JP7116126B2 - 形質導入T細胞選択のためのトランケート上皮増殖因子レセプタ(EGFRt) - Google Patents
形質導入T細胞選択のためのトランケート上皮増殖因子レセプタ(EGFRt) Download PDFInfo
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Description
材料及び方法
抗体及びフローサイトメトリ
FITC-、PE-及びPerCP-共役アイソタイプコントロール、PerCP-共役抗CD8、FITC共役抗CD4、PE-共役抗IFNγ、PerCP-共役抗CD45及びPE-共役ストレプトアビジンは、BD Biosciences(San Jose、CA)から入手した。ビオチン化抗Fcは、Jackson ImmunoResearch Laboratories、Inc.(Westgrove、PA)から購入した。PE-共役抗ビオチンはMiltenyi Biotec(Auburn、CA)から購入した。ビオチン化EGFはMolecular Probes(R)Invitrogen(Carlsbad、CA)から入手した。PE-共役抗EGFRはAbeam Inc.(Cambridge、MA)から購入した。全ての抗体及びビオチンEGFは製造者の指示書に沿って使用した。フローサイトメトリデータ取得は、FACScalibur(BD Biosciences)で行い、分析の領域での細胞パーセントは、 FCS Express V3(De Novo Software、LosAngeles、CA)を用いて計算した。
特に記載されない限り、全ての細胞は、2mMのL-グルタミン(Irvine Scientific)、25mMのN-2-ヒドロキシエチルピペラジン-N’-2-エタンスルホン酸(HEPES、Irvine Scientific)、100 U/mLのペニシリン、0.1mg/mLのストレプトマイシン(Irvine Scientific)、及び10%加熱-不活性化ウシ胎児血清(FCS、 Hyclone、Logan、UT)を加えたRPMI1640 (Irvine Scientific、 Santa Ana、CA)中(以下培養培地(CM)とする)で保存された。
細胞(107まで)を、ホスファターゼインヒビタカクテルII80μLを含む1%トリトン-X溶解バッファ(Sigma-Aldrich Corp.、St.Louis、MO)(インヒビタ対バッファ容積比1:20)で溶解させた。50μgのタンパク質をそれぞれのレーンに載せ、ウェスタンブロットを、プローブとしてホスフォ-EGFレセプタ抗体サンプルキット(Cell Signaling Technology、Inc.、Danvers、MA)を用いて行い、続いて山羊抗ウサギ抗体(LI-COR、Lincoln、NE)共役IRDye(TM)680CW又は800CWと、同様に抗ベータアクチン抗体 (LI-COR)共役IRDye(TM) 800を、製造者の指示書に沿って用いて行った。ブロットはOdyssey Infrared Imaging System(LI-COR)で画像化させた。
T細胞の細胞溶解活性が、4時間クロム遊離アッセイ(CRA)で決定された。ここでエフェクタ細胞は5x103のCr51ラベル化ターゲットT細胞(Na2 51CrO4;5mCi/ml);Amersham Pharmacia、Piscataway、NJ)を含むV底96ウェルマイクロプレートの3重ウェルに播種され、5%CO2中37℃で種々のE:T比で200μLのCM中で4時間インキュベートされた。プレートを遠心分離し、上澄みの100μlをそれぞれのウェルから除いてγカウンタ(Packard Cobra II、 Downer’s Grove、IL)を用いて遊離クロムを評価した。 特定溶解パーセントは次のように計算された:100x(実験的遊離-自発的遊離)/(最大遊離-自発的遊離)。最大遊離は、2%SDSで溶解されたラベル化標的を含むウェルのCr含有量の測定から決定された。
T細胞移植のために、6から10週齢NOD/ScidIL-2RγCnullマウスに、107T細胞(細胞株C)が0日に静脈内に注射された。2x107照射(8000ラド)NSO-GFP:IMPDH2-IL15(IL2ss)_pcDNA3.1(+)(cJ02096)細胞が、インビボでヒトIL-15の系統的供給を与えるために0日で週3回腹腔内投与される。骨髄を安楽死させた動物から採取しフローサイトメトリで分析した。抗体依存性細胞傷害アッセイは、EGFRt+T細胞に対するセツキシマブの活性を決定することで実施される。
EGFRt発現T細胞の免疫的磁気選別
トランケートヒトEGFR(EGFRt)は、全長EGFRの膜間ドメインと細胞外ドメインIII及びIVのみを含み、免疫的磁気選別と適合して非免疫的磁気選択エピトープとして調製された。図1の分子モデルに示されるように、EGFRtはセツキシマブにより結合され得る機能を保持するが、細胞間ドメインの欠失により全てのシグナル系を欠いている。さらに、これはEGF結合に必要なN末端ドメインを欠いている。
EGFRtが不活性であることを確認するために、EGFRリン酸化についてのウェスタン免疫ブロット分析を、EGFRr選別T細胞でEGF又はセツキシマブで培養後に行った。予想の通り、セツキシマブはバックグラウンド以上のEGFRリン酸化を誘導せず、EGFR+細胞株A431でさえもそうであった(図3A)。さらに、A431細胞で見られたこととは対照的に、EGFとコインキュベート後の細胞株Aの溶解物でもリン酸化は見られなかった。実際、ビオチン化EGFを用いてフローサイトメトリ分析では、EGFはEGFRt選別T細胞には結合せず(図3B)、これはそのN、末端をトランケートされていることによると予想される。これらのEGFRt+T細胞はまた、セツキシマブとは異なる他の抗EGFR抗体でも認識されなかった。
AutoMACS(TM)分離の直後、選別されたT細胞は、OKT3、照射PBMCフィーダー及びLCL、IL-2及びOL-5でのREM刺激の後12日以内に30倍以上に増殖した(図4A)。得られた増殖EGFRt+T細胞のフローサイトメトリ分析はさらに、それらがCD19CAR及びCD8、TCR、CD3、パーホリン、グランザイムなどのT細胞マーカーを発現していることが確認された(図4B)。さらに、これらのEGFRt選別細胞株のCD19CARによる細胞活性は、CD19発現腫瘍ターゲットを用いて遊離クロムアッセにより明らかである(図4C)。細胞株Eとその非選別又は「親の」細胞株のCD19特異的反応性の直接比較は、EGFRt選別において強化されたCD19CAR介在細胞傷害性があることを示す。さらに、CMV特的TCM-誘導CD19CAR+EGFRt+細胞株B細胞はまた、ターゲット発現CMV-pp65抗原に対するこれらの外因性T細胞レセプタを介して細胞傷害性を示す。
インビボでの移植T細胞を検出する可能性を試験するために、CD19CAR+EGFRt+細胞株Cで移植させたマウスから集めた骨髄細胞が、ビオチン化セツキシマブを用いてフローサイトメトリで分析された(図5)。T細胞を受けていないコントロールマウスは、マウスEGFRに対してある程度のセツキシマブの交差反応があることを示した。従って、移植細胞株C細胞の検出を可能とするためには、ヒトCD45及びEGFRtの両方の二重染色が必要であることが決定された。細胞はまた、免疫組織化学を用いて、生検材料をスクリーニングするための可能性を決定するために分析され得る。
セツキシマブはEGFR発現細胞を、抗体依存性細胞傷害(ADCC)を介して溶解することが知られていることから、EGFRt+T細胞に対するセツキシマブの活性を決定するためにアッセイを行った(図6)。51Crラベル化細胞株A細胞をターゲットとし、新たに単離したヒトPBMCをエフェクタとして用いて、セツキシマブは、CD20特異的ヒト化mAbリツキサン(Rituxan)を用いた場合を超える有意にクロム遊離を介在することが見出された。
高リスクの中間悪性度B細胞リンパ腫を持つ大人の対象体は、自己骨髄破壊的幹細胞移植の候補者であり、適合的に転移された自己TCM-誘導CD19R+CD8+EGFRt+T細胞移植物による移植後免疫治療を受け得る。
それぞれの患者から集めた白血球分離物が、TCM選別され、医療グレードのCD19CAR-T2A-EGFRt_epHIV7で遺伝子組換えされ、その後選別され閉鎖系内でEGFRt+T細胞の増殖を行う。得られた細胞物は品質管理試験(殺菌及び腫瘍特異的細胞傷害性試験)を経て、凍結保存される。一方で、白血球除去輸血後に、研究参加者は、腫瘍低減化学療法及びG-CSFとの自動HSC収集のための動員とともに標準のサルベージ化学的治療を開始する。EGFRt選別、CD19特異的T細胞はまた、通常のCD20+(CD19+)B細胞もターゲットとするものであり、遺伝子改変CTLを受ける際に患者の炎症応答を低減させ、およびまた直ぐに目標のリンパ球へ注射されたT細胞を増加させるために、リツキシマブ(TM)を用いて最初B細胞数を低減させることができる。さらに、リツキシマブ(TM)は、遺伝子組換えT細胞に対してホルモン性免疫応答を遅らせる可能性がある。リツキシマブ(TM)が、前記サルベージ/プライミング治療戦略の一部として与えられない場合には、研究参加者はリツキシマブ(TM)(キメラ抗CD20抗体)を375mg/m2で計画された自動HSCT手順の4週間内に1回の静脈注射を受けることができる。リツキシマブ注射は標準方法で実行され得る。これにはジフェンヒドラミン及びアセトアミノフェン及びヒドロコルチゾンの前投与が含まれる。HSCT後の2日目と3日目で、自己凍結保存CD19R+CD8+EGFRt+T細胞物が輸送され、患者の側で解凍される。研究参加者はT細胞注射の少なくとも30分前に、15mg/kgのアセトアミノフェン経口(最大650mg)及び15~1mg/kg静脈注射(最大投与50mg)のジフェンヒドラミンが前投与され得る。臨床及び実験室の相互関連フォローアップ研究は、医師の裁量で実施され得る。これには、CD19発現リンパ球細胞及び/又は適合性遺伝子組換えT細胞の適量的RT-PCR研究;FDG-PET及び/又はCTスキャン;疾患特異的病理学的評価のための骨髄検査;リンパ節生検;及び/又は長期間フォローアップであり、FDAのBiologic Response Modifiers Advisory Committeeにより設定されたガイドラインの沿った遺伝子組み換え研究に適用されるものが含まれる。図10は本発明に係る物及び方法の臨床試験のための可能なスキームを与える。
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Claims (13)
- EGFRドメインIII、EGFRドメインIV及びEGFR膜貫通ドメインを含むが、EGFRドメインI、EGFRドメインII、EGFR膜近傍ドメイン、及びEGFRチロシンキナーゼドメインからなるドメインの全てを欠失した、改変上皮増殖因子レセプタ(EGFR)をコードする核酸分子を含むヒトT細胞を濃縮又は選択するインビトロでの方法であって、ここで、前記EGFRには、(i)内因性シグナル伝達機能又は輸送機能はなく;(ii)治療用抗EGFR抗体に結合し;(iii)内因性EGFRリガンドに結合せず;かつ、(iv)マーカーとして作用し、かつ、ここで、前記方法は、前記核酸分子を含むヒトT細胞を含む細胞の集団を、前記EGFRに結合する抗EGFR抗体と接触させるステップを含む、方法。
- 核酸分子は、配列番号2の第67~1071番目のヌクレオチドを含む、請求項1に記載のインビトロでの方法。
- 核酸分子は、配列番号3の第23~357番目の残基を含むアミノ酸配列をコードする、請求項1に記載のインビトロでの方法。
- 核酸分子は、さらに、GMCSFRアルファ鎖シグナル配列を含む、請求項1に記載のインビトロでの方法。
- 核酸分子は、配列番号2を含む、請求項4に記載のインビトロでの方法。
- 核酸分子は、配列番号3と少なくとも90%の同一性があるアミノ酸配列をコードする、請求項4に記載のインビトロでの方法。
- 核酸分子は、配列番号3を含むアミノ酸配列をコードする、請求項4に記載のインビトロでの方法。
- 核酸分子は、ベクター内へ挿入される、請求項1に記載のインビトロでの方法。
- 核酸分子は、腫瘍関連抗原に特異的なキメラ抗原レセプタにC末端2A開裂性リンカを介して結合した改変EGFRを含むコンストラクトの一部であり、前記腫瘍関連抗原は、CD19、CD20、及びCD22からなる群から選択される、請求項1に記載のインビトロでの方法。
- 改変EGFRは、コドン最適化抗CD19共刺激キメラ抗原レセプタ(CD 19CAR)及びC末端2A開裂性リンカに結合する、請求項1に記載のインビトロでの方法。
- CD 19CAR及びC末端2A開裂性リンカに結合した改変上皮増殖因子レセプタ(EGFR)をコードする核酸分子を含むヒトT細胞を濃縮又は選択するインビトロでの方法であって、前記核酸分子は、配列番号6を含むアミノ酸配列をコードする、インビトロでの方法。
- 核酸分子は、ヒトT細胞の集団にベクター内に挿入されて形質導入される、請求項11に記載のインビトロでの方法。
- 改変上皮増殖因子レセプタ(EGFR)をコードする核酸分子を含むヒトT細胞を含む細胞の集団を以前に投与された患者に、抗EGFR抗体を投与して、改変EGFRをコードする核酸分子を含むヒトT細胞を枯渇させることにより、前記患者を治療するための、抗EGFR抗体を含む医薬組成物であって、
ここで、前記抗EGFR抗体は、前記改変EGFRに結合し;
ここで、前記改変EGFRは、EGFRドメインIII、EGFRドメインIV及びEGFR膜貫通ドメインを含むが、EGFRドメインI、EGFRドメインII、EGFR膜近傍ドメイン、及びEGFRチロシンキナーゼドメインからなるドメインの全てを欠失し、かつ、(i)内因性シグナル伝達機能又は輸送機能はなく;(ii)治療用抗EGFR抗体に結合し;(iii)内因性EGFRリガンドには結合せず;かつ、(iv)マーカーとして作用する、
医薬組成物。
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