JP2006506987A - 自己免疫および臓器または造血幹細胞移植に関連する免疫学的欠損を有する患者における免疫レパートリー回復のための組成物および方法 - Google Patents
自己免疫および臓器または造血幹細胞移植に関連する免疫学的欠損を有する患者における免疫レパートリー回復のための組成物および方法 Download PDFInfo
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Abstract
Description
発明の分野
本発明は全体として、T細胞を刺激するための方法に関し、特に混合T細胞集団から不要な(例えば、自己反応性、アロ反応性、病原性)T細胞亜集団を排除し、それによってT細胞の正常な免疫レパートリーを回復するための方法に関する。本発明は、免疫レパートリーを回復した刺激T細胞を含む細胞組成物およびその用途にも関する。
T細胞が様々な癌または感染性生物に関連する広範な抗原を認識する能力は、そのT細胞抗原レセプター(TCR)によって付与され、このTCRはα(アルファ)鎖およびβ(ベータ)鎖またはγ(ガンマ)およびδ(デルタ)鎖から構成される。これらの鎖を構成するタンパク質はDNAによってコードされ、TCRの極めて大きな多様性を生むための独特のメカニズムを採用している。このマルチサブユニット型の免疫認識レセプターはCD3複合体と関連し、抗原提示細胞(APC)の表面にある主要組織適合性遺伝子複合体(MHC)クラスIおよびIIタンパク質によって示されるペプチドに結合する。TCRのAPC上の抗原ペプチドへの結合はT細胞活性化の中心的イベントであり、T細胞とAPCが接触する免疫学的シナプスにおいて生じる。
本発明の一つの局面は、個体に由来する混合T細胞集団からクローン性T細胞集団の少なくとも実質的な部分を排除するための方法であって、少なくともその一部がT細胞を含む細胞集団を提供する工程;その細胞集団をエキソビボにおいて一つまたは複数のプロアポトーシス組成物に曝露して、この曝露によってT細胞の少なくとも一部にアポトーシスを誘発する工程;それによって混合集団からクローン性T細胞の少なくとも実質的な部分を排除する工程を含む方法を提供する。
本発明について述べる前に、以下に用いられる一部の用語の定義を説明することがその理解に役立つであろう。
一つの態様において、プロアポトーシスまたは成長阻害組成物および/または感作組成物に曝露されるべき細胞は個体の循環血に由来して、一単位もしくはそれよりも多い単位の血液またはアフェレーシスもしくは白血球搬出法から得られる。アフェレーシス産物は、一般に、T細胞を含むリンパ球、単球、顆粒球、B細胞、またはその他の有核白血球、赤血球および血小板を含む。感作組成物への曝露ならびにその後の活性化および/または刺激に先立って、対象からT細胞の供給源が得られる。「対象」という用語は、免疫応答を起こすことのできる生存有機体(例えば、哺乳動物)を含むことが意図される。対象の例には、ヒト、イヌ、ネコ、マウス、ラットおよびそれらのトランスジェニック動物が含まれる。T細胞は、末梢血単核細胞、骨髄、胸腺、組織生検、腫瘍、リンパ節組織、消化管関連リンパ組織、粘膜関連リンパ組織、脾臓、またはその他の何らかのリンパ組織、および腫瘍を含む多くの供給源から得ることができる。T細胞は、Tセルラインおよび自家または同種供給源から得ることができる。T細胞は、異種供給源、例えばマウス、ラット、ヒト以外の霊長類およびブタから得ることもできる。本発明の一部の態様において、T細胞は、Ficoll分離のような当業者に既知の任意の数の技術を用いて対象から採取した血液単位から得ることができる。一つの好ましい態様において、個体の循環血に由来する細胞はアフェレーシスまたは白血球搬出法によって得られる。アフェレーシス産物は、一般に、T細胞を含むリンパ球、単球、顆粒球、B細胞、その他の有核白血球、赤血球、および血小板を含む。一つの態様において、アフェレーシスによって採取される細胞は、血漿分画を除去するため、および後続の加工工程に備えて細胞を適切な緩衝液または媒質に混合するために洗浄することができる。本発明の一つの態様において、細胞はリン酸緩衝生理食塩液(PBS)で洗浄される。代替の態様において、洗浄液はカルシウムを含まず、かつ、マグネシウムを含まない可能性があり、または、必ずしもすべてが二価陽イオンでない場合は多くを含まない可能性がある。当業者が容易に認識するように、洗浄工程は、製造業者の説明書に基づく半自動「フロースルー」遠心分離(例えば、Cobe 2991セルプロセッサー、Baxter)を用いるなど、当業者に既知の方法によって行うことができる。洗浄後、細胞は、例えばカルシウム(Ca)フリー、マグネシウム(Mg)フリーPBSのような様々な生体適合緩衝液に再懸濁することができる。または、アフェレーシス試料の不要な成分を除去して、細胞を直接、培養培地に再懸濁することができる。
プロアポトーシス組成物への直接曝露
本発明は、免疫細胞集団から不要なクローン細胞集団、一般的にはT細胞、B細胞、NKTまたはNK細胞の少なくとも一部を排除するための方法を提供する。本発明は、不要な細胞をもはや含まない、または不要な細胞の数が著しく減少した細胞集団を持つ組成物およびそれらの用途をさらに提供する。
または、不要な細胞集団の少なくとも実質的な部分は、先ず細胞をさならる刺激/活性化に対して感作した後、本発明の表面に曝露することによってそれらをさらに刺激または活性化して、排除することができる。この追加の刺激/活性化は感作細胞のアポトーシスを誘発して、集団からそれらを排除する。本発明の感作組成物は上記のプロアポトーシス組成物の影響に対しても細胞を感作する。従って、本発明は、細胞の不要な集団をさらなる刺激/活性化またはプロアポトーシス組成物の影響に感作する一つまたは複数の組成物に曝露することによって、不要な細胞クローン集団の少なくとも実質的な部分、一般にT細胞またはB細胞を免疫細胞集団から排除するための方法を提供する。本発明は、もはや不要な細胞を含まない細胞集団を含む組成物およびその用途をさらに提供する。
本発明の一つの局面において、上記のような感作細胞を含む免疫細胞集団は、下記の「細胞集団の刺激/活性化」のセクションに述べられるようにアポトーシスを誘発するためにさらに活性化または刺激されて、それによって、混合細胞集団から自己反応性またはアロ反応性のT細胞またはB細胞のような感作細胞が排除される。同時に、アポトーシスを受けるように感作されていない細胞などの残っている所望の細胞を活性化および刺激して増幅し、それによって、T(またはB細胞)の不要な亜集団の少なくとも実質的な部分が排除された活性化細胞集団が得られる。前記の通り、本明細書に述べられる刺激/活性化は混合細胞集団をプロアポトーシス組成物に直接曝露した後に残った細胞について実施することができる。さらに、本発明によって提供されるその後の刺激および活性化は、スペクトルタイプ分析によって示される通り、発現したTCR遺伝子に関してT細胞集団の多クローン性を回復する。
本発明は、免疫細胞集団からCD3+CD28+ T細胞の実質的に純粋な集団を作製するための方法を提供する。本発明において、実質的に純粋なCD3+CD28+ T細胞の集団のCD3+CD28- T細胞含有率は10%よりも少ない。一部の態様において、実質的に純粋なCD3+CD28+ T細胞の集団のCD3+CD28- T細胞含有率は、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%または0.1%よりも少ない。
本発明の刺激および活性化されたT細胞は、活性化を誘発する細胞表面部分のライゲーションによって作製される。一部の態様において、刺激および活性化されたT細胞は、例えば抗CD3抗体またはTCRに対する天然のリガンドを用いるなど、単にTCRの接触を介してT細胞集団を活性化することによって作製される。一部の態様において、刺激および活性化されたT細胞は、T細胞集団を活性化して、例えば米国特許出願第08/253,694号、第08/435,816号、第08/592,711号、第09/183,055号、第09/350,202号および第09/252,150号、ならびに米国特許第6,352,694号、第5,858,358および第5,883,223号に述べられるように、アクセサリー分子を結合するリガンドを用いてT細胞表面のアクセサリー分子を刺激することによって作製される。上記の感作細胞の状況において、T細胞の感作集団の活性化、およびアクセサリー分子を結合するリガンドを用いた感作T細胞表面のアクセサリー分子の刺激はその細胞のアポトーシスおよびその後の排除を誘発する。
一般に、本発明はプロアポトーシス組成物または感作組成物への集団の曝露およびその後の不要な細胞亜集団、好ましくは自己反応性または不要なアロ反応性T細胞におけるアポトーシスの誘発後に残る細胞集団の増幅について定める。本発明の一つの態様において、残留T細胞は単一の物質によって刺激することができる。もう一つの態様において、残留T細胞は2つまたはそれよりも多い物質を用いて刺激され、一つは一次シグナルを誘発して、補足的物質は一つまたは複数の共刺激シグナルを誘発する。単シグナルの刺激または一次シグナルおよび第二シグナルを刺激するアクセサリー分子の刺激に有用なリガンドは、可溶性物質として使用して、細胞表面に接着して、または本明細書に述べるように表面に固定することができる。表面に接着するリガンドまたは物質は、「代理」抗原提示細胞(APC)として機能する。好ましい態様において、一次および二次的物質の双方が表面に共固定される。一つの態様において、CD3リガンドのような一次活性化シグナルを提供する分子およびCD28リガンドのような共刺激分子は、例えば粒子のような同一の表面に結合する。さらに、既述の通り、一つ、二つまたはそれよりも多い刺激分子を同一表面または異なる表面で使用することができる。
上記の通り、本発明の方法は好ましくは表面に結合したリガンドを使用する。この表面は、リガンドをそこに結合または内部に取り込ませることができ、生体適合性、つまり刺激対象である標的細胞に対して実質的に無毒である任意の表面とすることができる。生体適合性の表面は、生分解性または非生分解性であることができる。表面は天然または合成であることができ、合成表面はポリマーであることができる。表面はコラーゲン、精製タンパク質、精製ペプチド、ポリサッカライド、グリコサミノグリカン、細胞外マトリックス組成物、リポソームまたは細胞表面を含むことができる。ポリサッカライドは、例えば、セルロース、アガロース、デキストラン、キトサン、ヒアルロン酸またはアルギン酸を含むことができる。その他のポリマーは、ポリエステル、ポリエーテル、ポリ無水物、ポリアルキルシアノアクリレート、ポリアクリルアミド、ポリオルトエステル、ポリホスファゼン、ポリ酢酸ビニル、ブロック共重合体、ポリプロポレン、ポリテトラフルオロエチレン(PTFE)、またはポリウレタンを含むことができる。ポリマーは、乳酸または共重合体であることができる。共重合体は、乳酸・グリコール酸(PLGA)を含むことができる。非生分解性表面は、ポリ(ジメチルシロキサン)およびポリ(エチレン酢酸ビニル)のようなポリマーを含むことができる。生体適合性表面は、例えば、ガラス(バイオグラスなど)、コラーゲン、キチン、金属、ヒドロキシアパタイト、アルミン酸塩、バイオセラミックス材、ヒアルロン酸ポリマー、アルギン酸塩、アクリル酸エステルポリマー、乳酸ポリマー、グリコール酸ポリマー、乳酸/グリコール酸ポリマー、精製タンパク質、精製ペプチド、または細胞外マトリックス組成物を含むことができる。表面を含むその他のポリマーには、ガラス、シリカ、シリコン、ヒドロキシアパタイト、ヒドロゲル、コラーゲン、アクロレイン、ポリアクリルアミド、ポリプロピレン、ポリスチレン、ナイロン、または任意の数のプラスチックもしくは合成有機ポリマーなどを含むことができる。表面は、リポソームまたは細胞表面のような生物学的構造を持つことができる。表面は脂質、プレート、バッグ、ペレット、繊維、メッシュまたは粒子の形態をとることができる。粒子は、コロイド状粒子、ミクロスフェア、ナノ粒子、ビーズなどを含むことができる。様々な態様において、ビーズまたはその他の粒子のような市販の表面が有用である(例えば、Miltenyi Particles, Miltenyi Biotec, Germany;Sepharose beads, Pharmacia Fine Chemicals, Sweden;DYNABEADS(商標)、Dynal Inc., New York;PURABEADS(商標)、Prometic Biosciences)。
本発明により企図される物質には、タンパク質リガンド、天然リガンドおよび合成リガンドが含まれる。細胞表面部分に結合して一定条件においてシグナリングに至るライゲーションおよび凝集を惹起することのできる物質には、レクチン(例えば、フィトヘマグルチニン(PHA)、レンチルレクチン、コンカナバリンA)、抗体、抗体フラグメント、ペプチド、ポリペプチド、グリコペプチド、レセプター、B細胞レセプターおよびT細胞レセプターのリガンド、MHC-ペプチド二量体または四量体、細胞外マトリックスコンポーネント、ステロイド、ホルモン(例えば、成長ホルモン、コルチコステロイド、プロスタグランジン、テトラヨードチロニン)、細菌性部分(リポポリサッカライドなど)、マイトジェン、スーパー抗原およびそれらの誘導体、成長因子、サイトカイン、接着分子(L-セレクチン、LFA-3、CD54、LFA-1など)、ケモカインおよび小分子が含まれるが、これらに限定されるものではない。これらの物質は、細胞、血液製剤および組織のような天然の供給源から単離されるか、またはインビトロにおいて増殖した細胞から単離して、遺伝子組換え技術、化学的合成、または当業者に既知のその他の方法によって調製することができる。
一般に、本明細書に述べられる組成物および方法は、免疫細胞集団から少なくとも一部の不要なクローン性細胞集団、一般的にはT細胞、B細胞、NKTまたはNK細胞を排除するために用いることができる。本発明は、もはや不要な細胞を含まない、または不要な細胞の数が著しく減少した細胞集団を含む組成物、ならびにその用途をさらに提供する。本発明の組成物および方法は、造血幹細胞移植(血液、臍帯血および骨髄などの供給源から得られるアロ移植および自家移植を含む)、臓器移植(急性または慢性GVHDなど)、ならびに大顆粒性リンパ球(LGL)白血病、慢性リンパ性白血病(CLL)のような癌、または一般的な様々な免疫欠損症によって惹起される自己免疫疾患などの自己免疫疾患に伴う免疫欠損症の治療での使用に備えて、不要なクローン性集団について除去された細胞集団を選択的に増幅するために用いることもできる。結果として、T細胞集団の場合、抗原反応性に関しては多クローン性であるがCD4+またはCD8+に関しては本質的に均一であって、自己反応性細胞またはアロ反応性細胞のような不要なあらゆる細胞亜集団が除去されているTCRを発現する細胞集団を作製することができる。B細胞については、自己反応性抗体を産生する不要なB細胞亜集団が除去されている細胞集団を作製することができる。さらに、この方法は得られるT細胞またはB細胞の集団を、各個体のCD4+またはCD8+のT細胞集団全体またはB細胞集団を再構築するために十分な数に増幅させる(個体のリンパ球集団は約5×1011個である)。得られる細胞集団は当業者に既知の様々な技術を用いて遺伝的に導入して、免疫療法において使用することができる。
本発明のT細胞集団は、単独または希釈剤および/またはIL-2もしくはその他のサイトカインのような他のコンポーネントまたは細胞集団と組み合わせた薬学的組成物として投与することができる。つまり、本発明の薬学的組成物は本明細書に述べられるような標的細胞集団を一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、希釈剤もしくは賦形剤と配合して含むことができる。このような組成物は、中性緩衝生理食塩液、リン酸緩衝生理食塩液などの緩衝液;グルコース、マンノース、ショ糖またはデキストラン、マンニトールのような炭水化物;タンパク質;ポリペプチドまたはグリシンのようなアミノ酸;抗酸化剤;EDTAまたはグルタチオンのようなキレート剤;アジュバント(例えば、水酸化アルミニウム);および防腐剤を含むことができる。本発明の組成物は、好ましくは静脈内投与用に調製される。本発明は、本明細書に述べられるような感作組成物を含む薬学的組成物をさらに提供する。
CD3/CD28 XCELLERATE(商標)ビーズを用いた再刺激後の抗原特異的細胞の除去
この実施例は、CD3/CD28 XCELLERATE(商標)ビーズ(3×28ビーズ)を用いた再刺激による細胞混合集団からの抗原特異的T細胞の除去について説明する。本明細書に述べられるプロセスを用いたXCELLERATED T細胞(商標)の作製は、本質的に、米国特許出願第10/133,236号に述べられている通りである。
アポトーシスの測定
この実施例は、アポトーシス測定のための例示的なアッセイについて説明する。
XCELLERATED T細胞(商標)との同時培養によるB細胞におけるアポトーシスの誘発
この実施例は、XCELLERATED T細胞(商標)との同時培養によってB-CLL患者のサンプル中の白血病性B細胞の除去について述べる。
異なるビーズ:細胞比はメモリーCD8 T細胞を選択的に増幅または除去することができる
この実施例は、異なるT細胞集団の増幅に対してビーズ:細胞比が顕著な影響を及ぼすことができることを示す。特に、高いビーズ:細胞比(3:1〜10:1)は抗原特異的T細胞の死を誘発する傾向があり、ビーズ:細胞比が低いと(1:1〜1:10)、抗原特異的T細胞が増幅される。さらに、次に示すデータは、低いビーズ:細胞比が多クローン性細胞集団の細胞増幅も回復させることを示している。従って、この実施例は、低いビーズ:細胞比が全体の細胞増幅を改善することを示す。さらに、この実施例はビーズ:細胞比が高い場合、本明細書に示されるビーズはプロアポトーシス組成物として使用することができることを実証している。
CD3/CD28 XCELLERATE(商標)ビーズを用いた再刺激後のアロ反応性T細胞の除去
この実施例は、CD3/CD28 XCELLERATE(商標)ビーズを用いた再刺激後のアロ反応性T細胞の除去について説明する。
Claims (67)
- 個体由来の混合T細胞集団からクローン性T細胞亜集団の少なくとも実質的な部分を排除するための方法であって、少なくともその一部がT細胞を含む細胞集団を一つまたは複数のプロアポトーシス組成物または成長阻害組成物に曝露する工程であって、該曝露がその混合T細胞集団に含まれる少なくとも一つのクローン性T細胞集団の少なくとも実質的な部分にアポトーシスまたは生育阻害を引き起こす工程と、それによってその混合T細胞集団の該クローン性T細胞集団の少なくとも実質的な部分を排除する工程とを含む方法。
- 残留混合T細胞集団を増幅する工程をさらに含む、請求項1記載の方法。
- 残留混合細胞集団を、少なくとも一部の残留T細胞の細胞表面部分をライゲートして該残留T細胞を刺激する一つまたは複数の物質をそこに接着させている表面に曝露することによって残留混合細胞集団を増幅する、請求項2記載の方法。
- 表面がT細胞の第一のT細胞表面部分をライゲートする第一の物質をそこに接着させ、同一または第二の表面が該T細胞の第二の部分をライゲートする第二の物質をそこに接着させて、第一および第二の物質による該ライゲーションが該T細胞の増殖を誘発する、請求項3記載の方法。
- 請求項1〜3のいずれか一項記載の方法に従って作製されるT細胞集団。
- プロアポトーシス組成物または成長阻害組成物が自己抗原を含む、請求項1記載の方法。
- 自己抗原が、ミエリン塩基性タンパク質(MBP)、MBP84-102、MBP143-168、膵島細胞抗原、コラーゲン、甲状腺抗原、Scl-70、核酸、アセチルコリンレセプター、S抗原、およびII型コラーゲンからなる群より選択される、請求項6記載の方法。
- プロアポトーシス組成物が同種または異種細胞を含む、請求項1記載の方法。
- 少なくとも一部がT細胞を含む細胞集団を、インビボにおいて一つまたは複数のプロアポトーシス組成物に曝露する、請求項1記載の方法。
- 少なくとも一部がT細胞を含む細胞集団を、エキソビボにおいて一つまたは複数のプロアポトーシス組成物に曝露する、請求項1記載の方法。
- 細胞の表面への曝露が多クローン性の増大に十分な期間である、請求項3記載の方法。
- 増大が、少なくとも一つのVβ、Vα、VγまたはVδファミリー遺伝子のVβ、Vα、VγまたはVδスペクトルタイププロフィールによって測定される、T細胞集団の単一クローン性からオリゴクローン性または多クローン性への推移を含む、請求項11記載の方法。
- 請求項6または11記載の方法に従って作製されるT細胞集団。
- 患者に請求項13記載のT細胞集団を投与する工程を含む、患者における自己免疫疾患を治療するための方法。
- 請求項10記載のT細胞集団の投与に先立って患者が免疫除去剤により処置される、請求項14記載の方法。
- 免疫除去剤が、キャンパス、抗CD3抗体、シクロホスファミド、フルダラビン、シクロスポリン、FK506、ミコフェノール酸、ステロイド、FR901228、および放射線療法からなる群より選択される、請求項15記載の方法。
- 請求項10記載のT細胞集団の投与に先立って患者がT細胞除去療法により処置される、請求項14記載の方法。
- プロアポトーシス組成物または成長阻害組成物が、抗CD3抗体、抗CD2抗体、抗CD20抗体、標的抗原、MHC-ペプチド四量体または二量体、Fasリガンド、抗Fas抗体、IL-2、IL-4、TRAIL、ロリプラム、ドキソルビシン、クロラムブシル、フルダラビン、シクロホスファミド、アザチオプリン、メトトレキセート、シクロスポリン、ミコフェノレート、FK506、bcl-2阻害剤、トポイソメラーゼ阻害剤、インターロイキン-1β転換酵素(ICE)-結合物質、赤痢菌IpaBタンパク質、スタウロスポリン、紫外線照射、ガンマ線照射、腫瘍壊死因子、標的抗原核酸分子、タンパク質またはペプチド、および非タンパク質または非ポリヌクレオチド化合物からなる群より選択される一つまたは複数の組成物を含む、請求項1記載の方法。
- 少なくとも一つの物質が抗体または抗体フラグメントである、請求項3記載の方法。
- 第一の物質が抗体またはそのフラグメントであり、第二の物質が抗体またはそのフラグメントである、請求項3記載の方法。
- 第一および第二の物質が異なる抗体である、請求項3記載の方法。
- 第一の物質が、抗CD3抗体、抗CD2抗体、または抗CD3もしくは抗CD2抗体の抗体フラグメントである、請求項3記載の方法。
- 第二の物質が抗CD28抗体またはその抗体フラグメントである、請求項3記載の方法。
- 第一の物質が抗CD3抗体であり、第二の物質が抗CD28抗体である、請求項3記載の方法。
- 個体由来の混合T細胞集団からクローン性T細胞亜集団の少なくとも実質的な部分を排除するための方法であって、次の工程を含む方法:
(a)少なくとも一部がT細胞を含む細胞集団をさらに活性化または刺激するためにT細胞の少なくとも一部を感作する一つまたは複数の組成物に曝露する工程;
(b)感作したT細胞の少なくとも一部の細胞表面部分をライゲートし該感作T細胞を刺激する一つまたは複数の物質をそこに接着させている表面に細胞集団を曝露する工程であって、該感作T細胞の該表面への曝露が該感作T細胞のアポトーシスを誘発するために十分な時間である工程;
それによって該感作T細胞をその集団から排除する工程。 - 工程(b)が残留T細胞の少なくとも一部を刺激するために十分な期間にわたって細胞集団を表面に曝露する工程をさらに含み、該残留細胞の少なくとも一部が増殖する、請求項25記載の方法。
- 表面がT細胞の第一のT細胞表面部分をライゲートする第一の物質をそこに接着させ、同一または第二の表面が該T細胞の第二の部分をライゲートする第二の物質をそこに接着させて、第一および第二の物質による該ライゲーションが該T細胞の増殖を誘発する、請求項25記載の方法。
- 細胞の表面への曝露が多クローン性を増大させるために十分な期間である、請求項26記載の方法。
- 増大が、少なくとも一つのVβ、Vα、VγまたはVδファミリー遺伝子のVβ、Vα、VγまたはVδスペクトルタイププロフィールによって測定される、T細胞集団の単一クローン性からオリゴクローン性または多クローン性への推移を含む、請求項28記載の方法。
- 請求項25または28記載の方法に従って作製されるT細胞集団。
- 個体が造血幹細胞移植を必要とする、請求項25記載の方法。
- 感作する組成物が分裂を継続することができないように処理されているレシピエントPBMCを含み、細胞集団がドナーT細胞を含む、請求項31記載の方法。
- 請求項32記載の方法に従って作製されるT細胞集団。
- 請求項30または33記載のT細胞集団を患者に投与する工程を含む、造血幹細胞移植を受けている患者における有害なGVHDの影響のリスクまたは重篤度を軽減するための方法。
- 個体が臓器移植を必要とする、請求項25記載の方法。
- 感作する組成物が分裂できないように処理されているドナー細胞を含み、細胞集団がレシピエントT細胞を含む、請求項35記載の方法。
- 細胞の表面への曝露が多クローン性を増大するために十分な期間である、請求項36記載の方法。
- 増大が、少なくとも一つのVβ、Vα、VγまたはVδファミリー遺伝子のVβ、Vα、VγまたはVδスペクトルタイププロフィールによって測定される、T細胞集団の単一クローン性からオリゴクローン性または多クローン性への推移を含む、請求項37記載の方法。
- 請求項36または37記載の方法に従って作製されるT細胞集団。
- 請求項39記載のT細胞集団を患者に投与する工程を含む、臓器移植を受けている患者における臓器拒絶のリスクを軽減するための方法。
- 請求項36記載のT細胞集団の投与に先立って患者がT細胞除去療法により処置される、請求項40記載の方法。
- 感作する組成物が自己抗原を含む、請求項25記載の方法。
- 自己抗原が、ミエリン塩基性タンパク質(MBP)、MBP84-102、MBP143-168、Scl-70、膵島細胞抗原、S抗原、およびII型コラーゲンからなる群より選択される、請求項42記載の方法。
- 細胞の表面への曝露が多クローン性を増大するために十分な期間である、請求項43記載の方法。
- 増大が、少なくとも一つのVβ、Vα、VγまたはVδファミリー遺伝子のVβ、Vα、VγまたはVδスペクトルタイププロフィールによって測定される、T細胞集団の単一クローン性からオリゴクローン性または多クローン性への推移を含む、請求項44記載の方法。
- 請求項42または44記載の方法に従って作製されるT細胞集団。
- 請求項46記載のT細胞集団を患者に投与する工程を含む、患者における自己免疫疾患を治療するための方法。
- 請求項46記載のT細胞集団の投与に先立って患者がT細胞除去療法により処置される、請求項47記載の方法。
- 少なくとも一つの物質が抗体または抗体フラグメントである、請求項26記載の方法。
- 第一の物質が抗体またはそのフラグメントであり、第二の物質が抗体またはそのフラグメントである、請求項26記載の方法。
- 第一および第二の物質が異なる抗体である、請求項50記載の方法。
- 第一の物質が、抗CD3抗体、抗CD2抗体、または抗CD3もしくは抗CD2抗体の抗体フラグメントである、請求項26記載の方法。
- 第二の物質が抗CD28抗体またはその抗体フラグメントである、請求項26記載の方法。
- 第一の物質が抗CD3抗体であり、第二の物質が抗CD28抗体である、請求項26記載の方法。
- 個体由来のT細胞集団からCD3+/CD28+ T細胞の実質的に純粋な集団を作製するための方法であって、次の工程を含む方法;
少なくとも一部がT細胞を含む細胞集団を、エキソビボにおいて表面CD3およびCD28分子を刺激および/または選択する組成物に曝露する工程;
それによってCD3+/CD28+ T細胞の実質的に純粋な集団を作製する工程。 - 個体由来のT細胞集団からCD4+/CD3+/CD28+ T細胞の実質的に純粋な集団を作製するための方法であって、次の工程を含む方法;
少なくともその一部がT細胞を含む細胞集団を、エキソビボにおいて表面CD3およびCD28分子を刺激および/または選択する組成物に曝露する工程;
それによってCD4+/CD3+/CD28+ T細胞の実質的に純粋な集団を作製する工程。 - 個体由来のT細胞集団からCD8+/CD3+/CD28+ T細胞の実質的に純粋な集団を作製するための方法であって、次の工程を含む方法;
少なくともその一部がT細胞を含む細胞集団を、エキソビボにおいて表面CD3およびCD28分子を刺激および/または選択する組成物に曝露する工程;
それによってCD8+/CD3+/CD28+ T細胞の実質的に純粋な集団を作製する工程。 - 混入CD3+/CD28- T細胞の割合が約5%未満であるように十分な期間にわたってCD3+CD28+ T細胞を増幅する工程をさらに含む、請求項55〜57のいずれか一項記載の方法。
- 混入CD3+/CD28- T細胞の割合が約1%未満であるように十分な期間にわたってCD3+CD28+ T細胞を増幅する工程をさらに含む、請求項55〜57のいずれか一項記載の方法。
- 混入CD3+/CD28- T細胞の割合が0.1%未満であるように十分な期間にわたってCD3+CD28+ T細胞を増幅する工程をさらに含む、請求項55〜57のいずれか一項記載の方法。
- CD3分子が抗CD3抗体を用いて刺激され、CD28分子が抗CD28抗体を用いて刺激される、請求項55〜57のいずれか一項記載の方法。
- 細胞表面部分のライゲーションによってT細胞集団を活性化および増幅するための方法であって、次の工程を含む方法:
少なくともその一部がT細胞を含む細胞集団を、少なくとも一部のT細胞の細胞表面部分をライゲートし該T細胞を刺激する一つまたは複数の物質を接着させている表面であって、約8日間培養後に抗原特異的T細胞の少なくとも一つの集団の少なくとも実質的な部分が除去されるような該細胞に対する割合で含まれる表面に接触させる工程。 - 割合が約10:1から約5:1である、請求項62記載の方法。
- 割合が約5:1である、請求項62記載の方法。
- 割合が約10:1である、請求項62記載の方法。
- 混合T細胞集団を増幅する工程をさらに含み、残留混合T細胞集団をプロアポトーシス組成物に曝露する工程であって、該曝露が混合T細胞集団の増殖を誘発する工程を含む、請求項1記載の方法。
- プロアポトーシス組成物がビーズ上に共固定された抗CD3および抗CD28抗体を含む、請求項66記載の方法。
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JP2020512324A (ja) * | 2017-03-20 | 2020-04-23 | キューティー ホールディングス コーポレーションQt Holdings Corp | 免疫細胞の制御のための方法及び組成物 |
JP7321937B2 (ja) | 2017-03-20 | 2023-08-07 | キューティー ホールディングス コーポレーション | 増殖した免疫細胞の集団の生成方法 |
JP2021534747A (ja) * | 2018-08-22 | 2021-12-16 | セレクト バイオセラピューティクス リミテッド | アポトーシス感受性細胞のモジュレーション |
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ES2422193T3 (es) | 2013-09-09 |
EP1539929A2 (en) | 2005-06-15 |
WO2004003142A3 (en) | 2004-11-25 |
EP1539929B1 (en) | 2013-04-10 |
DK1539929T3 (da) | 2013-07-15 |
EP1539929A4 (en) | 2006-10-04 |
CA2490401A1 (en) | 2004-01-08 |
AU2003253684A1 (en) | 2004-01-19 |
US20040151704A1 (en) | 2004-08-05 |
TW200403340A (en) | 2004-03-01 |
WO2004003142A2 (en) | 2004-01-08 |
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