JP2006524991A - 抗原特異的t細胞の作製および単離の方法 - Google Patents
抗原特異的t細胞の作製および単離の方法 Download PDFInfo
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Abstract
Description
本発明は概して抗原特異的T細胞を作製し、単離し、拡大する方法に関する。本発明は抗原特異的T細胞の組成物にも関する。
種々の癌および感染性疾患においてT細胞によって認識される抗原の同定は、抗原特異的免疫療法を使った悪性疾患および感染性疾患の処置に大きな関心が寄せられる一因となっている。抗原特異的T細胞を用いる養子療法は、意図する免疫応答の特異性、表現型および規模を操作する手段を用意することにより、概念的に魅力的な戦略になる。養子療法の臨床試験に使用するための抗原特異的T細胞クローンを日常的に再現性よく拡大する方法が望ましいと考えられる。治療量の抗原特異的T細胞を作製するための現在の技術はまだ不十分であり、注入されるT細胞の機能を維持し、あるいは改善しつつ、製造工程を単純化することによって、改善され得る。
本発明は概して抗原特異的T細胞を活性化し、刺激し、単離する方法に関する。本発明は、抗原特異的T細胞の組成物、ならびに癌、感染性疾患、自己免疫疾患、加齢に関係する免疫機能不全、または抗原特異的T細胞が処置にとって望ましい他の疾患状態の処置および予防にそれらを使用する方法にも関する。
本発明を説明する前に、以下に使用する一定の用語の定義を記載しておくことは、その理解に役立つと思われる。
T細胞は、末梢血単核球、骨髄、胸腺、組織生検、腫瘍、リンパ節組織、腸管関連リンパ節組織、粘膜関連リンパ組織、脾臓組織、または他の任意のリンパ組織、および腫瘍を含む、数多くの供給源から得ることができる。T細胞はT細胞株から得ることができ、自己または同種異系の供給源から得ることができる。T細胞は異種供給源から、例えばマウス、ラット、非ヒト霊長類、およびブタから得ることもできる。
抗原提示細胞(APC)源は、典型的には、抗原を負荷しかつ/または必要なサイトカインもしくは因子で処理した時に、インビトロで増殖し、プロフェッショナルAPC(pAPC)に成熟する能力を有するAPC前駆体またはAPCを含む組織供給源である。本明細書にいう「プロフェッショナルAPC」(pAPC)または「抗原提示細胞」(APC)は、抗原に対するナイーブおよび/またはメモリーT細胞の応答を通常開始する細胞を指す。プロフェッショナルAPCには、DC、マクロファージ、およびB細胞が含まれるが、これらに限定されるわけではない。pAPCは高レベルのMHCクラスII、ICMA-1およびB7-2を発現させ得る。ある局面では、APC前駆細胞が、インビトロで増殖し、樹状細胞(DC)に成熟する能力を有する。多くの組織供給源を使用し得るが、典型的な組織供給源は、脾臓、胸腺、組織生検、腫瘍、輸入リンパ、リンパ節、骨髄、アフェレーシス産物もしくは白血球アフェレーシス産物、および/または末梢血を含む。一定の態様では、アフェレーシス産物、骨髄および末梢血が好ましい供給源である。胎児組織、胎児または臍帯血も成長因子に富み、やはりAPCおよび/または前駆APCを得るための血液源として使用することができる。例示的な前駆細胞として、胚性幹細胞、CD34+細胞、単球幹細胞、単球、およびプレB細胞先祖細胞を挙げることができるが、これらに限定されるわけではない。
本発明によれば、抗原源は、糖タンパク質を含むタンパク質、ぺプチド(オーバーラップぺプチドのプールを含む)、スーパー抗原(例えばSEA、SEB、TSST-1)、抗体/抗原複合体、腫瘍溶解物、ウイルス溶解物(例えばCMV溶解物など)、不溶性細胞残渣、アポトーシス小体、壊死細胞、全細胞(生きているもの、固定されたもの、照射されたもの、加熱殺滅されたもの、または他の操作を受けたもの)、分裂し続けることができないように処理された腫瘍または細胞株から得た全腫瘍細胞、分裂し続けることができないように処理された同種異系細胞、照射腫瘍細胞、照射同種異系細胞、天然または合成複合糖質、リボタンパク質、リポ多糖、RNAまたは該RNAの翻訳産物、およびDNAまたは該DNAがコードするポリぺプチドであることができるが、これらに限定されるわけではない。非形質転換細胞は、典型的には、約3000〜3600ラド、より好ましくは約3300ラドのγ線で照射される。リンパ芽球腫または腫瘍細胞株は、典型的には、約6000〜10,000ラド、より好ましくは約8000ラドのγ線で照射される。壊死細胞およびアポトーシス細胞は、物理的、化学的、または生物学的手段によって、作製することができる。壊死細胞は、典型的には、凍結融解によって作製され、一方、アポトーシス細胞は、UV照射を使って作製される。UV照射およびγ照射、ならびに凍結融解法は、当技術分野において周知であり、例えば「Current Protocols in Molecular Biology」または「Current Protocols in Immunology(John Wiley & Sons、ニューヨーク州ニューヨーク)などに記載されている。
本発明の一局面は、異なるビーズ:細胞比を用いることが、抗原特異的T細胞の拡大に関して異なる結果につながり得るという驚くべき発見に由来する。特に、ビーズ:細胞比を変化させることにより、抗原特異的(メモリー)T細胞を選択的に拡大または欠失させることができる。ある態様では、使用する特定のビーズ:細胞比により、抗原特異的T細胞が選択的に拡大される。したがって、本発明の一態様では、少なくともその一部がT細胞(例えば、ある個体から得た白血球アフェレ一シス産物、血液試料、腫瘍生検など)を含んでいる細胞集団を、ある表面と直接接触させることによって、抗原特異的T細胞が活性され、この場合、該表面にはT細胞の第1T細胞表面部分をリガンド結合する第1薬剤が取り付けられており、同じ表面または第2表面に該T細胞の第2部分をリガンド結合する第2薬剤が取り付けられていて、第1および第2薬剤による該リガンド結合が、細胞集団内に存在する抗原特異的T細胞の増殖(拡大)を誘導する。
本発明の抗原特異的T細胞の拡大は、抗原特異的T細胞を増殖するように再刺激する細胞表面部分リガンド結合によって行なわれる。本発明の一態様では、まず、抗原特異的T細胞が、抗原負荷APCへの曝露後に、本明細書に記載の方法によって単離される。本発明のもう一つの態様では、抗原特異的T細胞が、抗原負荷APCが存在する状態での培養物から、単離段階を経ないで直接拡大される。
本発明のもう一つの局面は、抗原特異的T細胞の集団または組成物を提供する。さらに本発明は、抗原特異的T細胞および薬学的に許容される担体を含む薬学的組成物を提供する。本発明の組成物は、単独で投与するか、薬学的組成物として、希釈剤および/または他の成分、例えばIL-2もしくは他のサイトカインもしくは細胞集団と組み合わせて投与することができる。簡単に述べると、本発明の薬学的組成物は、1つまたは複数の薬学的または生理学的に許容される担体、希釈剤または賦形剤と組み合わされた、本明細書に記載の標的細胞集団を含む。そのような組成物は、中性緩衝食塩水、リン酸緩衝食塩水などの緩衝液、グルコース、マンノース、スクロースまたはデキストラン、マンニトールなどの糖質、タンパク質、ポリペプチドまたはグリシンなどのアミノ酸、酸化防止剤、エチレンジアミン四酢酸(EDTA)またはグルタチオン、アジュバント(例えば水酸化アルミニウム)、および保存剤を含み得る。本発明の組成物は、一定の局面では、静脈内投与用に製剤化される。
実施例1
CMV抗原被覆ビーズは抗原特異的T細胞を活性化しその単離を容易にする
この実施例では、サイトメガロウイルス(CMV)被覆ビーズを使って、抗原特異的T細胞を活性化し単離した。
エクスビボで拡大したメモリーCD8 CMVテトラマー+T細胞は、再刺激すると、CD25をアップレギュレートする
この実施例では抗原被覆ビーズを使ってCMV特異的CD8+T細胞をエクスビボで活性化した。
ビーズ:細胞比を変化させることにより、メモリーCD8 T細胞を選択的に拡大または欠失することができる
この実施例では、ビーズ:細胞比が異なるT細胞集団の拡大に大きな影響を持ち得ることを示す。特に、高いビーズ:細胞比(3:1〜10:1、20:1およびそれ以上)は抗原特異的T細胞の死を誘導する傾向があり、一方、低いビーズ:細胞比(1:1〜1:10、1:20、1:30、1:40、1:50またはそれ以下)は抗原特異的T細胞の拡大につながる。さらに、以下のデータは、低いビーズ:細胞比がポリクローナル細胞集団における細胞拡大の向上にもつながることを示している。したがってこの実施例は、低いビーズ:細胞比が総細胞拡大を向上することを示す。
培養中にビーズ:細胞比を変化させ、ビーズを逐次的に添加することにより、メモリーT細胞の拡大を向上することができる
この実施例では、培養中に低いビーズ:細胞比でビーズを逐次的に添加することにより、メモリーT細胞の拡大を向上することができることを示す。
Xcellerate拡大法におけるCD4+ Tメモリー(「抗原経験」)T細胞の評価
この実施例では、Xcellerate(商標)拡大法においてCD4 T細胞サブセットを評価するためのモデル系を説明する。
様々な抗CD3:抗CD28抗体比を使ったT細胞拡大
3×28 DYNABEADS(登録商標)M-450上の様々な濃度の抗CD3:CD28抗体比を使って、T細胞拡大を評価した。ここに記載する実験では、米国特許出願第10/187,467号に記載されているように、XCELLERATE II(商標)と呼ばれる方法を使用した。簡単に述べると、この方法は、実施例3に記載したXCELLERATE I(商標)に似ていて、独立した単球枯渇段階を用いず、一部の方法では、ビーズとの最初の接触前に細胞を凍結し、さらなる濃縮および刺激を行なうなど、いくつかの変更点がある。図6に示すように、驚いたことに、ビーズ上の抗体が1:10の抗CD3:CD28比で、培養8日後に約68倍の拡大が観察された。ビーズ上1:3のCD3:CD28比では、培養8日後にT細胞の35倍の拡大が見られた。1:1の比では、約24倍の拡大が見られた。図7に示すように、CMVpp65特異的CD8+T細胞でも、1:30という低い抗CD3:抗CD28抗体比を使って、同様の結果が観察された。
Xcellerate法およびWave Bioreactorを使ったT細胞拡大
この実施例では、本質的に米国特許出願第10/350,305号、同第10/187,467号、同第10/133,236号、同第09/960,264号、同第09/794,230号、PCT/US01/06139、およびPCT/US02/28161に記載されているXcellerate II法を使用した後、Wave Bioreactorに細胞をプレーティングすることによるT細胞拡大を説明する。
Xcellerate法の最初の日は、本質的に、必要な数の低温保存したCryocte(商標)容器を貯蔵冷凍庫から取り出し、融解し、洗浄し、濾過した。
次に、約0.5×109個のCD3+細胞を含有する細胞液量を、Dynabeads M-450 CD3/CD28 Tと、3:1のDynabeads M-450 CD3/CD28 T:CD3+ T細胞比で混合し、回転させながらインキュベートした。インキュベーション後に、CD3+T細胞を磁気的に濃縮すると同時に活性化した。次に、CD3+T細胞をLifecell細胞培養バッグ中の完全培地に再懸濁した。次に、細胞およびビーズを含有するバッグを、患者専用インキュベータ(37℃、5%CO2)に入れた。
CD3+細胞を約3日間培養拡大し、その時点で、1つのバッグの内容物を4つの新しいLifecellバッグに分割する。次に、それら4つのバッグを患者専用インキュベータ(37℃、5%CO2)に戻した。
CD3+細胞をさらに約2日間培養拡大し、その時点で、培養バッグの内容物を、今度は体積10Lの培地を含有する20L Wave Bioreactorにプレーティングした。次に、15振動/分の揺動運動および1ml/分の灌流速度で、細胞を37℃、5%CO2で培養した。
Claims (41)
- 少なくともその一部が抗原特異的T細胞を含んでいる細胞集団を、第1薬剤および第2薬剤が取り付けられている表面と接触させることを含み、第1薬剤がT細胞上のCD3/TCR複合体をリガンド結合し、かつ第2薬剤が該T細胞上のアクセサリー分子をリガンド結合し、かつ該T細胞の該第1および第2薬剤によるリガンド結合が抗原特異的T細胞の増殖を誘導し、かつ表面が1:2またはそれ以下の表面対T細胞比で存在する、抗原特異的T細胞の集団を拡大する方法。
- 表面が常磁性ビーズ、脂質、および細胞表面からなる群より選択される、請求項1記載の方法。
- 表面が常磁性ビーズを含む、請求項2記載の方法。
- ビーズが抗体に結合されたビーズを含む、請求項3記載の方法。
- 表面が約1:2.5の表面対T細胞比で存在する、請求項1記載の方法。
- 表面が約1:5の表面対T細胞比で存在する、請求項1記載の方法。
- 表面が約1:10の表面対T細胞比で存在する、請求項1記載の方法。
- 表面が約1:25の表面対T細胞比で存在する、請求項1記載の方法。
- 表面が約1:50の表面対T細胞比で存在する、請求項1記載の方法。
- 表面が約1:100の表面対T細胞比で存在する、請求項1記載の方法。
- 抗原特異的T細胞を作製および/または濃縮する方法であって、以下の段階を含む方法:
(a)少なくともその一部が抗原提示細胞を含んでいる第1細胞集団を、抗原が取り付けられている表面に、抗原が取り付けられている前記表面が前記APCによって摂取されるように曝露する段階、
(b)少なくともその一部がT細胞を含んでいる第2細胞集団を(a)の細胞集団に曝露する段階、
その結果として抗原特異的T細胞を作製および/または濃縮する段階。 - APCが抗原特異的T細胞と直接接触する、請求項11記載の方法。
- 抗原特異的T細胞と直接接触しているAPCが、前記APCを磁場に曝露することによって単離される、請求項12記載の方法。
- 抗原特異的T細胞が、以下の方法に従って拡大される、請求項13記載の方法:
(a)T細胞を、ある表面上に固定化された抗CD3抗体に曝露すること、かつ
(b)T細胞の表面上のアクセサリー分子を、抗CD3抗体と同じ表面上に固定化された抗CD28抗体で刺激すること、
その結果として、前記抗原特異的T細胞の拡大を誘導すること。 - T細胞をIL-15に曝露する段階をさらに含む、請求項14記載の方法。
- T細胞をCD137の天然リガンドに曝露する段階をさらに含む、請求項14記載の方法。
- T細胞を抗CD137抗体に曝露する段階をさらに含む、請求項14記載の方法。
- T細胞を抗NKG2D抗体またはNKG2Dの天然リガンドに曝露する段階をさらに含む、請求項14記載の方法。
- 抗原特異的T細胞が、前記抗原特異的T細胞をマイトジェンに曝露することによって拡大される、請求項13記載の方法。
- マイトジェンがフィトヘマグルチニン(PHA)、酢酸ミリスチン酸ホルボール(PMA)およびイオノマイシン、リポ多糖(LPS)、ならびにスーパー抗原からなる群より選択される、請求項19記載の方法。
- 抗原が、タンパク質、糖タンパク質、ペプチド、抗体/抗原複合体、全腫瘍またはウイルス感染細胞、固定された腫瘍またはウイルス感染細胞、加熱殺滅された腫瘍もしくはウイルス感染細胞、腫瘍溶解物、不溶性細胞残渣、アポトーシス小体、壊死細胞、分裂し続けることができないように処理された腫瘍または細胞株由来の全腫瘍細胞、分裂し続けることができないように処理された同種異系細胞、照射腫瘍細胞、照射同種異系細胞、天然または合成複合糖質、リポタンパク質、リポ多糖、形質転換された細胞または細胞株、トランスフェクトされた細胞または細胞株、形質導入された細胞または細胞株、およびウイルスに感染した細胞または細胞株からなる群より選択される、請求項11記載の方法。
- 抗原が抗体/リガンド相互作用によって表面に取り付けられる、請求項11記載の方法。
- 抗原/リガンド相互作用が、抗MART-1抗体/MART-1抗原、抗WT-1抗体/WT-1、抗PR1抗体/PR1、抗PR3抗体/PR3、抗チロシナーゼ抗体/チロシナーゼ抗原、抗MAGE-1抗体/MAGE-1抗原、抗MUC-1抗体/MUC-1抗原、抗α-フェトプロテイン抗体/α-フェトプロテイン抗原、抗Her2Neu抗体/Her2Neu、抗HIV gp120抗体/HIV gp120、抗インフルエンザHA抗体/インフルエンザHA、抗CMV pp65/CMV pp65、抗C型肝炎抗体/C型肝炎タンパク質、抗EBV EBNA 3B抗体/EBV EBNA 3B抗原、ならびに抗ヒトIg重鎖および軽鎖/骨髄腫癌患者由来のIg、ならびに抗ヒトIg重鎖および軽鎖/CLL癌患者由来のIgからなる群より選択される抗体/リガンド対間の相互作用を含む、請求項22記載の方法。
- 抗原が表面に化学的に取り付けられる、請求項11記載の方法。
- 表面への抗原の取り付けがビオチン-アビジン相互作用を含む、請求項11記載の方法。
- 少なくともその一部がAPCを含んでいる細胞集団が、白血球アフェレーシス産物、末梢血、リンパ節、扁桃腺、胸腺、組織生検、腫瘍、脾臓、骨髄、臍帯血、CD34+細胞、単球、および接着細胞からなる群より選択される供給源に由来する、請求項11記載の方法。
- 抗原特異的T細胞を作製し、かつ拡大する方法であって、以下の段階を含む方法:
(a)少なくともその一部が抗原提示細胞を含んでいる第1細胞集団を、抗原に、前記抗原が前記APCによって取り込まれるように曝露する段階、
(b)少なくともその一部がT細胞を含む第2細胞集団を(a)の細胞集団に曝露し、その結果として抗原特異的T細胞を作製する段階、および
(c)(b)の前記抗原特異的T細胞を、ある表面上に固定化された抗CD3抗体に曝露し、かつT細胞表面上のアクセサリー分子を、抗CD3抗体と同じ表面上に固定化された抗CD28抗体で刺激し、その結果として該抗原特異的T細胞の拡大を誘導する段階。 - 抗原特異的T細胞が、T細胞をT細胞活性化マーカーに特異的な抗体と接触させることによって単離される、請求項27記載の方法。
- 抗体が、抗CD25、抗CD54、抗CD69、抗CD38、抗CD45RO、抗CD62L、抗CD49d、抗CD40L、抗CD137、抗CD62L、および抗CD134からなる群より選択される、請求項28記載の方法。
- 請求項1、14、19、27、または28のいずれか一項記載の方法に従って作製される抗原特異的T細胞の集団。
- 請求項30記載の抗原特異的T細胞および薬学的に許容される賦形剤を含む組成物。
- 哺乳動物に請求項31記載の組成物を投与する段階を含む、哺乳動物における免疫応答を刺激する方法。
- 哺乳動物における癌細胞の存在を減少させる方法であって、その細胞を請求項31記載の組成物に曝露する段階を含む方法。
- 癌細胞が、メラノーマ、非ホジキンリンパ腫、ホジキン病、白血病、形質細胞腫、肉腫、神経膠腫、胸腺腫、乳癌、前立腺癌、結腸直腸癌、腎癌、腎細胞癌、膵癌、食道癌、悪性脳腫瘍(brain cancer)、肺癌、卵巣癌、子宮頸癌、多発性骨髄腫、肝細胞癌、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、および慢性リンパ性白血病(CLL)からなる群より選択される癌に由来する、請求項33記載の方法。
- 哺乳動物に請求項31に記載の組成物を投与する段階を含む、哺乳動物における癌の発達を阻害する方法。
- 癌細胞が、メラノーマ、非ホジキンリンパ腫、ホジキン病、白血病、形質細胞腫、肉腫、神経膠腫、胸腺腫、乳癌、前立腺癌、結腸直腸癌、腎癌、腎細胞癌、膵癌、食道癌、悪性脳腫瘍、肺癌、卵巣癌、子宮頸癌、多発性骨髄腫、肝細胞癌、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、および慢性リンパ性白血病(CLL)からなる群より選択される癌に由来する、請求項35記載の方法。
- 哺乳動物に請求項31記載の組成物を投与する段階を含む、哺乳動物における免疫応答機能不全を寛解させる方法。
- 哺乳動物に請求項31記載の組成物を投与する段階を含む、哺乳動物における感染性生物の存在を減少させる方法。
- 生物が、ウイルス、一本鎖RNAウイルス、一本鎖DNAウイルス、二本鎖DNAウイルス、ヒト免疫不全ウイルス(HIV)、A型、B型またはC型肝炎ウイルス、単純ヘルペスウイルス(HSV)、ヒトパピローマウイルス(HPV)、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、寄生虫、細菌、結核菌(M. tuberculosis)、ニューモシスチス・カリニ(Pneumocystis carinii)、カンジダ(Candida)、アスペルギルス(Aspergillus)からなる群より選択される、請求項38記載の方法。
- 哺乳動物に請求項31記載の組成物を投与する段階を含む、哺乳動物における感染性疾患の発生を阻害する方法。
- 生物が、ウイルス、一本鎖RNAウイルス、一本鎖DNAウイルス、二本鎖DNAウイルス、ヒト免疫不全ウイルス(HIV)、A型、B型またはC型肝炎ウイルス、単純ヘルペスウイルス(HSV)、ヒトパピローマウイルス(HPV)、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス(EBV)、寄生虫、細菌、結核菌、ニューモシスチス・カリニ、カンジダ、アスペルギルスからなる群より選択される、請求項40記載の方法。
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JP2020530486A (ja) * | 2017-08-04 | 2020-10-22 | トゥルティノ バイオサイエンシズ インコーポレイテッド | 免疫細胞を活性化させる方法 |
US11999967B2 (en) | 2021-02-05 | 2024-06-04 | Children's National Medical Center | Generating HPV antigen-specific cells from a naive T cell population |
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EP1623017A1 (en) | 2006-02-08 |
US7977095B2 (en) | 2011-07-12 |
US20090137017A1 (en) | 2009-05-28 |
DE60334250D1 (de) | 2010-10-28 |
TW200502391A (en) | 2005-01-16 |
US20040224402A1 (en) | 2004-11-11 |
CA2525519A1 (en) | 2004-12-02 |
DK1623017T3 (da) | 2011-01-10 |
JP2011036263A (ja) | 2011-02-24 |
US20070212767A1 (en) | 2007-09-13 |
AU2003300359A1 (en) | 2004-12-13 |
WO2004104185A1 (en) | 2004-12-02 |
ATE481476T1 (de) | 2010-10-15 |
MXPA05012080A (es) | 2006-02-22 |
EP1623017A4 (en) | 2006-07-05 |
EP1623017B1 (en) | 2010-09-15 |
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