JP6010136B2 - ナチュラルキラー細胞の製造方法、その方法により製造されたナチュラルキラー細胞、並びにそれを含む腫瘍及び感染性疾患治療用組成物 - Google Patents
ナチュラルキラー細胞の製造方法、その方法により製造されたナチュラルキラー細胞、並びにそれを含む腫瘍及び感染性疾患治療用組成物 Download PDFInfo
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Description
本発明の本出願の発明者らは、臨床的使用のため健康な支援者らから収得したNK細胞を大量増殖及び活性化するための簡単で効率的な方法を打ち立てた。CD3+T細胞を磁性除去する段階を経てT細胞が除去されたPBMCsを刺激してOKT3及びIL−2存在下で反復的に不活性化支持細胞と共に増殖した結果、同種目的のため、望ましい高純度のCD3−CD16+CD56+NK細胞集団を製造した。
(ii)分離したNK細胞を抗−CD3抗体及びサイトカインが含有された培地に入れた後、支持細胞を添加して刺激し、細胞間接触が起こるように2〜15日間、好ましくは5〜10日間静置培養する段階;
(iii)(ii)段階の静置培養が完了した後、サイトカイン、抗−CD3抗体及び支持細胞を添加して再刺激し、細胞間接触が起こるように2〜7日間、好ましくは3〜5日間さらに静置培養する段階;
(iv)静置培養が完了した後、浮遊培養のために必要なサイトカインなどが含有された培地を追加し、細胞濃度及びサイトカイン濃度を一定に維持しながら浮遊培養する段階。
(1)支持細胞で繰り返して刺激することによるNK細胞の培養
健常なドナーから採取した末梢血単核球を1回生産分量に小分けしてバイアルに入れた後、液体窒素で凍結させた。凍結した一つのPBMCバイアルを解凍して50mLのチューブに移し、1体積%のFBSまたは自己血漿(autoplasma)を含有するPBS20mLで懸濁して、1200rpm、4℃で10分間遠心分離した。
インビトロ細胞生存率を比較及び評価するために、細胞内の核と結合できるPI染色液を用いる細胞カウンタ方法の一つであるNucleoCounter(chemometec社)システムを用いた。
標的腫瘍細胞株(K562など)を回収し、3×106個の細胞を15mLのチューブに入れて遠心分離した。細胞ペレットを600μLのRPMI培地で懸濁した後、そのうち400μLを新しい15mLのチューブに移し、Calcein−AM(Molecular probe、C34852)を50nMの濃度で入れた。次に、銀箔で光を遮断し、37℃の培養器で20分間染色した。一方、残りの細胞懸濁液200μLには、RPMI培地800uLを入れて、1×106細胞/mLの濃度となるように準備した。Calcein−AM染色が終わった腫瘍細胞株は、RPMI培地15mLを入れて洗浄し、遠心分離した後、ペレットを2mLのRPMI培地で懸濁して、1×106細胞/mLの濃度となるようにした。
実施例1の(1)に記載の培養方法により培養されたNK細胞の培養前及び培養後の細胞を回収して1200rpmで5分間遠心分離し、培養溶液を吸込み(suction)により除去した。1mLのFACSバッファー(2.5%のFBSが含有されたPBS)で希釈して細胞数を測定し、5×106細胞/mLとなるようにFACSバッファーで希釈した。5mLのFACSチューブ(Falcon、352052)で希釈した細胞溶液を100μLずつ入れた後、次のように抗体を入れた。
ハートマン溶液に添加されたアルブミンの濃度(2重量%、1重量%、0.5重量%)による、培養された細胞の安定性を評価するために、実施例1の(1)の方法により最終培養された細胞を4℃で72時間保存しながら、24時間単位でインビトロ細胞殺傷能及びインビトロ細胞生存率を評価した。
実施例1の(1)に記載の方法により培養されたNK細胞間の凍結安定性を確認した。
(1)リンパ腫動物モデルの構築
1)Raji、SU−DHL−4細胞株の培養
Raji及びSU−DHL−4(ヒトB細胞リンフォーマ細胞株)(DSMZ、ACC495)細胞株を、RIMI培地(L−グルタミン2mM、ピルビン酸ナトリウム1mM、FBS10重量%、2−メルカプトエタノール0.055mM、ペニシリン100U/ml、ストレプトマイシン100ug/ml)を用いて、37℃、CO25%の培養器で培養した。
6〜8週齢のC.B−17雌性マウスに対して、7日間の順化期間を経た後、1mLの注射器を用いてRaji及びSU−DHL−4細胞株をそれぞれ1×105細胞/100μLずつ尾静脈内に注入した。
1)ナチュラルキラー細胞の投与
腫瘍移植後、無作為に群を分離し、個体識別法により表示した。次に、対照群には、400μLのPBSを尾静脈内に注入した。また、実験群には、1×107/400μLのナチュラルキラー細胞を、0日から2〜3日間隔で尾静脈内に5回投与した。
実験を行った後、マウスの一般的な状態変化、運動性、下肢麻痺発病及び生存率を毎日確認した。公知のリンパ腫モデルであるRaji及びSU−DHL−4をマウスの尾静脈内に投与すると、脊髄の周辺に腫瘍が生じて、下肢麻痺症状が現れ、2〜3日後には死亡することになる。したがって、下肢麻痺の発病有無及び生存率をともに評価して、抗癌効果の指標として判断した。
(1)脳腫瘍動物モデルの構築
6週齢のBALB/C−nu/nuマウスに対して、一度に7匹に同時に腫瘍を植えることができる自動化装置であるセブンフレーム(seven frame)及びマルチ−シリンジインジェクタ(multi−syringe injector)を用いて、2×105細胞/5μLのU−87MG(ヒト神経膠芽腫細胞株)(ATCC HTB−14)を大脳に注入した。この際、ハミルトンシリンジ(hamilton syringe)を用いて10分間注入し、5分間中断した後、5分間シリンジの針を抜いて消毒後、縫合した。実験期間中にマウスの状態及び重量を観察し、実験日程に応じて犠牲(sacrifice)にして組職分析を行った。
脳腫瘍動物モデルにおけるNK細胞の抗腫瘍効果を確認するために、U−87MGを投与し、1週目から1週間隔でNK細胞を3回注入した。NK細胞は、脳に直接注入する頭蓋内投与(intracranial)方式及びマウスの尾静脈に注射する静脈内投与(intravenous)方式により投入した。頭蓋内投与方式を利用する場合には、1×103、1×104、1×105個のNK細胞を、静脈内投与方式を利用する場合には、1×105、1×106、1×107個のNK細胞を投与した。U−87MGを投与して4週後に犠牲にして、抗癌効果を評価した。
腫瘍のサイズを測定するために、ヘマトキシリン、エオシン染色法を用いた。脳を摘出してブレインマトリックス(brain matrix)に載せ、2mm間隔で切片を製作した。緩衝化した10%のホルマリン溶液に入れ、4℃で24時間固定した後、パラフィンブロックを製作した。パラフィンフォーマットされた組職を4μL切片として、コーティングされたスライドガラスに付けて、一晩乾燥させた。組職をキシレンで脱パラフィン処理した後、アルコールを順に作って(100体積%、95体積%、80体積%、エタノール/蒸溜水)再水和(rehydration)処理し、Gill’sヘマトキシリン及びエオシンで染色した。その染色程度を確認した後、脱水過程及びシール過程を行った。上記のように染色された組職から、腫瘍の長さ及び幅を算出した後、次の式で腫瘍の体積を計算した。
(1)卵巣癌動物モデルの構築
1)OVCAR−3−Luc細胞株の製作
ルシフェラーゼ遺伝子をpGL3ベクターにクローニングしてOVCAR−3細胞株に一過性導入(transient transfection)させた。ルシフェリンによりルシフェラーゼが発現される細胞株を1次選別し、表現型及びNK細胞による細胞毒性がOVCAR−3と同等な細胞株を2次選別した。
OVCAR−3−Luc(ヒト卵巣癌細胞株、KTCC(韓国細胞バンク)30162)細胞株は、RIMI培地(2mMのL−グルタミン、1mMのピルビン酸ナトリウム、10%のFBS、0.055mMの2−メルカプトエタノール、100U/mlのペニシリン、100ug/mlのストレプトマイシン、100ug/mLのG418)組成培地を用いて、37℃、5%のCO2培養器で培養した。
6〜8週齢のC.B−17 SCID雌性マウスに対して、7日間の順化期間を経た後、OVCAR−3−Luc細胞株5×106細胞/100uLを腹腔内に注入した。
1)NK細胞の投与
腫瘍移植後、無作為に群を分離し、個体識別法により表示した。対照群には、200μLのハートマン溶液(中外製薬)を腹腔内に注入した。NK細胞投与群には、1×107/200μL個のNK細胞を腫瘍移植1週後から2〜3日間隔で腹腔内に5回投与した。
OVCAR−3−Luc移植後、マウスの一般的な状態の変化及び運動性を毎日観察し、2〜7日間隔でルシフェリンを腹腔内に投与して、IVISイメージングシステム(Xenogen社)を利用してルシフェラーゼイメージを撮影し、腫瘍移植8週後に、全ての群のマウスを開腹して腫瘍のサイズを測定した。
(1)肝臓癌動物モデルの構築
NK細胞の肝臓癌に対する抗癌効能を評価するため、人体由来肝臓癌細胞株であるSNU−354を移植した人間腫瘍移植モデルを構築し、NK細胞投与した。人体由来肝臓癌細胞株であるSNU−354は6×106細胞/マウスの濃度でヌードマウス側面に皮下移植した。
1)NK細胞の投与
SNU−354移植2時間後に1×106細胞または1×107細胞の容量でNK細胞をマウスの尾静脈を通じて200μL投与した。最初の投与以降、同じ容量のNK細胞を1週間隔で3回以上投与した。
試験期間の間、NK細胞による毒性を評価するため、一般症状を毎日観察して、動物の体重及び腫瘍体積を試験終了時まで11回(0、7、9、12、14、16、19、21、23、26及び28日)測定した。28日以降、動物を犠牲にして抽出した腫瘍の重さを測定した。
(1)神経芽細胞腫動物モデルの構築
1)NB−1691luc細胞株培養
NB−1691(ヒト神経芽細胞腫細胞株,st.Jude Children’s Research Hospital)にルシフェラーゼ遺伝子を形質感染させて製造したNB−1691luc(ヒト神経芽細胞腫)細胞株を、RIMI培地(L−グルタミン2mM、ピルビン酸ナトリウム1mM、FBS10重量%、2−メルカプトエタノール0.055mM、ペニシリン100U/ml、ストレプトマイシン100μg/ml,G418 100μg/ml)を使用して、37℃、CO225%の培養器で培養した。
7週齢のC.B−17 SCID雌性マウスに対して、7日間の順化期間を経た後、NB−1691luc細胞株5×105細胞/100μLをマウスの尾静脈に注入した。
1)NK細胞の投与
腫瘍移植後、マウスをランダムに分類し、表示した。対照群としては200μLのハートマン溶液(中外製薬、韓国)を尾静脈に注入した。NK細胞投与群には、腫瘍移植した1週後から2〜3日間隔で1×107細胞/200μLのNK細胞を尾静脈に5回注入した。
NB−1691luc移植後、マウスの一般的な状態の変化及び運動性を毎日観察した。腫瘍の生成を確認するため、ルシフェリンをマウスの腹腔に投与して、IVISイメージングシステム(Xenogen社)を利用して7日間隔でルシフェラーゼイメージ映像を撮影した。
実施例1に記載されたように製造されたNK細胞を使用して、NK細胞の殺害能を実施例1(3)に記載されたように評価した。
5×106細胞/mL NK細胞と5×106細胞/mL ターゲット腫瘍細胞株(K562等)を準備し、準備されたNK細胞及びターゲット腫瘍細胞株を丸底96−ウェルプレートにいれた。細胞内に蓄積されたサイトカインの分泌を防ぐため、GolgiStop(BD Pharmingen, 554724)を共に入れた。
ウェル1:懸濁されたNK細胞100μL、RPMI培地100μL、抗ヒトCD107a−APC(BD Pharmingen,560664)1μL
ウェル2:懸濁されたNK細胞100μL、懸濁されたターゲット腫瘍細胞株100μL、抗ヒトCD107a−APC(BD Pharmingen,560664)1μL
ウェル3:懸濁されたNK細胞100μL、懸濁されたターゲット腫瘍細胞株100μL、APCマウスIgG1kイソタイプコントロール(BD Pharmingen,555751)5μL
ウェル1,2:希釈されたPerm/washバッファー100μL、抗ヒトIFN−g−FITC(BD,554700)1μL,抗ヒトTNF−a−PE−Cy7(eBioscience,25−7349−82)1μL
ウェル3:希釈されたPerm/washバッファー100μL、FITCマウスIgG1kイソタイプコントロール(BD,555748)5μL、PE−Cy7マウスIgG1kイソタイプコントロール(BD,557872)5μL
(a)K562細胞株(白血病)
(b)Raji細胞株(リンパ腫)
(c)SK−N−SH細胞株(神経芽細胞腫)
(d)SNUOT−Rb1細胞株(網膜芽腫)
(e)U87−MG細胞株(神経膠芽腫)
(f)OVCAR−3細胞株(卵巣癌)
(g)Huh−7細胞株(HCC,原発性肝細胞癌)
(h)SNU398細胞株(HBV感染HCC)
(i)Huh−7.5(HCV感染HCC)
Claims (8)
- (i)ヒト末梢血からNK細胞を分離する段階と;
(ii)抗−CD3抗体、サイトカイン、及び支持細胞としての不活性化された末梢血単核球細胞(PBMC)を含む培地に2〜15日間静置培養してNK細胞を刺激し、細胞間接触を生じさせる段階と;
(iii)前記段階(ii)から静置培養が完了した後、サイトカイン、抗−CD3抗体、及び支持細胞としての不活性化された末梢血単核球細胞を添加して再刺激し、再び静置培養し、細胞間接触を誘導する段階と、ここで、前記の細胞の再刺激及び静置培養の実施は、2回以上繰り返されるものとし;
(iv)静置培養が完了した後、静置または浮遊培養のために必要なサイトカインが含有された培地を追加し、細胞濃度及びサイトカイン濃度を一定に維持しながら静置または浮遊培養する段階と;
を含み、ここで、前記サイトカインは、インターロイキン−2(IL−2)、インターロイキン−12(IL−12)、インターロイキン−15(IL−15)、インターロイキン−18(IL−18)、及びインターロイキン−21(IL−21)からなる群より選択される一つ以上であるものとする、NK細胞の製造方法。 - 前記(iii)段階の静置培養は2〜7日間行うことを特徴とする請求項1に記載の方法。
- 前記(iv)段階の浮遊培養は振盪フラスコ、振盪培養器、発酵槽、T−フラスコ及び使い捨ての細胞培養バックからなる群より選択される反応器を用いて行うことを特徴とする請求項1に記載の方法。
- 前記(ii)または前記(iii)段階の静置培養及び前記(iv)段階の静置または浮遊培養は同じ反応器または相異な反応器で行うことを特徴とする請求項1に記載の方法。
- 前記(iv)段階の静置または浮遊培養の間に、細胞濃度及びサイトカイン濃度を測定し、サイトカインを含む培地を添加することにより細胞濃度及びサイトカイン濃度を一定に維持することを特徴とする請求項1に記載の方法。
- 前記抗−CD3抗体はOKT3、UCHT1、及びHIT3aからなる群より選択される一つ以上であることを特徴とする請求項1に記載の方法。
- 前記抗−CD3抗体はOKT3であることを特徴とする請求項6に記載の方法。
- 前記サイトカインは、IL−2であることを特徴とする請求項1に記載の方法。
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