK細胞を、10ng/mlの組換えTGF−βで48時間処理し、K562標的に対するこれらの応答を評価した。TGF−β−RIIノックアウトNK細胞は、外因性TGF−βの免疫抑制効果に対して耐性であることがわかった(図6B)。CRISPR/CAS9技術によるTGFβ−RIIノックアウトも、CAS9のみで処理したNK細胞と比較して、10ng/mlの組換えTGF−βに応答して、下流のSmad−2/3リン酸化を無効化することがわかった(図6C)。したがって、CRISPR−CAS9が介在するTGFβ−RIIのノックアウトによって、NK細胞をTGFβ耐性にする。
免疫細胞(例えば、T細胞またはNK細胞)は、血液、例えば、臍帯血由来であり、腫瘍特異的な抗原受容体、例えば、CARおよび/またはTCRを発現するように遺伝的に操作されている(図7A〜7D)。遺伝子改変のために、細胞を、レトロウイルス構築物(図7D)を用いて形質導入し、2つ以上の腫瘍抗原を認識するように、その特異性を再変更させた。形質導入効率および導入遺伝子発現をモニタリングする。これに加え、抗原特異的な標的細胞の死滅時の免疫細胞の効能を、細胞毒性アッセイによって測定する。
Claims (68)
- ヒトIL−15(hIL−15)および少なくとも2個の抗原受容体を発現するように操作された免疫細胞であって、前記少なくとも2個の抗原受容体が、キメラ抗原受容体(CAR)および/またはT細胞受容体(TCR)を含む、免疫細胞。
- 前記免疫細胞が、hIL−15、CARおよびTCRを発現するように操作されている、請求項1に記載の免疫細胞。
- 前記免疫細胞が、hIL−15および2個のCARを発現するように操作されている、請求項1に記載の免疫細胞。
- 前記免疫細胞が、hIL−15および2個のTCRを発現するように操作されている、請求項1に記載の免疫細胞。
- 前記免疫細胞が、3個、4個または5個の抗原受容体を発現するように操作されている、請求項1に記載の免疫細胞。
- 前記免疫細胞が、T細胞、末梢血リンパ球、NK細胞、インバリアントNK細胞、NKT細胞または幹細胞としてさらに定義される、請求項1〜5のいずれか一項に記載の免疫細胞。
- 前記免疫細胞がT細胞である、請求項1〜5のいずれか一項に記載の免疫細胞。
- 前記免疫細胞がNK細胞である、請求項1〜5のいずれか一項に記載の免疫細胞。
- 前記幹細胞が、間葉系幹細胞(MSC)または人工多能性幹(iPS)細胞である、請求項6に記載の免疫細胞。
- 前記免疫細胞が、iPS細胞に由来する、請求項1に記載の免疫細胞。
- 前記T細胞が、CD8+T細胞、CD4+T細胞またはガンマデルタT細胞である、請求項7に記載の免疫細胞。
- 前記T細胞が、細胞傷害性Tリンパ球(CTL)である、請求項7に記載の免疫細胞。
- 前記免疫細胞が、同種異系である、請求項6に記載の免疫細胞。
- 前記免疫細胞が、自己由来である、請求項6に記載の免疫細胞。
- 前記免疫細胞が、1つ以上のさらなるサイトカインを発現するように操作されている、請求項1〜13のいずれか一項に記載の免疫細胞。
- 前記1つ以上のさらなるサイトカインが、IL−21および/またはIL−2である、請求項15に記載の免疫細胞。
- 前記免疫細胞が、グルココルチコイド受容体、TGFβ受容体および/またはCISHの発現を本質的に有さないように操作されている、請求項1〜13のいずれか一項に記載の免疫細胞。
- 前記免疫細胞が、1つ以上のガイドRNAおよびCas9酵素を用いて操作されている、請求項17に記載の免疫細胞。
- 前記1つ以上のガイドRNAが、配列番号1〜2を含む、請求項18に記載の免疫細胞。
- 前記1つ以上のガイドRNAが、配列番号3〜4を含む、請求項18に記載の免疫細胞。
- 前記TGFβ受容体が、TGFβ−RIIとしてさらに定義される、請求項17に記載の免疫細胞。
- 前記免疫細胞が、末梢血、臍帯血または骨髄から単離される、請求項1〜13のいずれか一項に記載の免疫細胞。
- 前記免疫細胞が、臍帯血から単離される、請求項1〜13のいずれか一項に記載の免疫細胞。
- 前記臍帯血が、2人以上の個人の臍帯血単位からプールされる、請求項23に記載の免疫細胞。
- 前記免疫細胞が、自殺遺伝子をさらに発現する、請求項1〜13のいずれか一項に記載の免疫細胞。
- 前記自殺遺伝子は、CD20、CD52、EGFRv3または誘導性カスパーゼ9である、請求項25に記載の免疫細胞。
- 前記自殺遺伝子が、誘導性カスパーゼ9である、請求項25に記載の免疫細胞。
- 少なくとも2個の抗原受容体をコードするDNAが、前記細胞のゲノムに組み込まれる、請求項1に記載の免疫細胞。
- 前記CARおよび/またはTCRをコードするDNAが、前記細胞のゲノムに組み込まれる、請求項1に記載の免疫細胞。
- 前記少なくとも2個の抗原受容体が、F(ab’)2、Fab’、Fab、FvおよびscFvからなる群から選択される抗原結合領域を含む、請求項1に記載の免疫細胞。
- 前記少なくとも2個の抗原受容体の抗原結合領域が、1つ以上の腫瘍関連抗原に結合する、請求項30に記載の免疫細胞。
- 前記腫瘍関連抗原は、CD19、CD319/CS1、ROR1、CD20、癌胎児性抗原、アルファフェトプロテイン、CA−125、MUC−1、上皮性腫瘍抗原、メラノーマ関連抗原、変異p53、変異ras、HER2/Neu、ERBB2、葉酸結合タンパク質、HIV−1外被糖タンパク質gp120、HIV−1外被糖タンパク質gp41、GD2、CD123、CD23、CD30、CD56、c−Met、メソテリン、GD3、HERV−K、IL−11Rα、κ鎖、λ鎖、CSPG4、ERBB2、WT−1、EGFRvIII、TRAIL/DR4および/またはVEGFR2である、請求項31に記載の免疫細胞。
- 第1の抗原受容体の抗原結合領域は、第2の抗原受容体の抗原結合領域とは異なる、請求項30に記載の免疫細胞。
- 前記第1の抗原受容体の抗原結合領域は、第1の抗原に結合し、前記第2の抗原受容体の抗原結合領域は、第2の抗原に結合する、請求項32に記載の免疫細胞。
- 前記第1の抗原がEGFRvIIIであり、前記第2の抗原がNY−ESOである、請求項34に記載の免疫細胞。
- 前記第1の抗原がHER2/Neuであり、前記第2の抗原がMUC−1である、請求項34に記載の免疫細胞。
- 前記第1の抗原がCA−125であり、前記第2の抗原がMUC−1である、請求項34に記載の免疫細胞。
- 前記第1の抗原がCA−125であり、前記第2の抗原がWT−1である、請求項34に記載の免疫細胞。
- 前記第1の抗原がEGFRvIIIであり、前記第2の抗原が、Mage−A3、Mage−A4またはMage−A10である、請求項34に記載の免疫細胞。
- 前記第1の抗原がEGFRvIIIであり、前記第2の抗原がTRAIL/DR4である、請求項34に記載の免疫細胞。
- 前記第1の抗原がCEA−CARであり、前記第2の抗原が、Mage−A3−TCR、Mage−A4−TCRまたはMage−A10である、請求項34に記載の免疫細胞。
- 前記第1の抗原が、HER2/Neu、CEA−CARおよび/またはCA−125、EGFRvIIIであり、前記第2の抗原が、MUC−1、WT−1、TRAIL/DR4Mage−A3−TCR、Mage−A4−TCRおよび/またはMage−A10である、請求項34に記載の免疫細胞。
- 前記少なくとも2個の抗原受容体が、1つ以上の細胞内シグナル伝達ドメインを含む、請求項1〜13のいずれか一項に記載の免疫細胞。
- 前記1つ以上の細胞内シグナル伝達ドメインが、Tリンパ球活性化ドメインである、請求項42に記載の免疫細胞。
- 前記1つ以上の細胞内シグナル伝達ドメインが、CD3ξ、CD28、OX40/CD134、4−1BB/CD137、FcεRIγ、ICOS/CD278、ILRB/CD122、IL−2RG/CD132、DAP12、CD70、CD40、またはこれらの組み合わせを含む、請求項42に記載の免疫細胞。
- 前記1つ以上の細胞内シグナル伝達ドメインが、CD3ξ、CD28、4−1BB−Lおよび/またはDAP12を含む、請求項42に記載の免疫細胞。
- 前記少なくとも2個の抗原受容体が、1つ以上の膜貫通ドメインを含む、請求項1に記載の免疫細胞。
- 前記1つ以上の膜貫通ドメインが、CD28膜貫通ドメイン、IgG4Fcヒンジ、Fc領域、CD4膜貫通ドメイン、CD3ξ膜貫通ドメイン、システイン変異ヒトCD3ξドメイン、CD16膜貫通ドメイン、CD8膜貫通ドメインおよび/またはエリスロポエチン受容体膜貫通ドメインを含む、請求項47に記載の免疫細胞。
- 請求項1〜48のいずれか一項に記載の免疫細胞の有効量を含む医薬組成物。
- 対象における免疫関連障害の治療のための、請求項1〜48のいずれか一項に記載の免疫細胞の免疫細胞の有効量を含む組成物。
- 対象における免疫関連障害の治療のための、請求項1〜48のいずれか一項に記載の免疫細胞の免疫細胞の有効量を含む組成物の使用。
- 請求項1〜48のいずれか一項に記載の免疫細胞の有効量を対象に投与することを含む、前記対象において免疫関連障害を治療する方法。
- 前記免疫関連障害が、癌、自己免疫障害、移植片対宿主病、同種移植拒絶または炎症状態である、請求項52に記載の方法。
- 前記免疫関連障害が炎症状態であり、前記免疫細胞は、グルココルチコイド受容体の発現を本質的に有さない、請求項52に記載の方法。
- 前記対象が、ステロイド治療を施されていたか、または施されている、請求項54に記載の方法。
- 前記免疫細胞が、自己由来である、請求項52に記載の方法。
- 前記免疫細胞が、同種異系である、請求項52に記載の方法。
- 前記免疫関連障害が癌である、請求項52に記載の方法。
- 前記癌が、固形癌または血液悪性腫瘍である、請求項58に記載の方法。
- 前記癌が、卵巣癌であり、前記免疫細胞が、MUC−1、CA−125および/またはWT−1に対する抗原特異性を有する、請求項58に記載の方法。
- 前記癌が、肺癌であり、前記免疫細胞が、NY−ESO、EGFR−vIII、Mage−A3、Mage−A4、Mage−A10および/またはTRAIL/DR4に対する抗原特異性を有する、請求項58に記載の方法。
- 前記癌が、膵臓癌または結腸癌であり、前記免疫細胞が、Mage−A3、Mage−A4、Mage−A10および/またはCEAに対する抗原特異性を有する、請求項58に記載の方法。
- 前記癌が乳癌であり、前記免疫細胞が、MUC−1およびHER2/Neuに対する抗原特異性を有する、請求項58に記載の方法。
- 前記癌が膠芽腫であり、前記免疫細胞が、Mage−A3、Mage−A4、Mage−A10vおよび/またはEGFRvIIIに対する抗原特異性を有する、請求項58に記載の方法。
- 前記癌が肉腫であり、前記免疫細胞が、NY−ESOおよびEGFR−vIIIに対する抗原特異性を有する、請求項58に記載の方法。
- 少なくとも第2の治療剤を投与することをさらに含む、請求項52に記載の方法。
- 前記少なくとも第2の治療剤は、化学療法、免疫療法、外科手術、放射線療法または生物学的療法を含む、請求項66に記載の方法。
- 前記免疫細胞および/もしくは前記少なくとも第2の治療剤は、静脈内、腹腔内、気管内、腫瘍内、筋肉内、内視鏡的、病変内、経皮的、皮下的、局所的に投与されるか、または直接的な注射もしくは灌流によって投与される、請求項66に記載の方法。
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CN110753555A (zh) | 2020-02-04 |
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CA3060443A1 (en) | 2018-10-25 |
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