JP6821688B2 - キメラ抗原受容体および使用方法 - Google Patents
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Description
本出願は、米国特許法第119条(e)の下で、その全内容が参照により本明細書に組み込まれる、2015年10月9日出願の米国仮特許出願第62/239,509号に対する優先権の利益を主張する。
本出願は、がんの分野、特に、腫瘍壊死因子受容体スーパーファミリーメンバーの膜貫通ドメインを含むキメラ抗原受容体(CAR)および使用方法に関する。
がんは、ヒトの健康に対する重大な脅威の1つである。米国だけで、がんは毎年ほぼ130万人の新たな患者が罹患し、心血管疾患に次いで2番目に多い死因であり、死亡数の約4分の1を占めている。固形腫瘍が、これらの死亡のほとんどの原因である。ある特定のがんの医学的処置においては顕著な進歩があったものの、全てのがんについての5年全生存率は過去20年間で約10%しか改善しなかった。がんまたは悪性腫瘍は、制御されずに迅速に転移および成長し、処置を非常に困難にする。
腫瘍壊死因子受容体スーパーファミリー(TNFRSF)メンバーの膜貫通ドメインを含む新規のキメラ抗原受容体(CAR)、および受容体を発現する宿主細胞(例えばT細胞)、および受容体をコードする核酸分子が本明細書で提供される。CARは、形質導入T細胞での高い表面発現、高度の細胞溶解ならびに形質導入T細胞のin vivoでの増殖および持続を示す。例えば対象におけるがんを処置するための、開示されるCAR、宿主細胞、および核酸分子を使用する方法も提供される。
定義
本明細書で使用する場合、単数形「1つの(a)」、「1つの(an)」および「この(the)」とは、文脈が明らかに他を示さない限り、単数形および複数形の両方を指す。例えば、用語「1つの抗原」は、単数または複数の抗原を含み、語句「少なくとも1つの抗原」と等価とみなされ得る。本明細書で使用する場合、用語「含む(comprises)」とは、「含む(includes)」を意味する。したがって、「1つの抗原を含む(comprising)」とは、他の要素を排除することなく、「1つの抗原を含む(including)」を意味する。語句「および/または」とは、「および」または「または」を意味する。核酸またはポリペプチドについて与えられた任意のおよび全ての塩基サイズまたはアミノ酸サイズ、ならびに全ての分子量または分子質量値は、特記しない限り、おおよそであり、便宜的に提供されていることをさらに理解すべきである。本明細書に記載されるものと類似または等価な多くの方法および材料が使用され得るが、特に適切な方法および材料が以下に記載される。矛盾する場合、用語の説明を含む本明細書が支配する。さらに、材料、方法および実施例は、例示にすぎず、限定を意図しない。種々の実施形態の再検討を容易にするために、以下の用語の説明が提供される。
本明細書で開示されるCARは、抗原に結合することが可能な少なくとも1つの細胞外ドメイン、少なくとも1つの腫瘍壊死因子受容体スーパーファミリー(TNFRSF)の膜貫通ドメイン、および少なくとも1つの細胞内ドメインを含む。
一実施形態では、CARは、さもなければ抗原結合性ドメインまたは部分と呼ばれる標的特異的結合エレメントを含む。ドメインの選択は、標的細胞の表面を規定するリガンドの型および数に依存する。例えば、抗原結合性ドメインは、特定の疾患状態と関連する標的細胞上の細胞表面マーカーとして作用するリガンドを認識するように選択され得る。したがって、CAR中の抗原結合性ドメインに対するリガンドとして作用し得る細胞表面マーカーの例には、ウイルス、細菌および寄生生物感染、自己免疫疾患ならびにがん細胞と関連するものが含まれる。
膜貫通ドメインに関して、CARは、CARの細胞外ドメインに融合された1つまたは複数のTNFRSF膜貫通ドメインを含む。
CARでは、スペーサードメインは、細胞外ドメインとTNFRSF膜貫通ドメインとの間、または細胞内ドメインとTNFRSF膜貫通ドメインとの間に配置され得る。スペーサードメインは、TNFRSF膜貫通ドメインを細胞外ドメインと連結させるように、および/またはTNFRSF膜貫通ドメインを細胞内ドメインと連結させるように機能する、任意のオリゴペプチドまたはポリペプチドを意味する。スペーサードメインは、最大で300アミノ酸、好ましくは10〜100アミノ酸、最も好ましくは25〜50アミノ酸を含む。
CARの細胞質ドメインまたはさもなければ細胞内シグナル伝達ドメインは、CARが中に置かれた免疫細胞の正常なエフェクター機能のうち少なくとも1つの活性化を担う。用語「エフェクター機能」とは、細胞の特殊化した機能を指す。例えば、T細胞のエフェクター機能は、サイトカインの分泌を含む細胞溶解活性またはヘルパー活性であり得る。したがって、用語「細胞内シグナル伝達ドメイン」とは、エフェクター機能シグナルを伝達し、特殊化した機能を実行するように細胞を指示する、タンパク質の部分を指す。通常は細胞内シグナル伝達ドメイン全体が使用され得るが、多くの場合、鎖全体を使用する必要はない。細胞内シグナル伝達ドメインの短縮された部分が使用される限りにおいて、かかる短縮された部分は、それがエフェクター機能シグナルを伝達する限り、インタクトな鎖の代わりに使用され得る。したがって、用語、細胞内シグナル伝達ドメインとは、エフェクター機能シグナルを伝達するのに十分な、細胞内シグナル伝達ドメインの任意の短縮された部分を含むことを意味する。
本明細書で開示されるCARの機能的部分もまた、本発明の範囲内に明示的に含まれる。用語「機能的部分」とは、CARに関して使用する場合、本明細書に開示されるCARの1または複数の任意の一部または断片を指し、この一部または断片は、それがその一部であるCAR(親CAR)の生物学的活性を保持する。機能的部分は、例えば、親CARと類似の程度、同じ程度、またはより高い程度まで、標的細胞を認識する能力、または疾患を検出、処置もしくは予防する能力を保持する、CRAの一部を包含する。親CARに関して、機能的部分は、例えば、親CARの約10%、25%、30%、50%、68%、80%、90%、95%またはそれ超を構成し得る。
一実施形態は、CAR、CARを発現するT細胞、本明細書で開示された抗原のうち1または複数に特異的に結合する抗体またはその抗原結合性ドメインもしくは部分をさらに提供する。本明細書で使用する場合、「CARを発現するT細胞」または「CAR T細胞」とは、CARを発現するT細胞を意味し、例えば、CARの抗体由来の標的化ドメインによって決定される抗原特異性を有する。
CAR、CARを発現するT細胞、または本明細書に開示された抗原のうち1もしくは複数に対して特異的なモノクローナル抗体もしくはその抗原結合性断片は、当業者に公知のいくつもの手段を使用して、エフェクター分子または検出可能なマーカーなどの薬剤にコンジュゲートされ得る。共有結合および非共有結合の両方の手段が使用され得る。コンジュゲートには、本明細書に開示された抗原のうち1または複数に特異的に結合する抗体または抗原結合性断片へのエフェクター分子または検出可能なマーカーの共有結合的連結が存在する分子を含むがこれらに限定されない。当業者は、化学療法剤、抗血管新生剤、毒素、放射活性剤、例えば、125I、32P、14C、3Hおよび35S、ならびに他の標識、標的部分およびリガンドなどを含む(がこれらに限定されない)種々のエフェクター分子および検出可能なマーカーが使用され得ることを理解する。
本明細書に記載されるCAR、抗体またはその抗原結合性部分(その機能的部分および機能的バリアントを含む)のいずれかをコードするヌクレオチド配列を含む核酸が、本発明の一実施形態によってさらに提供される。本発明の核酸は、本明細書に記載されるリーダー配列、抗原結合性ドメイン、膜貫通ドメインおよび/または細胞内T細胞シグナル伝達ドメインのいずれかをコードするヌクレオチド配列を含み得る。
本明細書で開示されるCARは、哺乳動物において疾患を処置または予防する方法において使用され得ることが企図される。これに関して、一実施形態は、CAR、核酸、組換え発現ベクター、宿主細胞、細胞の集団、抗体および/もしくはその抗原結合性部分、ならびに/または医薬組成物を、哺乳動物においてがんを処置または予防するのに有効な量で哺乳動物に投与するステップを含む、哺乳動物においてがんを処置または予防する方法を提供する。
担体(例えば、医薬的に許容される担体)中に、開示されたCAR、またはCARを発現するT細胞、抗体、抗原結合性断片、コンジュゲート、CAR、または本明細書に開示された1もしくは複数の抗原に特異的に結合するCARを発現するT細胞のうち1または複数を含む、遺伝子治療、免疫療法および/または細胞療法における使用のためのバイオ医薬組成物または生物製剤組成物(本明細書で以下「組成物」)が、本明細書で提供される。これらの組成物は、対象への投与のために単位投薬形態で調製され得る。所望の転帰を達成するための投与の量およびタイミングは、処置を行う臨床医の裁量である。これらの組成物は、全身(例えば、静脈内)または局所(例えば、腫瘍内)投与のために製剤化され得る。一例では、開示されたCAR、またはCARを発現するT細胞、抗体、抗原結合性断片、コンジュゲートは、静脈内投与などの非経口投与のために製剤化される。本明細書に開示されるCAR、またはCARを発現するT細胞、コンジュゲート、抗体もしくは抗原結合性断片を含む組成物は、腫瘍、例えば、限定としてではなく、神経芽細胞腫の、例えば、処置および検出などのために使用される。一部の例では、これらの組成物は、癌の処置または検出に有用である。本明細書に開示されるCAR、またはCARを発現するT細胞、コンジュゲート、抗体もしくは抗原結合性断片を含む組成物は、例えば、病理学的血管新生の検出にも使用される。
一態様では、本明細書に開示されるCARを使用するキット、例えば、対象における腫瘍を処置するためのキットまたは本明細書に開示されるCARのうち1もしくは複数を発現するCAR T細胞を作製するためのキットもまた提供される。キットは、典型的には、本明細書に開示される、開示された抗体、抗原結合性断片、コンジュゲート、核酸分子、CARまたはCARを発現するT細胞を含む。開示された抗体、抗原結合性断片、コンジュゲート、核酸分子、CARまたはCARを発現するT細胞のうち1よりも多くが、キット中に含まれ得る。
TNFRSF膜貫通ドメインを含むキメラ抗原受容体
新規の膜貫通配列を有するCARの生成を、本明細書に記載される手順に従って達成した。
キメラ受容体を発現するT細胞は高い表面発現および細胞溶解活性を示す。
本明細書で開示されるCARは、Raji細胞株で高レベルに発現された。CARを発現する細胞は、高い増殖速度を有し、多量のサイトカインを産生し、CARが結合する抗原を表面に有する細胞に対し高い細胞傷害活性を有していた。
次いで、ルシフェラーゼをコードするLVが形質導入されたRaji細胞株(ATCCのCCL−86)(Raji−luc)を伴う細胞溶解アッセイでCARを試験した。Raji−luc培養および細胞溶解アッセイ自体は、標準的な組織培養条件下で、10%ウシ胎児血清を含むRPMI−1640培地で実施する。ルシフェラーゼ基質の添加により、一定数の標的細胞を含む96ウェル組織培養プレートの各ウェル中の生Raji細胞数を正確に測定することができる。血清不含条件下で、IL−2を含むTexMACS培地(Miltenyi Biotec)において、抗CD3/CD28ビーズ(TransACT、Miltenyi Bitoec)での刺激によりCAR T細胞を生成した。細胞を3日間活性化させ、LVに曝露し、さらに10日間まで培養した。Raji−lucを、活性化T細胞(対照)、LVにコードされる対照タンパク質を発現する活性化T細胞(LNGFR対照)、またはRaji−lucに存在する細胞表面抗原に特異的なCARをコードするLVを発現する活性化T細胞(この場合CD19)とコインキュベーションすることにより、CARを発現するT細胞の細胞溶解活性の決定を実施した。ウェルあたりのエフェクターCAR−T細胞数を増加させることで、様々なエフェクター対標的比を試験することができた。ルシフェラーゼ基質を添加し、プレートリーダーで発光を測定することにより、24時間のコインキュベーション期間終了時の生Raji−lucを決定した。CAR−T細胞とコインキュベートしたRaji−lucと比較した、T細胞不含ウェルあたりの生Raji−lucのルシフェラーゼシグナルのパーセンテージとして細胞傷害性を定量化した。
次いで、CARの細胞外側面の軽鎖由来ドメインに結合するビオチン化プロテインLへの曝露を伴う、フローサイトメトリーベースの細胞表面発現アッセイでCAR−T細胞を試験した。CARドメインに結合したビオチン化プロテインLの量を、フィコエリトリン(PE)にコンジュゲートされたアビジンによる二次染色で決定した。MACS−QuantフローサイトメーターでPEシグナルから決定されるプロテインLとの結合について染色陽性となった単細胞のパーセンテージを使用して、CAR発現を算出した。
以下のCARを発現するレンチウイルス発現ベクター(LV)を作り出し、抗白血病活性について試験したところ、TNFRSFを含むCARの予想外に高い溶解活性が実証された(図5を参照のこと)。
T細胞細胞膜でのCARの細胞表面発現が、CARを発現する治療的細胞集団の強力な活性に必要な重要なパラメータでもあることが実証されている。T細胞細胞膜でのCARの細胞表面発現はフローサイトメトリー分析により検出した。
TNFRSFメンバー由来のリンカーおよび/または膜貫通ドメインの利用により、CAR T抗腫瘍機能の微調整が可能になる。
(a)細胞株(PBMCおよび標的)
特記しない限り、細胞株および試薬は全てAmerican Tissue Culture Collection(ATCC、Manassas、VA)から購入した。RajiおよびK562細胞株は、10%熱不活化ウシ胎児血清および2mMグルタミンを添加したRPMI−1640培地で培養した。ヒト胎児腎臓細胞株293Tは、10%熱不活化FBSを添加したダルベッコ改変イーグル培地(DMEM)で繁殖させた。
CARの抗原結合性ドメイン、scFvは、配列がCD19に対するマウスハイブリドーマFMC−63(FMC−63:aa1−267、GenBank ID:HM852952.1)に由来していた。FMC63 scFvをインフレームで、指定の連結および膜貫通ドメイン、次いで4−1BB(CD137、aa214−255、UniProt配列ID Q07011)シグナル伝達ドメインおよびCD3ゼータシグナル伝達ドメイン(CD247、aa52−163、Ref配列ID:NP_000725.1)に連結することにより、CAR T構築物を生成した。構築物1494は、公表されているCD19 CAR編成(Chimeric receptors with 4−1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia、2004、C Imai、K Mihara、M Andreansky、IC Nicholson、C−H Pui、TL Geiger、D Campana.Leukemia、18:676−84)(本明細書では「1494」と呼ぶ)に近付くように設計した。1494構築物は、ヒトCD8アルファタンパク質(UniProt配列ID P01732、aa138−206)由来のリンカーおよび膜貫通ドメインを組み込んでいる。CAR構築物配列を第3世代のレンチウイルスプラスミド骨格(Lentigen Technology Inc.、Gaithersburg、MD)にクローニングした。HEK293T細胞の一過性トランスフェクションによりレンチウイルスベクター(LV)を含む上清を生成し、レンチウイルスベクターを含む上清を遠心処理することによりベクターをペレットにして、−80℃で保存した。
正常なドナー由来のヒト初代T細胞を、CD4+およびCD8+細胞を免疫磁性ビーズで選択した後にバフィーコートから精製し、密度0.3および2×106細胞/mlで、40IU/ml IL−2を添加したTexMACS培地で培養し、CD3/CD28MACS(登録商標)GMP TransAct試薬(Miltenyi Biotec)で活性化し、3日目に10μg/ml硫酸プロタミン(Sigma−Aldrich、St.Louis、MO)存在下で一晩、CAR構築物をコードするレンチウイルスベクターを形質導入し、4日目に培地を交換した。5日目に、200IU/ml IL−2を添加したTexMACS培地に培養物を移し、10〜13日目の採取まで繁殖させた。
細胞媒介性の細胞傷害性を決定するため(CTLアッセイ)、ホタルルシフェラーゼが安定に形質導入された標的細胞5,000個を種々のエフェクター対標的比でCAR T細胞と組み合わせ、一晩インキュベートした。SteadyGlo試薬(Promega、Madison WI)を各ウェルに添加し、生じた発光を秒あたりのカウントとして定量化した(試料CPS)。標的のみのウェル(最大CPS)および1%Tween−20を加えた標的のみのウェル(最小CPS)を使用してアッセイ範囲を決定した。特異的な溶解のパーセントを(1−(試料CPS−最小CPS)/(最大CPS−最小CPS))として算出した。サイトカイン放出アッセイでは、エフェクターおよび標的細胞を10:1の比で組み合わせて一晩インキュベートした。採取した上清を、MACSplexヒトサイトカインビーズアレイキット(Miltenyi Biotec)を使用して、分泌されたサイトカインについて分析した。
CAR T細胞200万個を低温のPBS(Lonza、Walkersville、MD)で2回洗浄し、プロテアーゼおよびホスファターゼ阻害剤カクテルを含む低温のRIPA緩衝液中で溶解させた。溶解物を4℃で20分間インキュベートし、4℃で10分間、卓上遠心機で、13000RPMでペレットにし、上清を収集して−20℃で凍結させた。製造業者のプロトコールに従って、MOPS緩衝液(Thermo−Fisher Scientific、Grand Island、NY)中の4%〜12%グラジエントSDS−PAGEゲルで試料を分離させた。タンパク質を0.45ミクロンニトロセルロース転写膜に転写し、CD3ゼータに対する抗体(クローンab40804、Abcam、Cambridge、MA)でプローブ付与した。Vectastain ABC−AMP試薬キット(Vector Laboratories、Burlingame、CA)を使用してバンドを可視化し、Odysseyイメージングシステム(LI−COR、Lincoln、Nebraska)で画像を撮影した。
細胞染色では、CAR T形質導入細胞100万個を培養物から採取し、低温の染色緩衝液で2回洗浄して、プロテインL−ビオチンコンジュゲート(ストック1mg/ml、1:1000希釈、GenScript、Piscataway、NJ)を用いて4℃で30分間染色し、その後2回洗浄し、ストレプトアビジン−PEコンジュゲート(ストック:1.0ml、1:200希釈、Jackson ImmunoResearch Laboratories、West Grove、PA)を用いて4℃で30分間染色することによりCAR表面発現を検出した。陰性対照として非形質導入細胞を使用した。全ての研究で、死滅した細胞は7AAD染色(BD Biosciences、San Jose、CA)により除外した。細胞を2回洗浄し、フローサイトメトリーによる定量分析前に染色緩衝液200μlで再懸濁させた。
動物研究は全てJackson Laboratory Animal Care and Use Committee(Sacramento、CA)の承認を受けた。マウス適応Raji−luc細胞50万個をNSG(NOD.Cg−Prkdcscid Il2rgtm1Wjl/SzJ)マウスの尾静脈に注射した。Raji−luc注射後6日目に、150mg/kgルシフェリンをi.p.注射することにより腫瘍移植について測定し、10分後にXenogen IVIS−200装置(Caliper Biosciences)で40秒間画像化した。Living Image、バージョン4.1、ソフトウェア(Perkin Elmer)を使用して画像を分析し、各マウスについての生物発光シグナルフラックスを平均輝度(光子/秒/cm2/ステラジアン)として表した。7日目にCAR T細胞を尾静脈注射によりマウスに投与した。表示する注射後日数目に画像化を実施し、腫瘍増殖動態およびCAR T細胞による根絶を立証した。
GraphPad Prism 7.01統計ソフトウェア(La Jolla、CA)を使用して、図の凡例に示す通り統計解析を実施した。
CAR T細胞の機能における膜貫通およびリンカードメインの役割を調べるため、腫瘍壊死因子受容体スーパーファミリー(TNFRSF)のタンパク質メンバー由来の膜貫通およびリンカーエレメントを、CAR19設計に組み込んだ(図6および表3)。
一部の具体的実施形態の前述の記載によって、他者が、本発明の知識を適用することによって、一般的概念から逸脱せずに、具体的実施形態などの様々な適用例に関して容易に変更または適合させることができるのに充分な情報を与え、したがってこのような適合および変更形態は、開示した実施形態の均等物の意味および範囲内と理解すべきであり、理解することが意図されている。本明細書で利用する語句または述語は、限定の目的ではなく記載の目的であることは理解される。図面および記載中、例示的実施形態を開示しており、特異的用語が利用された可能性はあるが、他に言及しない限り、それらは限定の目的ではなく一般的および叙述的な意味でのみ使用され、したがって特許請求の範囲もそのように限定されない。さらに当業者は、本明細書で論じた方法の、ある特定ステップは別の順序で順に並べることができ、またはステップを組合せることができることを理解する。したがって、添付の特許請求の範囲は本明細書で開示した詳細な実施形態に限られないことが意図される。当業者は、ごく普通の実験を使用した、本明細書に記載した本発明の実施形態の多くの均等物を理解し、把握することができる。このような均等物は以下の特許請求の範囲によって包含される。
Claims (19)
- 配列番号8のアミノ酸配列を含むキメラ抗原受容体(CAR)をコードする、単離された核酸分子。
- 前記CARをコードする核酸分子は配列番号7の核酸配列を含む、または、
前記CARをコードする核酸分子は配列番号40の核酸配列を含む、請求項1に記載の核酸分子。 - 請求項1に記載の単離された核酸分子によりコードされるキメラ抗原受容体(CAR)。
- 請求項1に記載の核酸分子を含むベクター。
- DNAベクター、RNAベクター、プラスミドベクター、コスミドベクター、ヘルペスウイルスベクター、麻疹ウイルスベクター、レンチウイルスベクター、アデノウイルスベクター、またはレトロウイルスベクター、またはそれらの組合せからなる群から選択される、請求項4に記載のベクター。
- プロモーターをさらに含む、請求項4に記載のベクター。
- 前記プロモーターが、誘導性プロモーター、構成的プロモーター、組織特異的プロモーター、自殺プロモーター、またはそれらの任意の組合せである、請求項6に記載のベクター。
- 請求項4に記載のベクターを含む細胞。
- T細胞である、請求項8に記載の細胞。
- 前記T細胞がCD8+T細胞である、請求項9に記載の細胞。
- ヒト細胞である、請求項8に記載の細胞。
- 哺乳動物における抗腫瘍免疫をもたらすための医薬を製造するための、請求項8に記載の細胞の使用。
- 哺乳動物においてがんを処置または予防するための医薬を製造するための、請求項3に記載のキメラ抗原受容体(CAR)の使用。
- 抗腫瘍有効量のヒトT細胞集団を含む医薬組成物であって、前記T細胞が配列番号8のアミノ酸配列を含むキメラ抗原受容体(CAR)をコードする核酸配列を含む、医薬組成物。
- 前記T細胞が、がんを有するヒトのT細胞である、請求項14に記載の医薬組成物。
- 前記がんが、白血病またはリンパ腫である、請求項15に記載の医薬組成物。
- 前記白血病が、慢性リンパ性白血病(CLL)、急性リンパ性白血病(ALL)もしくは慢性骨髄性白血病(CML)であり、または、
前記リンパ腫が、マントル細胞リンパ腫、非ホジキンリンパ腫またはホジキンリンパ腫である、請求項16に記載の医薬組成物。 - 前記がんが多発性骨髄腫である、請求項15に記載の医薬組成物。
- がんが、口腔および咽頭がん(舌、口、咽頭、頭頸部)、消化器系がん(食道、胃、小腸、結腸、直腸、肛門、肝臓、肝内胆管、胆嚢、膵臓)、呼吸器系がん(喉頭、肺および気管支)、骨および関節のがん、軟組織がん、皮膚がん(黒色腫、基底細胞癌および扁平上皮癌)、小児腫瘍(神経芽細胞腫、横紋筋肉腫、骨肉腫、ユーイング肉腫)、中枢神経系の腫瘍(脳腫瘍、星状細胞腫、神経膠芽腫、神経膠腫)、ならびに乳房、生殖系(子宮頸部、子宮体、卵巣、外陰部、腟、前立腺、精巣、陰茎、子宮内膜)、泌尿器系(膀胱、腎臓および腎盂、尿管)、眼および眼窩、内分泌系(甲状腺)ならびに脳および他の神経系のがん、またはそれらの任意の組合せを含む成人癌を含む、請求項15に記載の医薬組成物。
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CA3001306A1 (en) | 2017-04-13 |
CN108779162B (zh) | 2021-12-07 |
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