JPWO2011021503A1 - 一過性生着ctlを含む医薬品組成物 - Google Patents
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Abstract
Description
ヒト臍帯血試料は、母親のインフォームド・コンセント署名を得た後に採血され、理化学研究所バイオリソースセンター内の液体窒素システムで凍結保存された。採血方法はRubinstein,P.ら(Blood,81:1679−1690(1993))に説明され、凍結保存方法はRubinstein,P.ら(Proc. Natl. Acad. Sci. USA, 92:10119−10122(1995))に説明される。
培地としてX−Vivo15(商標、TaKaRa Bio、滋賀)が使用された。一部の実験では最終濃度0ないし5%のヒトAB型血清(Lonza)が添加された。Peprotech(Rocky Hill,ニュージャージー州)製の組換えヒトインターロイキン−2(IL−2)が最終濃度0ないし1,500IU/mL添加された。
理化学研究所から入手した臍帯血25mLは37°Cの温水浴で解凍され、Ficoll−Paque(商標、GE Healthcare)上に重層され、室温にて1,500rpm、30分間遠心された。バフィーコートが回収され、PBS中に再浮遊された、得られた白血球はPBSでさらに3回洗浄された。その後、前記白血球懸濁液に細胞107個あたり25μLのDynal(商標)免疫磁気ビーズCD14(Invitrogen)が添加され、氷上又は4°Cで30分以上攪拌された。CD14陽性細胞と、ビーズを貪食した単球マクロファージとが磁気粒子分離器(MPC−1、Dynal)を用いて除去された。残りの細胞はPBS中に再浮遊され、細胞107個あたり25μLのDynal(商標)免疫磁気ビーズCD3(Invitrogen)が添加され、氷上又は4°Cで30分以上攪拌された。CD3陽性細胞が磁気粒子分離器(MPC−1、Dynal)を用いて分離された。
前記CD3陽性細胞は5%ヒトAB型血清を添加したXVivo15培地に106個/mLの濃度で浮遊され、Dynabeads CD3/CD28 T cell expander(Invitrogen)と、組換えIL−2とを添加して培養された。培養4、7、9、12及び14日目にトリパンブルー染色を用いて生細胞数が測定された。組換えIL−2を含む5%ヒトAB型血清を添加したExVivo15培地で、106個/mLの細胞濃度になるように希釈された。
図1に臍帯血由来CD3陽性細胞の増殖条件の検討結果を示す。図1の縦軸は培養開始時のCD3陽性細胞の総数を1とする増殖倍率を表し、横軸は培養開始後の日数を表す。刺激に用いるCD3/CD28免疫ビーズは細胞1個あたりビーズ約2個の割合で用いられた。培地に添加される組換えIL−2及びヒト血清の濃度とに関係なく、いずれの培養条件でも臍帯血由来CD3陽性細胞は培養9日目までほぼ同様の速度で増殖した。しかし、培養12日目になると、IL−2濃度が1,500IU/mLで、かつ、ヒト血清が5%の培養条件の細胞だけが増殖速度を維持し、他の培養条件の細胞は増殖速度の低下や細胞数の減少がみられた。培養14日目になると、IL−2濃度が1,500IU/mLの条件で培養された細胞のみが同じ速度で増殖した。以上に示したとおり、臍帯血由来の白血球から、CD3陽性のT細胞のみを精製し、これに***刺激を与えて選択的に増殖することが可能になった。
CD3/CD28免疫ビーズで刺激され、5%ヒトAB型血清及び1,500IU/mLのIL−2を添加したExVivo15培地で培養増幅された臍帯血由来CD3陽性細胞を培養14日目に回収して、APC標識抗ヒトCD8マウスモノクローナル抗体と、PE標識HLA−A*2402WT1(wild)CMTWNQMNL−テトラマーとで二重染色し、フロー・サイトメトリー解析を行った。
図2に前記フロー・サイトメトリー解析結果を示す。図の縦軸はPEの蛍光強度で、HLA−A*2402WT1(wild)CMTWNQMNL−テトラマーとの反応を表し、横軸はAPCの蛍光強度で、抗CD8抗体との反応を表す。図2に示すとおり、増幅された臍帯血由来CD3陽性細胞のうちCD8陽性細胞、すなわち、細胞傷害性T細胞の約11.6%は、HLA−A*2402アリルのコンテキストで癌抗原であるWT1由来ペプチドを特異的に認識した。WT1特異的な細胞傷害性T細胞は、リンパ腫その他のWT1を過剰発現する悪性細胞とは反応するが、WT1を比較的少量しか発現しない正常細胞を攻撃しないことが知られている(Gao,L.ら、Blood、95:2198−2203(2000)、Oka、Y.ら、Curr. Op. in Immunol.、20:211−220(2008))。
Claims (12)
- ヒト造血幹細胞由来の細胞を含む医薬品組成物であって、
前記細胞のヒトHLAクラスI分子のいずれか1つの遺伝子座は、前記細胞の適合型が患者の適合型と一致する抗原を少なくとも1個含むこと、及び
前記細胞のヒトHLAクラスI及びII分子の遺伝子座の抗原は、前記細胞の適合型が患者の適合型と一致しない抗原を少なくとも1個含み、かつ、前記造血幹細胞由来の細胞は前記患者の体内で、永続的生着も、重症度III又はIVの急性GVH病も起こさないことを特徴とする、医薬品組成物。 - 前記医薬品組成物は前記患者のリンパ球が除去された後に投与され、
該医薬品組成物は前記患者の体内で一過的に生着するが前記患者のリンパ球が再増殖するとともに消失することを特徴とする、請求項1に記載の医薬品組成物。 - 前記細胞のヒトHLAクラスI分子のいずれか1つの遺伝子座はHLA−A、HLA−B及びHLA−Cからなるグループから選択され、前記細胞のヒトHLAクラスII分子の遺伝子座はDRB1であること、及び、
前記細胞のヒトHLAクラスI及びII分子の遺伝子座の抗原は、前記細胞の適合型が患者の適合型と一致しない抗原を少なくとも1個含み、かつ、前記造血幹細胞由来の細胞は前記患者の体内で、永続的生着も、重症度III又はIVの急性GVH病も起こさないことを特徴とする、請求項1又は2に記載の医薬品組成物。 - 前記細胞のHLA−A、HLA−B及びDRB1の遺伝子座の抗原は、前記細胞の適合型が患者の適合型と一致しない抗原を5個ないし6個含み、かつ、前記造血幹細胞由来の細胞は前記患者の体内で、永続的生着も、重症度III又はIVの急性GVH病も起こさないことを特徴とする、請求項3に記載の医薬品組成物。
- 前記ヒト造血幹細胞は臍帯血幹細胞であることを特徴とする、請求項1ないし4のいずれか1つに記載の医薬品組成物。
- 前記ヒト造血幹細胞由来の細胞は、ヒトHLAクラスI分子拘束性エピトープに特異的な細胞傷害性T細胞であることを特徴とする、請求項1ないし5のいずれか1つに記載の医薬品組成物。
- 癌治療用であることを特徴とする、請求項1ないし6のいずれか1つに記載の医薬品組成物。
- 感染症治療用であることを特徴とする、請求項1ないし6のいずれか1つに記載の医薬品組成物。
- 前記ヒトHLAクラスI分子拘束性エピトープに特異的な細胞傷害性T細胞は前記ヒトHLAクラスI分子拘束性エピトープによる刺激を受けることなく増幅されることを特徴とする、請求項8に記載の医薬品組成物。
- 前記細胞のHLA−A遺伝子座は、前記細胞の適合型が患者の適合型と一致する抗原を少なくとも1個含むこと、及び、
前記細胞傷害性T細胞はウィルムス腫瘍原因遺伝子産物(WT1)に特異的であることを特徴とする、請求項9に記載の医薬品組成物。 - ヒト臍帯血由来の細胞傷害性T細胞を含む医薬品組成物であって、
前記細胞傷害性T細胞は、HLA−A、HLA−B及びHLA−Cのうちいずれか1種類の遺伝子座のHLAクラスI分子拘束性エピトープに特異的であること、
前記ヒトHLAクラスI分子拘束性エピトープに特異的な細胞傷害性T細胞は前記ヒトHLAクラスI分子拘束性エピトープによる刺激を受けることなく増幅されること、
前記細胞のいずれか1種類の遺伝子座のHLAクラスI分子は、前記細胞の適合型が患者の適合型と一致する抗原を少なくとも1個含むこと、及び、
前記細胞のHLA−A、HLA−B及びDRB1の遺伝子座は、前記細胞の適合型が患者の適合型と一致しない抗原を5個ないし6個含み、かつ、前記造血幹細胞由来の細胞は前記患者の体内で、永続的生着も、重症度III又はIVの急性GVH病も起こさないことを特徴とする、医薬品組成物。 - ヒト臍帯血をCD3/CD28免疫ビーズで刺激するステップを含むことを特徴とする、請求項9に記載の医薬品組成物の製造方法。
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WO2003106682A1 (ja) * | 2002-06-12 | 2003-12-24 | 中外製薬株式会社 | Hla−a24拘束性癌抗原ペプチド |
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JP2004002312A (ja) * | 2002-04-08 | 2004-01-08 | Lymphotec:Kk | 腫瘍・感染症および自己免疫疾患の予防・治療用hla一致他人由来活性化リンパ球および該リンパ球を主成分とする製剤ならびに該製剤の製造方法、該製剤調製用キット |
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