JP2017169594A - T細胞増殖のためのプロセス - Google Patents
T細胞増殖のためのプロセス Download PDFInfo
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- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
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Abstract
Description
1)細胞産物の生産において、効率的、頑強、実行可能でかつ/または、経済的にコスト効率に優れる
2)最小の培養期間で抗原特異的T細胞の治療用量(産成量)を提供する。
3)患者、特に臨床的に適切な文脈で移植臓器対個体反応疾患において、不要な毒性を引き起こし得る他の細胞からの混入を最小限にする。
4)GMP要件に一致しない既存の技術に対して、新しく創造性のある技術的を適応させることで、GMP製造要件へのコンプライアンスを保証する。
5)外因性IL−2を追加する必要のないオプションを提供する。
6)動員を受けたと考えられるドナーの血液試料からの増殖を可能とする。動員とは骨髄(造血幹細胞)提供前に、G−CSFをドナーへ投与することと定義される。
7)抗原特異的T細胞集団の適切な増殖と、有害となる恐れのある汚染細胞集団の存在との間の実現すべき所望のバランスを最適化することで、産物に従来技術と等しい、または従来技術より優れた特徴を付与する。
8)50〜100mlsという少量のドナー試料から増殖できる。
(i)細胞増殖を支援するのに適切であり、培養中の細胞にガスを送出できるガス透過性部分、および
基部に接した少なくとも1つの壁を有する容器であって、
前記容器は内部の容積を画定し、前記容器は細胞培養を支援するために必要な容積の培地を含むよう適応される容器、
(ii)液体が通過する内部開口部とこれに対して遠位にある外部開口部を画定する導管を含む通気管であって、この導管はシステムの構造上の特徴として閉鎖系の外部から伸長し、容器の内部へ伸長し、容器内部の内部開口部で終結し、内部開口部は、液体培地の充填および排出の際、液体によって遮断されにくいよう配置され、
外部開口部は無菌フィルタに連結するよう適応され、これによって容器中へ、または容器外へフィルタを通して、液体および細胞を容器へ出し入れするために必要なガスの出入りを可能とする、通気管、
(iii)容器へ液体および細胞を無菌的に導入できるよう適合され、システムを外的環境に曝さずに、システムから液体を排出できるように適合され、出口ポートから流体の流れに細胞を載せるようシステムが傾き、出口ポートが開いた時に、容器内で培養した細胞が重力によってシステムから排出できるよう適応されたポート(複数可)、を含む。
同一性:CD45+細胞中でCD3+が50%を超える
生存度:CD45+細胞の70%以上
安全性:CD3+用量が指定したT細胞の数を超過しない。
ウイルス特異性:特定のIFNg産生により定義されるkg当たり最低100個のウイルス特異的細胞
DMSOの量は、一般に12%以下であり、例えば約10%w/wである。
CD3+T細胞集団を含み、全集団においてCD3+は、患者1kg当たり5×105細胞を超えず、前記CD3+T細胞集団は、Th1集団としての特性を有するCD4+細胞の治療的T細胞集団を、例えばCD8+CTLと一緒に含み;
任意で、非CD3+細胞の集団を組成物の全細胞集団の20パーセント以下であり、
適切な増殖させた抗原特異的T細胞集団はインビボで増殖可能であるという特徴を有する。
少なくとも70%のCD3+T細胞集団および30パーセント未満の非CD3+細胞を含み、CD3+細胞の全集団は、患者1kg当たり5×104細胞(または5×105)を超えず、前記CD3+T細胞集団は、主にTh1として特性を有するCD4+細胞の治療的T細胞集団を含み、
適切な増殖させた抗原特異的T細胞集団はインビボで増殖可能であるという特徴を有する。
Sili UらLarge−scale expansion of dendritic cell−primed polycolonal human cytotoxic T−lymphocyte lines using lymphoblastoid cells for adoptive immunotherapy. J.Immuother.2003 May−Jun:26(3):241−56
Leen AMらContact−activated monocytes:efficient antigen presenting cells for the stimulation of antigen−specific T cells. J Immunother.2007 Jan:30(1):96−107.
Bollard CMらThe generation and characterization of LMP2−specific CTL for use as adoptive transfer from patients with relapsed EBV−positive Hodgkin disease J.Immunother.
MG Wing,らAn Improved Method for the Detection of Cell Surface Antigens in Samples of Low Viability using Flow Cytometry. J Immunol Methods 126:21−27,1990
DR Parks,らChapter 29 Flow Cytometry and Fluorescence−Activated Cell Sorting (FACS). Handbook of Experimental Immunology, DM Weir(ed),Blackwell Scientific Publications,MA,1986
I SchmidらDead Cell Discrimination with 7−aminoactinomycin D in Combination with Dual Colour Immunofluorescence in Single Laser Flow Cytometry. Cytometry 13:204, 1992
F deBoerらExtensive early apoptosis in frozen thawed CD34+ stem cells decreases threshold doses for haematological recovery after autologous peripheral blood progenitor cell transplant.Bone marrow Transplant 29:249−255,2002
RS Anthony,らFlow cytometry using annexin V can detect early apoptosis in peripheral blood stem cell harvests from patients with leukemia and lymphoma.Bone Marrow Transplant 21:441−446,1998.
James W Tung,ら Modern Flow Cytometry: A Practical Approach. Clin Lab Med 27(3):453, 2007(September)
抗原特異的T細胞産成物の増殖
試薬
本手順では、Wilson Wolfe GRexシステムを使用して産生された養子細胞免疫療法の産生および凍結保存を記載する。
全ドナーは、血液を採取して30日以内に感染症(B型肝炎表面抗原、C型肝炎、梅毒、HTLVIおよびIIおよびHIVのマーカー)マーカーの検査を受けなくてはならない。万一ドナーに何らかの感染症に陽性の結果が出た場合、産物の採取は行われず、プロセスはキャンセルされる。
IL−4の50μgバイアルを注射用水250μlで希釈して保存溶液200μg/ml産生した。必要に応じて、希釈試料20μLを培養毎に添加する。残った試料を1.8mlのNuncCryovialsに50μLで小分けする。凍結バッチのIL−4を使用する場合、物質が使用前に完全に溶解されていることを確認する。
IL−7の50μgバイアルを注射用水(WFI)200μlで希釈した。溶液を、WFI240μlを加えてさらに1:25に希釈し、10μg/mlの作業溶液を産生する。その後、この20μlを培養毎に使用する。残った試料を1.8mlのNuncCryovialsに50μLで小分けする。凍結バッチのIL−7を使用する場合、物質が使用前に完全に溶解されていることを確認する。
ペプチドを、100μg/ペプチドバイアルにWFIを2ml加えて再構成する。再構成したペプチド100μlを取り出して、WFI900μlでさらに希釈する。その後、希釈したペプチド20μLを各培養に添加する。再構成したペプチドの50μlアリコートをNunccryovialsに分注する。濃縮したペプチドの残りの1500μl(50μg/ml)は、QC分析で使用するためにリリースする。
RPMIの5Lバッグを600mlの輸送パックの連結器に取り付ける。風袋はかりの上に輸送パックを置き、RPMI約500ml(500g)を移した。一旦、バッファーをすべて移したら、線状に3回熱圧してヒートシールする。「患者識別子、洗浄用500ml、使用まで2〜8℃で保存」と記載したラベルを貼る。
RPMIの5Lバッグに結合されているチューブに新規の600mlの輸送パックを接続する。風袋はかりを使用して100mlのRPMIをバッグへ移した。
1000mlバッグの連結器にLymphoprepのボトルを取り付ける。2つの給気口をLymphoprepに取り付け、100mlをバッグへ入れる。「患者識別子、Lymphoprep100ml」と記載したラベルを貼る。
PBMCをsepaxの装置で密度勾配遠心法により調製する。プロトコルは当業者に既知である。
−0日目
緩衝液調製
IL−4
IL−4(USPグレード、CellGenixcat1003−050)の50μgバイアルをWFI(USPグレードInvitrogenCatA12873)250μlで希釈して保存溶液200μg/mlを産生した。保存溶液はポット接種に使用するため保存されているアリコートと一緒に−80℃で保管した。
IL−4(GMP、Cellgenix cat 1010−050)の50μgバイアルを、WFI(USPグレード Invitrogen Cat A12873)200μLで希釈し、保存溶液を生成した。溶液を、WFIで1:25に希釈し、作業溶液を産生し、その後、ポット接種に使用するため保存されているアリコートと一緒に−80℃で保管した。
60nmol/ペプチドのペプチド(GMP PepTivator pp65)を2mlのWFI(USPグレード Invitrogen Cat A12873)で再構成した。再構成したペプチド100μlを採取し、WFI900μlでさらに希釈した。希釈ペプチドの20μLを小分けした残りの容積と一緒にポット接種のために保持し、−80℃で保存した。
RPMI+Glutamaxの5Lバッグ(Invitrogen Cat 61870)を600mlの輸送パックに接続し、RPMI500ml(産物洗浄)を移した。RPMIを2番目の600ml輸送パックに接続して、さらに100ml移した(ポット接種)。
Lymphoprep(Axis Shield Cat 1114740)100mlを1000ml輸送パックへ移し、DGBS(密度勾配に基づく分離)サイクルで使用するため保管した。
非動員アフェレーシス100mlは、一致したドナーから2〜8℃の温度監視の下出荷された後、サイトに到着した。細胞生成物から3ml試料(STA)を取り、1mlは1セットのBactecsへ接種した。以下のQCおよび工程内試験を残りの出発物質で実施した。下記のテーブルに結果を示す。
細胞計数、自動細胞カウンタで実施
TrucountによるT細胞の絶対的計数(CD3−FITC、CD8−PE、CD45−PerCP)
生存度染色(CD3−FITC、CD45−PE、CD8−PerCP)
細胞計数、自動細胞カウンタで実施
TrucountによるT細胞の絶対的計数(CD3−FITC、CD8−PE、CD45−PerCP)
生存度染色(CD3−FITC、Cd45−PE、CD8−PerCP)
細胞洗浄
10日目に、ポットをインキュベータから出し、静かに揺動してWilson Wolfe biopotの基部の細胞を再懸濁する。2mlの試料を採取し、2×250μLはマイコプラズマ試験に使用する。残りの試料は以下の工程内試験において使用する。
トリパンブルーでのマニュアルの細胞計数
T細胞同定 CD3−FITC、CD56−PE、CD45−PerCP
細胞内γ染色
4.5%HSA(BPL)中20%のDMSO(Cryosure−DMSO,Wak−Chemie)溶液100mlを、氷嚢上で調製し冷却した。
必要な細胞用量=3×104T細胞/kg
患者の体重=16kg
したがって必要とされる細胞=480,000T細胞
以下の容積をCryocytemanifoldセットにより適切な大きさのCryocyteバッグへ移した。
−0日目
緩衝液調製
IL−4
IL−4(USPグレード、CellGenix cat 1003−050)の50μgバイアルを、WFI(USPグレード Invitrogen Cat A12873)250μLで希釈し、保存溶液200μg/mlを生成した。保存溶液を、ポット接種で使用するために残したアリコートと一緒に−80℃で保管した。
IL−4(GMP、Cellgenix cat 1010−050)の50μgバイアルを、WFI(USPグレード Invitrogen Cat A12873)200μLで希釈し、保存溶液を生成した。溶液を、WFIで1:25に希釈し、作業溶液を産生し、その後、ポット接種に使用するため保存されているアリコートと一緒に−80℃で保管した。
60nmol/ペプチドのペプチド(GMP PepTivator hexon V)を2mlのWFI(USPグレード Invitrogen Cat A12873)で再構成した。再構成したペプチド100μlを採取し、WFI900μlでさらに希釈した。希釈ペプチドの20μLを小分けした残りの容積と一緒にポット接種のために保持し、−80℃で保存した。
RPMI+Glutamaxの5Lバッグ(Invitrogen Cat 61870)を600mlの輸送パックに接続し、RPMI500ml(産物洗浄)を移した。RPMIを2番目の600ml輸送パックに接続して、さらに100ml移した(ポット接種)。
Lymphoprep(Axis Shield Cat 1114740)100mlを1000ml輸送パックへ移し、DGBS(密度勾配に基づく分離)サイクルで使用するため保管した。
非動員アフェレーシス100mlは、一致したドナーから2〜8℃の温度監視の下出荷された後、サイトに到着した。細胞生成物から3ml試料(STA)を取り、1mlは1セットのBactecsへ入れた。以下のQCおよび工程内試験を残りの出発物質で実施した。下記のテーブルに結果を示す。
細胞計数、自動細胞カウンタで実施
TrucountによるT細胞の絶対的計数(CD3−FITC、CD8−PE、CD45−PerCP)
生存度染色(CD3−FITC、CD45−PE、CD8−PerCP)
細胞計数、自動細胞カウンタで実施
TrucountによるT細胞の絶対的計数(CD3−FITC、CD8−PE、CD45−PerCP)
生存度染色(CD3−FITC、CD45−PE、CD8−PerCP)
細胞洗浄
10日目に、ポットをインキュベータから出し、静かに揺動してWilson Wolfe biopotの基部の細胞を再懸濁する。2mlの試料を採取し、2×250μLはマイコプラズマ試験に使用する。残りの試料は以下の工程内試験において使用される。
トリパンブルーでのマニュアルの細胞計数
T細胞同定CD3−FITC、CD56−PE、CD45−PerCP
細胞内γ染色
4.5%HSA(BPL)中20%DMSO(Cryosure−DMSO、Wak−Chemie)溶液の100mlを調製し氷嚢上で冷却した。
必要な細胞用量は=3×104T細胞/kg
患者の体重=16kg
したがって必要とされる細胞=480,000T細胞
細胞の開始集団は、図で示したような適合させたG−Rexシステムで培養した。培養には、10%ヒト血清、IL4、IL7および所望の抗原に特異的なオーバーラップペプチドプールの存在下、RPMI1640培地を使用した。その後のCMV特異的増殖に使用したペプチドはpp65だった。アデノウイルス(ADV)に対してはad5ヘキソンのオーバーラップペプチドを使用した。0.5,1または2×106/cmの播種密度を使用した。2×106/cm2で最大の細胞増殖が得られた。
Claims (34)
- 抗原特異的T細胞(例えば同種抗原特異的T細胞)を急速に増殖させるためのインビトロ増殖プロセスであって、標的抗原に関するペプチドまたはペプチドミックスの存在下、サイトカインが外因性IL−2以外であるという特徴を有する外因性サイトカインの存在下、ガス透過性容器においてPBMC(例えば同種PBMC)の集団を培養するステップを含む、インビトロ増殖プロセス。
- 同種抗原特異的T細胞等の抗原特異的T細胞を急速に増殖させるためのインビトロ増殖プロセスであって、抗原、例えば標的抗原に関するペプチドまたはペプチドミックスの存在下、所望のT細胞集団を提供する増殖が14日間以下、例えば、9、10、11または12日間、例えば10日間であることを特徴とする外因性のサイトカインの存在下で、ガス透過性容器においてPBMC(例えば同種PBMC)の集団を培養するステップを含む、インビトロ増殖プロセス。
- 前記外因性サイトカインが、IL−4、IL−7、IL−15またはそれらの組み合わせを含む群から選択される、請求項1に記載のインビトロ増殖プロセス。
- 前記外因性サイトカインが、IL−4、IL−7、IL−12、IL−15またはそれらの組み合わせを含む群から選択される、請求項2に記載のインビトロ増殖プロセス。
- 前記外因性サイトカインが、IL−4およびIL−7の組み合わせである、請求項3または4に記載のインビトロ増殖プロセス。
- 前記培養が、T細胞増殖培地が存在する状態で実施される、請求項1から5のいずれか1項に記載のインビトロプロセス。
- 前記ペプチドミックスが、2から500のペプチド、例えば2から400のペプチド、2から300または2から200のペプチドを含む、請求項1から6のいずれか1項に記載のインビトロプロセス。
- 前記ペプチドが、例えば、2、3、4、5、6、7、8、9、10、11、12またはそれ以上のアミノ酸をオーバーラップする、請求項7に記載のインビトロプロセス。
- 前記ペプチドが平均で、10、11、12、13、14、15、16、17、18、19または20アミノ酸長、例えば15アミノ酸長である、請求項1から8のいずれか1項に記載のインビトロプロセス。
- 前記増殖が、14日間以下で実施される、請求項1および3から9のいずれか1項に記載のインビトロプロセス。
- 前記増殖が、13、12、11、10またはそれ以下の日数で実施される、請求項1から10のいずれか1項に記載のインビトロプロセス。
- ドナー由来の前記最初のPBMC試料が、動員された試料または動員されたアフェレーシス試料である、請求項1から11のいずれか1項に記載のインビトロプロセス。
- 前記ガス透過性容器が、GRexシステムまたは派生したもしくは等価のシステムである、請求項1から12のいずれか1項に記載のインビトロプロセス。
- 前記GRexシステムを、例えば図3に示したように、無菌的な製造に適した閉鎖系を提供できるよう適応させた、請求項13に記載のインビトロプロセス。
- 前記プロセスが、無菌的にまたはクリーンルームで実施される、請求項1から14のいずれか1項に記載のインビトロプロセス。
- 培地および栄養が、前記増殖プロセスの開始の後に追加または交換されない、請求項1から15のいずれか1項に記載のインビトロプロセス。
- 薬学的に許容できる組成物を調製するステップをさらに含み、このステップがさらに希釈剤、安定剤、保存剤および/または他の薬剤的に許容できる添加剤を追加するステップを含む、請求項1から16のいずれか1項で定義されたプロセス。
- 前記抗原特異的T細胞の集団またはこれを含む医薬組成物を注入バッグ等のコンテナに充填し、前記コンテナを密閉するさらなるステップを含む、請求項17に記載のプロセス。
- 請求項1から16のいずれか1項で定義されたプロセスから得た、または得ることのできる抗原特異的T細胞集団(例えば同種抗原特異的T細胞集団等)。
- 前記細胞のうちの30パーセント以下がCD3−である、請求項19に記載の抗原特異的T細胞集団(例えば同種抗原特異的T細胞集団)。
- 前記増殖が、CD4+細胞の増殖となる傾向がある、請求項19または20に記載の抗原特異的T細胞集団(例えば同種抗原特異的T細胞集団)。
- 前記CD4+T細胞集団が、主としてTh1集団である、請求項21に記載の抗原特異的T細胞集団(例えば同種抗原特異的T細胞集団)。
- 患者用の医薬組成物である増殖した抗原特異的T細胞集団であって、前記組成物が:少なくとも70%のCD3+T細胞集団および30パーセント未満の非CD3+細胞を含み、CD3+細胞の全集団が、患者1kg当たり5×104細胞を超えず、前記CD3+T細胞集団は、主にTh1として特性を有するCD4+細胞の治療的T細胞集団を含み、適切に増殖させた抗原特異的T細胞集団はインビボで増殖可能であるという特徴を有する、医薬組成物である増殖した抗原特異的T細胞集団。
- 注射用に適応させた請求項23に記載の医薬組成物。
- 増殖した抗原特異的T細胞集団が、全細胞集団の少なくとも1%パーセントである、請求項1から4のいずれか1項に記載の医薬組成物。
- 前記増殖した抗原特異的T細胞集団が、少なくとも5,000個の細胞、例えば10,000個の細胞である、請求項23から25のいずれか1項に記載の医薬組成物。
- 前記増殖した抗原特異的T細胞集団が、CD3+T細胞集団の20から80パーセントの範囲に存在する、請求項23から26のいずれか1項に記載の医薬組成物。
- 前記増殖した抗原特異的T細胞集団が、CMVに感染した、および/またはCMV抗原を提示する細胞に特異的である、請求項23から27に記載の医薬組成物。
- 前記増殖した抗原特異的T細胞集団が、アデノウイルスに感染した、および/またはアデノウイルス抗原を提示する細胞に特異的である、請求項23から27のいずれか1項に記載の医薬組成物。
- 前記組成物の前記増殖した抗原特異的T細胞集団が、動員された血液試料から増殖された、請求項23から29のいずれか1項に記載の医薬組成物。
- 前記細胞集団が、14日間以下、例えば12、11または10日間培養される、請求項23から28のいずれか1項に記載の医薬組成物。
- 患者、例えば、HS細胞移植を受けた患者の治療または予防で使用するための、請求項23から31のいずれか1項で定義された医薬組成物。
- 前記治療または予防がウイルス感染、例えばCMVまたはADVに対してのものである、請求項32に記載の医薬組成物。
- 請求項19から22で定義された抗原特異的T細胞集団、または請求項23から31のいずれか1項に記載の医薬組成物の量の治療上有効な量を投与することを含む、患者を治療する方法。
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AU2012351843B2 (en) | 2016-05-12 |
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US11963979B2 (en) | 2024-04-23 |
EP2791163B1 (en) | 2017-03-01 |
US20140341951A1 (en) | 2014-11-20 |
JP2020022505A (ja) | 2020-02-13 |
JP6203745B2 (ja) | 2017-09-27 |
JP2015501653A (ja) | 2015-01-19 |
GB201121308D0 (en) | 2012-01-25 |
ES2626492T3 (es) | 2017-07-25 |
HK1203219A1 (en) | 2015-10-23 |
US20220152111A1 (en) | 2022-05-19 |
US20190134092A1 (en) | 2019-05-09 |
AU2012351843A1 (en) | 2014-07-31 |
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