JP2021500859A - Nfkbシグナル伝達の増強を伴うキメラ抗原受容体 - Google Patents
Nfkbシグナル伝達の増強を伴うキメラ抗原受容体 Download PDFInfo
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Abstract
Description
本願は、2017年9月22日に出願された米国仮出願第62/561,815号、2017年12月11日に出願された米国仮出願第62/597,128号、2018年3月8日に出願された米国仮出願第62/640,153号、2018年5月3日に出願された米国仮出願第62/666,381号、および2018年5月3日に出願された米国仮出願第62/666,385号の利益を主張し、これらすべては参照によりその全体が本明細書に組み込まれる。
本願は、2018年8月31日に作成された「320103-2020 Sequence Listing_ST25」という題名のASCII.txtファイルとして電子形式で提出された配列表を含む。配列表の内容はその全体が本明細書に組み込まれる。
SP−TAA−HG−TM−CSR−ISD;
ここで、「SP」は任意のシグナルペプチドを表し、
「TAA」はTAA結合領域を表し、
「HG」は任意のヒンジドメインを表し、
「TM」は膜貫通ドメインを表し、
「CSR」は共刺激シグナル伝達領域を表し、
「ISD」は細胞内シグナル伝達ドメインを表し、
「−」は、ペプチド結合またはリンカーを表す。
開示される免疫エフェクター細胞においてCARの発現を可能にする、開示されるCARをコードするポリヌクレオチドおよびポリヌクレオチドベクターもまた開示される。
開示されるCARを発現するように設計された免疫エフェクター細胞(本明細書では「CAR−T細胞」とも呼ばれる)も開示される。この細胞は、好ましくは処置される対象から取得される(すなわち自家性である)。しかしながら、いくつかの実施態様において、免疫エフェクター細胞株またはドナーエフェクター細胞(同種)が使用される。免疫エフェクター細胞は、多数の供給源(末梢血単核細胞、骨髄、リンパ節組織、臍帯血、胸腺組織、ならびに感染、腹水、胸水、脾臓組織および腫瘍の部位由来の組織を含む)から取得され得る。免疫エフェクター細胞は、当業者に公知の多くの技術(FICOLL(商標)分離など)を用いて対象から採取された血液から取得され得る。例えば、個体の循環血由来の細胞はアフェレーシスによって取得され得る。いくつかの実施態様において、免疫エフェクター細胞は、(例えば、PERCOLL(商標)勾配による遠心分離によって、または向流遠心溶出法によって)赤血球を溶解して単球を枯渇させることにより末梢血リンパ球から単離される。免疫エフェクター細胞の特定の亜集団は、陽性または陰性選択の技術によってさらに単離され得る。例えば、免疫エフェクター細胞は、陽性選択される細胞に特有の表面マーカーに対する抗体の組合せを用いて(例えば、所望の免疫エフェクター細胞の陽性選択に十分な時間、抗体を結合したビーズとともにインキュベートすることによって)単離され得る。あるいは、免疫エフェクター細胞集団の濃縮は、陰性選択される細胞に特有の表面マーカーに対する抗体の組合せを用いた陰性選択によって達成され得る。
開示されるCARを発現する免疫エフェクター細胞は、TAA発現がん細胞に対する抗腫瘍免疫応答を誘発し得る。開示されるCARで修飾された免疫エフェクター細胞によって誘発される抗腫瘍免疫応答は、能動的または受動的免疫応答であり得る。さらに、CAR媒介性免疫応答は、CARで修飾された免疫エフェクター細胞がTAAに特異的な免疫応答を誘導する養子免疫療法の手法の一部であり得る。
用語「アミノ酸配列」は、アミノ酸残基を表す略称、文字、または単語のリストを指す。本明細書で使用されるアミノ酸の略称は従来のアミノ酸の一文字コードであり、以下のように表される:A、アラニン;B、アスパラギンまたはアスパラギン酸;C、システイン;D、アスパラギン酸;E、グルタメート、グルタミン酸;F、フェニルアラニン;G、グリシン;H、ヒスチジン;I、イソロイシン;K、リジン;L、ロイシン;M、メチオニン;N、アスパラギン;P、プロリン;Q、グルタミン;R、アルギニン;S、セリン;T、スレオニン;V、バリン;W、トリプトファン;Y、チロシン;Z、グルタミンまたはグルタミン酸。
方法
マウス
C57BL/6、Thy1.1(B6.PL−Thy1a/CyJ)、およびRag1−/−(B6.129S7−Rag1tm1Mom/J)マウスをJackson Laboratory (Bar Harbor, ME)から購入し、NF−κB−RE−luc(BALB/c−Tg(Rela−luc)31Xen)トランスジェニックマウスをTaconic (Hudson, NY)から購入した。Traf1−/−マウスはトロント大学のTania Watts博士から頂戴し、Moffittの動物施設で維持および飼育した。NSGマウス(NOD.Cg−Prkdcscid Il2rgtm1Wjl/SzJ)をJackson Laboratoryから購入し、Moffittの動物施設で飼育した。8〜12週齢の雌性および/または雄性マウスを研究に使用した。生存研究のために、マウスにEμ−ALL(1×106細胞/マウス、0日目)を静脈内注射し、その後シクロホスファミド(250〜300mg/kg、6〜7日目)およびmCD19標的CAR T細胞(0.15〜5×106個のCAR T細胞/マウス、7〜10日目)を腹腔内注射した。マウスを病気についてモニターし、白血病の進行が認められた場合(活動の低下、猫背の姿勢および毛の乱れ(ruffled coat)など)に屠殺した。特定の時点で、血液および/または骨髄を分析のために収集した。Rag1−/−マウスの研究のために、マウスに1×106個のmCD19標的CAR T細胞を静脈内注射した。フローサイトメトリーのために血液およびBMを採取した。
Eμ−ALL細胞株が記載されている(Davila ML, et al. PLoS One. 2013 8(4):e61338)。細胞を、フィーダーとしての(30Gyで)照射されたNIH/3T3線維芽細胞とともに培養した。培地は、等量の1)2mM L−グルタミン、55μM β−メルカプトエタノール、100U/mlペニシリン、100μg/mlストレプトマイシンおよび10%FBSを添加したIMDM、ならびに2)2mM L−グルタミン、100U/mlペニシリン、100μg/mlストレプトマイシンおよび10%ウシ血清を添加したDMEMからなる。EL4−mCD19細胞を標的細胞として用いた。EL4−mCD19細胞が記載されている(Davila ML, et al. PLoS One. 2013 8(4):e61338)。3T3−mCD19および3T3−hCD19細胞は、マウスまたはヒトCD19をレトロウイルスにより形質導入したNIH/3T3細胞であり、標的細胞として用いた。CHO−hCD33細胞は、ヒトCD33をレトロウイルスにより形質導入したチャイニーズハムスター卵巣(CHO)細胞であり、ヒトCD33標的CAR T細胞の標的細胞として用いた。NIH/3T3およびCHO細胞をATCC (Manassas, VA)から購入した。マウスT細胞完全培地は、RPMI1640培地、10%FBS、1mMピルビン酸ナトリウム、1×NEAA(非必須アミノ酸)、10mM HEPES、55μM β−メルカプトエタノール、2mM L−グルタミン、100U/mlペニシリン、および100μg/mlストレプトマイシンからなる。健常なドナー由来のヒトPBMCをReachBio (Seattle, WA)から購入した。ヒトT細胞完全培地は、RPMI1640培地、10%FBS、2mM L−グルタミン、100U/mlペニシリン、および100μg/mlストレプトマイシンからなる。すべての培地および添加物は、ThermoFisher Scientific (Waltham, MA)からのものであった。NF−κB/293/GFP−LucTM転写レポーター細胞をSystem Biosciences (Palo Alto, CA)から購入し、製造者の説明書に従って維持および使用した。FFLuc−GFP NALM6(NALM6−GL)細胞が記載されている(Zhao Z, et al. Cancer Cell. 2015 28(4):415-28)。
SFGレトロウイルスコンストラクトをすべてのコンストラクトに用いた。m19Δz、m19z、m1928z、およびm19−musBBz CARが記載されている(Davila ML, et al. PLoS One. 2013 8(4):e61338; Ghosh A, et al. Nat Med. 2017 23(2):242-9)。マウス4−1BBエンドドメインをヒト4−1BBエンドドメインまたは変異型マウス4−1BBドメインに置換するように、これらのコンストラクトを改変した(図2Aおよび9A)。ヒトCD19標的CARは、図9Aに記載のヒト対応物とマウス4−1BBエンドドメインを組み合わせたFMC63 scFvを含むようにGenewiz (South Plainfield, NJ)によって合成された。TRAFおよびTRAF DN(ドミナントネガティブ)コンストラクトは、コード配列、グリシンセリンリンカー、cerulean、および終止コドンを含み、これらは合成され、SFGレトロウイルスベクターにサブクローニングされた。TRAF DNコード配列が記載されている(Duckett CS, et al. Mol Cell Biol. 1997 17(3):1535-42)。TRAF1 DN(184〜417aa)はTRAFドメインのみからなり、TRAF2 DN(87〜501aa)はリングフィンガードメインを持たず、TRAF3 DN(382〜568aa)もリングフィンガードメインを持たない。すべてのSFGコンストラクトをH29細胞にリン酸カルシウム法で遺伝子導入した。遺伝子導入されたH29細胞のレトロウイルス上清を採取し、マウスT細胞の形質導入のためにPhoenix E細胞またはヒトT細胞の形質導入のためにRD114細胞を形質導入するのに用いた。Phoenix EまたはRD114生成細胞のレトロウイルス上清を回収し、0.45μMでろ過し、記載されているようにマウスまたはヒトT細胞を形質導入するのに用いた(Davila ML, et al. PLoS One. 2013 8(4):e61338; Li G, et al. Methods Mol Biol. 2017 1514:111-8)。TRAF過剰発現CAR T細胞のために、1日目および2日目においてT細胞にCARまたはTRAFを含むレトロウイルスを同時形質導入した。3日目または4日目にCAR T細胞を収集し、ビーズを除去し、下流の実験的使用の前に計数および生存率評価を行った。生存率を、細胞をトリパンブルーで染色することによって測定し、自動セルカウンター(Bio-Rad, Hercules, CA)上で数えた。形質導入効率を、フローサイトメトリーによって検出したGFP+またはCherry+生細胞の割合として推定した。一部の実験では、CARの発現を、記載されるように、T細胞を1μgのビオチン−プロテインL(GenScript, Piscataway, NJ)およびその後の蛍光色素標識ストレプトアビジン(eBioscience)で染色し、フローサイトメトリーによって評価した(Zheng Z, et al. Journal of translational medicine. 2012 10:29)。下流の実験のために、CAR T細胞の用量をCAR遺伝子導入に基づいて正規化したが、CAR陰性T細胞を排除するようにソートしなかったため、T細胞全体の用量は様々であった。照射研究のために、CAR T細胞を10Gyで照射した。CD33標的CARの開発は補足方法に記載されている。
記載されているクローンを含むこれらの抗マウスまたは抗ヒト抗体を、eBioscience (San Diego, CA)から入手した:抗mCD16/CD32(93)、抗mB220(RA3−6B2)、抗mCD19(eBio1D3)、抗mCD3(145−2C11)、抗mCD4(GK1.5)、抗mCD8(53−6.7)、抗mThy1.1(HIS51)、抗mCD44(1M7)、抗mCD62L(MEL−14)、抗mTER119(TER−119)、抗mCD11b(M1/70)、抗mGr1(RB6−8C5)、抗mNK1.1(PK136)、抗mIFNγ(XMG1.2)、抗mTNFα(MP6−XT22)、抗mBcl2(10C4)。これらはBiolegend (San Diego, CA)からのものであった:抗mCD3(17A2)、抗mCD4(RM4−5)、抗mCD8(53−6.7)。これらはBD Bioscience (San Jose, CA)からのものであった:抗hCD3(UCHT1)、抗hCD4(SK3)、抗hCD8(RAP−T8)。抗BCL−XL(54H6)は、Cell Signaling Technology (Danvers, MA)からのものであった。
100万個のマウスCAR T細胞を1×105個の3T3−mCD19細胞と24時間共培養した。上清を回収し、マウスluminexキット(R&D Systems, Minneapolis, MN)を用いて分析した。データをLuminex100システム(Luminex, Austin, TX)で収集した。製造者の説明書に従った。ヒトCAR T細胞研究のために、CAR T細胞を3T3−hCD19細胞と10:1で24時間共培養した。上清を回収し、Ella machine(ProteinSimple, San Jose, CA)上でSimple Plexアッセイキット(R&D systems)を用いて分析した。製造者の説明書に従った。
EL4−mCD19を標的細胞とし、マウスCD19標的CAR T細胞をエフェクターとして、4時間のクロム放出アッセイを行った。本発明者らの方法が記載されている(Davila ML, et al. PLoS One. 2013 8(4):e61338)。細胞毒性アッセイを、xCELLigence RTCA(リアルタイム細胞分析)装置(ACEA Biosciences, San Diego, CA)上で製造者の説明書に従って実行した。簡潔に述べると、3T3−mCD19または3T3−hCD19細胞をE−Plate96に1ウェルあたり10,000細胞で播種した。翌日、マウスまたはヒトCAR T細胞をIL2を含まない新鮮な完全培地に再懸濁し、標的細胞上に種々のE:T比で添加し、細胞増殖をモニターした。
CAR T細胞を3T3−mCD19で10:1の比率で4時間刺激した。細胞溶解物を、6x106個のCAR T細胞について240μlの細胞溶解緩衝液(Cell Signaling Technology, Danvers, MA)を用いて調製した。30μlの還元および変性させた細胞溶解物を10% Mini−PROTEAN TGX Precastゲル(Bio-Rad, Hercules, California)により電気泳動し、ニトロセルロースブロット膜に移行してブロックし、膜を分子量に基づいて切断して種々のタンパク質をプローブした。膜を一次抗体と1:1000で一晩4度でインキュベートした。ブロットを洗浄し、HRP結合抗ウサギIgG(Cell Signaling Technology)と1:10,000で室温で1時間インキュベートした。ブロットを再度洗浄し、SuperSignal west femto maximum sensitivity substrate(ThermoFisher, Waltham, MA)とともにインキュベートした。Odyssey Fcイメージングシステム(LI-COR Biotechnology, Lincoln, NE)上で画像を取得した。ImageJソフトウェアを用いてタンパク質の半定量化を行った。抗BCLXL(54H6)、抗BCL2(D17C4)および抗βアクチンウサギmAb(13E5)は、Cell Signaling Technologyからのものであった。
NF−κB/293/GFP−Luc細胞(System Biosciences, Palo Alto, CA)に、TRAFまたはTRAF−DNコンストラクトおよびCD19標的CARをレトロウイルスにより形質導入した。NF−κBシグナル伝達を、GFP発現をフローサイトメトリーにより測定することによって評価した。CAR T細胞を、NF−κB−RE−lucトランスジェニック脾細胞から作製した。CAR T細胞を、(30Gyで)照射された3T3−mCD19細胞と6ウェルプレート中で4時間共培養した。各群について、1ウェルあたり3×106個のmCD19標的CAR T細胞に正規化したT細胞を、1ウェルあたり3×105個の3T3−mCD19細胞とともにインキュベートした。刺激後、細胞溶解物をCell Culture Lysis Reagent(Promega, Madison, WI)を用いて調製した。ルシフェラーゼアッセイを、ルシフェラーゼアッセイキット(Promega)を用いて製造者の説明書に従って行った。細胞溶解物を96ウェルホワイトプレート(Corning, Corning, NY)に1ウェルあたり20μl添加し、その後1ウェルあたり100μlのルシフェラーゼアッセイ試薬を添加し、生物発光をSpectraMax Lマイクロプレートルミノメーター(Molecular Devices, Sunnyvale, CA)上で直ちに測定した。各試料を3通りで行った。
正規化した数(1または2×106)のヒトCAR T細胞を、組織培養処理されていない6ウェルプレート中で1ウェルあたり2×105個の3T3−hCD19 AAPCと3通りで共培養した。細胞を60IU/ml IL2を添加したヒトT細胞完全培地中で増殖させ、2〜3日ごとまたは培地が黄色に変化するたびに分割した。各ウェルにおける細胞生存率および総細胞数を、トリパンブルー染色を用いてセルカウンター(Bio-Rad)上で(T単離を0日目として)毎日または2〜4日ごとに測定した。インビトロでの増殖のフローサイトメトリー分析のために、CAR T細胞をeFluor670増殖色素(eBioscience)で染色し、その後標的細胞と5:1の比率で4日間共培養した。
平均値を対応のないパラメトリックな両側t検定を用いて比較した。細胞毒性曲線をコルモゴルフ−スミルノフ検定を用いて比較した。インビトロでのヒトCAR T細胞の増殖を二元配置分散分析を用いて比較した。生存率をログランク検定を用いて比較した。統計分析を、GraphPad Prismソフトウェア7(Graphpad, La Jolla, CA)およびRソフトウェアパッケージを用いて行った。*P<0.05を有意であると見なした。**P<0.01;***P<0.001;****P<0.0001;ns、有意でない。
マイクロアレイ。m19z、m1928zおよびm19−musBBzの比較のために、300万個のCAR T細胞を3×105個の3T3−mCD19細胞と一晩インキュベートした。翌日、生きているCAR T細胞をTrizol(Thermo Fisher Scientific, Waltham, MA)中にソートした。RNAを製造者の説明書に従って単離し、Genomics Core FacilityにおいてMOE 430A 2.0 array Mouse Genechip(Affymetrix, Santa Clara, CA)上に流した。遺伝子発現解析およびグラフ表現を、Partek Genomics Suiteソフトウェアを用いて行った。RMAの正規化を行い、すべての試料の各プローブセットについて値を生成した。差次的に発現した遺伝子を分散分析によって検出し、統計的有意性を有するプローブセットを倍率変化>2およびFDR £0.05によって規定した。
抗CD33抗体は、標準的な方法を用いてVanderbilt Antibody and Protein Resourceにおいて開発された(Markham NO, et al. Hybridoma (Larchmt). 2012 31(4):246-54)。簡潔に述べると、一連の免疫化を完了した後、免疫化マウスの脾細胞を単離し、Ig非分泌型骨髄腫細胞株と融合させ、半固体プレート中で増殖させた。抗体を分泌するクラスターを半固体プレートにおいて同定し、96ウェルプレートにおけるクローン増殖のために選択した。増殖中に上清を収集し、ELISAおよびフローサイトメトリーによってCD33結合についてアッセイした。このスクリーニングに基づいて、RNAの増殖および単離のためにハイブリドーマを選択し、これを用いてIgHおよびIgLの再構成を増幅した。IgHおよびIgLの再構成に基づいてscFvを設計し、SFGレトロウイルスカセット内の本発明者らのヒトCD19標的CARのNcoI/NotI部位にクローニングした。これは、抗ヒトCD19 scFvを抗ヒトCD33 scFvに置換することを可能とした。次に、これらのコンストラクトを用いて、方法に記載されるようにガンマレトロウイルス上清を生成した。
NALM6白血病マウスモデルが記載されている(Zhao Z, et al. Cancer Cell. 2015 28(4):415-28)。簡潔に述べると、NALM6−GL細胞をNSGマウスに5x105個の用量で静脈内注射した。4日後にマウスを3x105〜1x106個のヒトCD19標的CAR T細胞で処理した。過剰なTRAF2を含むヒトCD19標的CAR T細胞を、CARおよびマウスTRAF2の同時形質導入、またはCARおよびヒトTRAF2を組み合わせたバイシストロニックなコンストラクトによる形質導入によって作製した。血液試料をフローサイトメトリーのために毎週収集した。白血病の負荷を、IVISシステム上で生物発光イメージングを用いて毎週評価した。生存率をモニターした。進行性白血病の兆候を示した場合にマウスを屠殺した。
ストレス用量のレベルにおいて、マウス4−1BBエンドドメインを有するCD19標的CAR T細胞(m19−musBBz)は、CD28エンドドメインを含むCARを有するT細胞(m1928z)ほど効果的に白血病を根絶しない。
臨床結果(Davila ML, et al. Sci Transl Med. 2014 6(224):224ra25; Maude SL, et al. N Engl J Med. 2014 371(16):1507-17; Lee DW, et al. Lancet. 2015 385(9967):517-28; Turtle CJ, et al. J Clin Invest. 2016 126(6):2123-38; Park JH, et al. N Engl J Med. 2018 378(5):449-59; Maude SL, et al. N Engl J Med. 2018 378(5):439-48)は、CD28または4−1BBエンドドメインを含む第2世代のヒトCAR T細胞で処置した場合、B−ALL患者について類似した有効なCR率を示している。しかしながら、本発明者らのマウスモデルにおいてストレス試験用量を用いると、4−1BB共刺激の根拠があったにもかかわらず、m19−musBBzはm1928zよりもやや効果が低いようであった(図9C〜9E)。ヒトとマウスとの間の4−1BBエンドドメインの配列の差異(これらは54%同一である(図2A))が、第2世代のCAR T細胞の臨床観察と一致しないやや低下した有効性に寄与していることが推測された。以前の研究では、マウスおよびヒト4−1BBエンドドメインはともにTRAFに結合し、これはTNF受容体ファミリータンパク質(4−1BBなど)の下流のシグナル伝達を増強することが示されている(Jang IK, et al. Biochem Biophys Res Commun. 1998 242(3):613-20; Arch RH, et al. Mol Cell Biol. 1998 18(1):558-65; McPherson AJ, et al. J Biol Chem. 2012 287(27):23010-9; Saoulli K, et al. J Exp Med. 1998 187(11):1849-62; Ye H, et al. Mol Cell. 1999 4(3):321-30)。しかしながら、インビトロアッセイ(Jang IK, et al. Biochem Biophys Res Commun. 1998 242(3):613-20; Arch RH, et al. Mol Cell Biol. 1998 18(1):558-65)では、ヒト4−1BBはTRAF1−3に結合するが、マウス4−1BBはTRAF1−2のみに結合することが示唆されており、これはmCD19標的CAR T細胞におけるヒト4−1BBの置換がTRAF3結合およびCAR T細胞機能を増強し得るという仮説をもたらす(Vallabhapurapu S, et al. Nat Immunol. 2008 9(12):1364-70)。さらに、異なるTRAF結合能を有する4−1BBエンドドメインの比較は、4−1BB共刺激に依存するCAR T細胞によるインビボでの機能の増強を支持するシグナル伝達経路を同定することを可能にし得る。したがって、他の抗マウスCD19 CARに含まれるマウスscFv、CD8およびCD3zドメインと対になるヒト4−1BBエンドドメインを含むバリアントCAR(m19−humBBz)を作製した(図9A)。
ヒトCAR T細胞における4−1BB共刺激が、免疫不全マウスにおいて持続性の増強を支持したことが最近報告された(Zhao Z, et al. Cancer Cell. 2015 28(4):415-28.)。したがって、インビトロでの異なる機能にもかかわらず、m19−humBBzおよびm1928z CAR T細胞による同等のインビボでの抗白血病の死滅は、4−1BB共刺激に伴う増強されたm19−humBBz CAR T細胞の持続性によるものであったと仮定した。この仮説を評価するための本発明者らの理論的根拠は、増強された持続性に寄与するシグナル伝達経路の同定がこの特性の増強を可能にしているということであった。しかしながら、本発明者らのモデルにおいて第2世代のCAR T細胞の持続性の差異は同定されなかった(図2E)。したがって、持続性の増強を示した以前の報告(Zhao Z, et al. Cancer Cell. 2015 28(4):415-28.)が免疫不全マウスにおいて実施されていたため、mCD19抗原を持たないRag1−/−マウスにおいてmCD19標的CAR T細胞のインビボでの増殖を評価した。Rag1−/−マウスに1×106個のCAR T細胞を静脈内注射し、骨髄(BM)を1週間後に単離した。m19−humBBz CAR T細胞は、m1928z CAR T細胞よりも1.5倍高い最も大きなインビボでの持続性を有していた(図3A)。
CAR T細胞の減少は患者に再発をもたらす(Maude SL, et al. N Engl J Med. 2014 371(16):1507-17)ため、CAR T細胞のインビボでの持続性を調節するシグナル伝達経路を同定し、これらの経路を最適化し、持続性をさらに増強することを試みた。したがって、抗原刺激の後にm19z、m19−humBBzおよびm1928z CAR T細胞をソートし、RNA−SEQを実施し、これにより各CAR群が固有の転写プロファイルを有することを確認した(図13Aおよび13B)。遺伝子セット濃縮分析(GSEA)は、4−1BB対CD28を共刺激するか、または共刺激を欠いたCAR T細胞を比較した場合に、NF−κBを調節する経路の濃縮を明らかにした(図13C)。NF−κBはT細胞の生存(Watts TH. Annu Rev Immunol. 2005 23:23-68)および抗腫瘍制御(Barnes SE, et al. J Immunother Cancer. 2015 3(1):1)に重要な制御因子であるため、種々のレベルのNF−κBがインビボでのCAR T細胞の持続性および/またはm19−humBBz CAR T細胞の機能の増強の原因となるか否かを評価した。4−1BB共刺激の機構の研究(Arch RH, et al. Mol Cell Biol. 1998 18(1):558-65)が、野生型4−1BBを形質導入した293細胞を用いて実施されている。本発明者らは、NF−κBシグナル伝達の指標としてGFP蛍光の測定を可能とする類似のレポーター細胞株であるNF−κB/293/GFP−Lucを用いた。マウスCD19標的CARをNF−κB/293/GFP−Lucレポーター細胞にレトロウイルスにより形質導入し、m19−humBBz形質導入のみがNF−κBを誘導した(図5A)。抗原で刺激した初代mCD19標的CAR T細胞においてこの観察を検証した。CAR T細胞を、NF−κB応答配列によって調節されるホタルルシフェラーゼ導入遺伝子を有するNF−κB−RE−lucトランスジェニックマウスから作製した(Carlsen H, et al. J Immunol. 2002 168(3):1441-6)。3T3−mCD19 AAPCで4時間刺激した後、CAR T細胞溶解物を調製し、生物発光を評価した。m19Δzと比較して、NF−κBシグナル伝達はm19−humBBz CAR T細胞において29倍増加し、m1928z CAR T細胞において約5倍増加した(図5B)。
本発明者らは、4−1BBドメインを含むCARを有するmCD19標的T細胞が増殖およびNF−κBシグナル伝達を増強したことを示した。本発明者らは初代ヒトT細胞においてこれらの観察を検証し、NF−κBシグナル伝達がCAR T細胞の生存率および増殖と相関しているか否かを直接評価することによってそれらを拡張することを試みた。野生型(h19BBz)または変異型(mut01〜mut04)4−1BBエンドドメインを含むヒトCD19(hCD19)標的CAR(図5C)を開発し、NF−κBシグナル伝達を調節した。41BBエンドドメイン変異体は以前に同定された(Jang IK, et al. Biochem Biophys Res Commun. 1998 242(3):613-20; Arch RH, et al. Mol Cell Biol. 1998 18(1):558-65;Saoulli K, et al. J Exp Med. 1998 187(11):1849-62; Ye H, et al. Mol Cell. 1999 4(3):321-30)TRAF1−3結合ドメイン内に位置していた。hCD19標的CARがレポーター細胞においてNF−κBを誘導する能力を測定した。h19BBz CARおよび二重4−1BBエンドドメインを有するCAR(mut04)は、それぞれ高いレベル(26%)および中程度のレベル(12%)のNF−κB上方制御を有していた(図5D)。しかしながら、変異したTRAF結合ドメインを有する3つのCAR(mut01〜03)はすべて、形質導入後に最小限のNF−κB誘導を示した(図5D)。次に、これらの異なるレベルのNF−κBシグナル伝達がヒトT細胞のインビトロでの機能にどのように影響を与えるかを評価した。健常なドナーのヒトT細胞にh19BBzまたは変異したCARをレトロウイルスにより形質導入し、これらは類似の遺伝子導入およびCD4/CD8比を示した(図14)。3T3−hCD19 AAPCで刺激した後、細胞増殖をモニターした。より高いレベルのNF−κBシグナル伝達を有するヒトCAR T細胞(h19BBzおよびmut04)はまた、TRAF結合ドメインに変異を有するCAR T細胞(mut01〜mut03、55.3〜65.6%)と比較して最も高い生存率(70〜74.3%)を有していた(図5E)。同様に、h19BBzおよびmut04 hCD19標的CAR T細胞はともに、mut01〜mut03 hCD19標的CAR T細胞(約5倍、図5F)よりも著しく多く増殖した(それぞれ18.6倍および12.2倍)。しかしながら、10:1のE:T比では、NF−κBシグナル伝達の差異にもかかわらず、すべての群のCAR T細胞が3T3−hCD19細胞を同様に死滅させた(図5G)。
研究により、T細胞におけるNF−κBシグナル伝達が、少なくとも部分的にTRAF1−3と4−1BBの細胞内ドメインとの結合により媒介されていることが示されている(Jang IK, et al. Biochem Biophys Res Commun. 1998 242(3):613-20; Arch RH, et al. Mol Cell Biol. 1998 18(1):558-65; McPherson AJ, et al. J Biol Chem. 2012 287(27):23010-9; Saoulli K, et al. J Exp Med. 1998 187(11):1849-62; Ye H, et al. Mol Cell. 1999 4(3):321-30)。TRAF2はCAR T細胞において4−1BB共刺激によって媒介される機能の増強に重要であることが推測されるが、直接的な証拠は存在しない(Zhao Z, et al. Cancer Cell. 2015 28(4):415-28; Gomes-Silva D, et al. Cell Rep. 2017 21(1):17-26)。さらに、変異型4−1BBを含むCARで改変されたヒトT細胞の機能の本発明者らの分析(図5D)は、NF−κBシグナル伝達がhCD19標的CAR T細胞の増殖および生存率と相関していることを示しているが、標的ドメインはTRAF1、2または3に結合し得るため、どのTRAFがNF−κBを調節しているかを区別することはできない。したがって、本発明者らのモデルを適用して、TRAF1、TRAF2またはTRAF3がNF−κBシグナル伝達およびCAR T細胞機能を調節しているか否かを決定した。
m19−musBBz CAR T細胞の有効性の低下はNF−κBシグナル伝達が最適化されていないためであり、NF−κBシグナル伝達を増強する変異によって最適化され得ると仮定した。したがって、マウス4−1BBの最初の5つのN末端アミノ酸ミスマッチ(図2Aにおいて下線が引かれている)をヒト4−1BBアミノ酸に置換したm19−musBBz mut01 CARを作製した。ヒト4−1BBのこの領域はそのマウスの対応物よりもTRAF3に結合することが以前に確認されており(Arch RH, et al. Mol Cell Biol. 1998 18(1):558-65)、本発明者らは最適なNF−κBに必要であると特徴付けた(図6A)。T細胞のドナーとしてNF−κB−RE−lucトランスジェニックマウスを用いて、m19−musBBz mut01 CAR T細胞がm19−musBBzと比較して約2倍のNF−κBシグナル伝達を有することを示し、これはサイトカイン産生および抗アポトーシスタンパク質産生の増加と相関していた(図16A〜16C)。m19−musBBz mut01のインビボでの評価により、B細胞の死滅およびCAR T細胞の持続性がm19−humBBzに類似しており、m19−musBBzよりも有意に高かったことが示された(図16D〜16G)。
本発明者らの免疫適格動物モデルにおいて、高用量のm19−musBBz CAR T細胞はm1928z CAR T細胞と同等の抗白血病効果を有していたが、ストレス試験用量(3x105)では効果が低下した(図1C〜1F)。本発明者らは、m19−musBBz CARは最適ではなく、配列の改変がm1928z CARと同等になるようにその有効性を増加させ得ると仮定した。したがって、マウス4−1BBエンドドメインをヒト4−1BBエンドドメインに置換した(m19−humBBz)(図2)。m19−humBBz CAR T細胞のインビボでの機能(図2D)はストレス試験用量レベルにおいてm1928z CAR T細胞と同等であり、これはh19BBzまたはh1928z CAR T細胞で処置した患者において同等のCR率を示す臨床結果と一致していた(Lee DW, et al. Lancet. 2015 385(9967):517-28; Neelapu SS, et al. N Engl J Med. 2017 377(26):2531-44, Maude SL, et al. N Engl J Med. 2018 378(5):439-48; Value in Using CAR T Cells for DLBCL. Cancer Discov. 2018 8(2):131-2)。しかしながら、m19−humBBz CAR T細胞のインビトロでの機能は、サイトカイン産生および細胞毒性によって測定されるように、m1928z CAR T細胞と比較して劣っていた(図2Bおよび2C)。これらの結果は、ヒトCAR T細胞が、CD28共刺激により分泌されるサイトカイン(IL2、IFNγおよびTNFαなど)を4−1BB共刺激ドメインを持つCARよりも高いレベルで与えたことを実証した以前の研究と一致している(Imai C, et al. Leukemia. 2004 18(4):676-84; Milone MC, et al. Mol Ther. 2009 17(8):1453-64; Brentjens RJ, et al. Clin Cancer Res. 2007 13(18 Pt 1):5426-35; Zhong XS, et al. Mol Ther. 2010 18(2):413-20)。
Claims (21)
- 腫瘍関連抗原(TAA)結合ドメイン、膜貫通ドメイン、細胞内シグナル伝達ドメイン、および共刺激シグナル伝達領域を含むキメラ抗原受容体(CAR)ポリペプチドであって、ここで共刺激シグナル伝達領域が、核内因子κB(NFκB)のシグナル伝達を増強する41BBの細胞質ドメインの変異型、CAR−T細胞融合を増強するCD28の細胞質ドメインの変異型、またはそれらの組合せを含む、キメラ抗原受容体(CAR)ポリペプチド。
- 共刺激シグナル伝達領域が、YMNMサブドメインを持たないCD28の細胞質ドメインを含む、請求項1記載のポリペプチド。
- 共刺激シグナル伝達領域が、PRRPサブドメインを持たないCD28の細胞質ドメインを含む、請求項1または2に記載のポリペプチド。
- 共刺激シグナル伝達領域が、PYAPサブドメインを持たないCD28の細胞質ドメインを含む、請求項1〜3のいずれかに記載のポリペプチド。
- 共刺激シグナル伝達領域が、41BBの2つの細胞質ドメインを含む、請求項1〜4のいずれかに記載のポリペプチド。
- 共刺激シグナル伝達領域が、TRAF結合領域に少なくとも1つの変異を有する41BBの2つの細胞質ドメインを含む、請求項1〜5のいずれかに記載のポリペプチド。
- 共刺激シグナル伝達領域が、TRAF結合領域に少なくとも2つの変異を有する41BBの2つの細胞質ドメインを含む、請求項1〜6のいずれかに記載のポリペプチド。
- CARポリペプチドが以下の式によって規定される、請求項1〜7のいずれかに記載のポリペプチド:
SP−TAA−HG−TM−CSR−ISD;または
SP−TAA−HG−TM−ISD−CSR
ここで、「SP」はシグナルペプチドを表し、
「TAA」は腫瘍関連抗原結合領域を表し、
「HG」は任意のヒンジドメインを表し、
「TM」は膜貫通ドメインを表し、
「CSR」は共刺激シグナル伝達領域を表し、
「ISD」は細胞内シグナル伝達ドメインを表し、
「−」は二価のリンカーを表す。 - 細胞内シグナル伝達ドメインが、CD3ゼータ(CD3ζ)シグナル伝達ドメインを含む、請求項1〜8のいずれかに記載のポリペプチド。
- 請求項1〜9のいずれかに記載の組換えポリペプチドをコードする単離された核酸配列。
- 請求項10記載の単離された核酸配列を含むベクター。
- 請求項11記載のベクターを含む細胞。
- αβT細胞、γδT細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、B細胞、自然リンパ球(ILC)、サイトカイン誘導キラー(CIK)細胞、細胞傷害性Tリンパ球(CTL)、リンホカイン活性化キラー(LAK)細胞、制御性T細胞、またはそれらのあらゆる組合せからなる群から選択される、請求項12記載の細胞。
- CARの抗原結合ドメインがTAAに結合した場合に抗腫瘍免疫を示す、請求項13記載の細胞。
- 異種キメラ抗原受容体(CAR)ポリペプチドおよび1以上のTRAFタンパク質を共発現する、免疫エフェクター細胞。
- TRAFタンパク質が、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、またはそれらのあらゆる組合せを含む、請求項15記載の免疫エフェクター細胞。
- CARが請求項1〜9のいずれかに記載の組換えポリペプチドを含む、請求項16または17に記載の免疫エフェクター細胞。
- TAAを発現するがんを有する対象に抗腫瘍免疫を与える方法であって、請求項1〜9のいずれかに記載のCARポリペプチドを発現するように遺伝子改変された有効量の免疫エフェクター細胞、または請求項12〜17のいずれかに記載の有効量の免疫エフェクター細胞を対象に投与し、それにより哺乳類に抗腫瘍免疫を与えることを含む方法。
- 免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)および制御性T細胞からなる群から選択される、請求項18記載の方法。
- チェックポイント阻害剤を対象に投与することをさらに含む、請求項18または19に記載の方法。
- チェックポイント阻害剤が、抗PD−1抗体、抗PD−L1抗体、抗CTLA−4抗体、またはそれらの組合せを含む、請求項20記載の方法。
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