JP7335001B2 - 新規cd16+ナチュラルキラーおよびcd16+ナチュラルキラー細胞の培養方法 - Google Patents
新規cd16+ナチュラルキラーおよびcd16+ナチュラルキラー細胞の培養方法 Download PDFInfo
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Description
i)CD16受容体を発現する、
ii)少なくとも3ヶ月間継代培養した後に増殖能力を保持している、および
iii)x)合成、遺伝子改変、および/又は意図的に導入された、CD16受容体をコードするポリヌクレオチドを含まない、又はy)ddPCRシステムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブは配列番号:12である。
i)CD16受容体を発現していること、
ii) 少なくとも3ヶ月間継代培養した後に増殖能力を保持していること、および
iii)x)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まない、又はy)ddPCR システムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブは配列番号:12である。
i)CD16受容体を発現していること、
ii)x)合成、遺伝子改変、および/又は意図的に導入されたポリヌクレオチドを含まない、又はy)ddPCR システムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブは配列番号:12である。
i)CD16受容体を発現していること、
ii)x)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まない、又はy)ddPCRシステムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブの配列は配列番号:12である。
i)CD16受容体を発現していること、
ii)少なくとも3ヶ月間継代培養した後に増殖能力を保持していること、および
iii)x)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まない、又はy)ddPCR システムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブの配列は配列番号:12である。
i)CD16受容体を発現していること、
ii)少なくとも3ヶ月間継代培養した後に増殖能力を保持していること、および
iii)x)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まない、又はy)ddPCR システムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブの配列は配列番号:12である。
i)CD16受容体を発現していること、
ii)少なくとも3ヶ月間継代培養した後に増殖能力を保持していること、および
iii)x)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まれない、又はy)ddPCR システムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブの配列は配列番号:12である。
ステップS11:寄託番号ATCCCRL-2407を有する細胞集団に由来するヒト末梢血ナチュラルキラー細胞集団の取得。ステップS12:ヒト末梢血ナチュラルキラー細胞の集団をCD16受容体に特異的な抗体と接触させる。ステップS13:抗体が特異的に結合している細胞を分離し、それによって非トランスジェニックヒトCD16+ナチュラルキラー細胞株を取得する。
ステップS21’:ヒトCD16+ナチュラルキラー細胞を取得し、
ステップS22’:容器内で、ヒトCD16+ナチュラルキラー細胞をヒト血小板溶解物とIL-2を含有する培地と接触させ、そして、
ステップS23:ヒトCD16+ナチュラルキラー細胞を複数日間培養して、ヒトCD16+ナチュラルキラー細胞を増殖させる。
ステップS231:複数日間の培養後、細胞培養液中の細胞数は最初の細胞数に達し、最初の細胞数は1.25×106~5×106であった。
ステップS233:細胞懸濁液を第3の容器に入れて、第3の容器内の細胞の数を第2の細胞数にする。複数日間の培養後、ヒトCD16+ナチュラルキラー細胞が実質的に濃縮された組成物を取得するために、細胞数は第3の細胞数に達した。第3の細胞数は、例えば、5×109又は1×1040であった。
実施形態3.1: 本発明の培養法による非トランスジェニックヒトCD16+ナチュラルキラー細胞株の長期培養
この実施形態には2つの実験的試行がある。精製CD16+細胞集団の最初のバッチと精製CD16+細胞集団の2番目のバッチ(両方のバッチでCD16受容体を発現する細胞の割合は99%くらい高かった)は、実施形態1.1の方法で分類された。次に、精製CD16+細胞集団の第1のバッチおよび精製CD16+細胞集団の第2のバッチを、実験2.1の培養方法によってそれぞれ培養して、第1の実験試行の細胞懸濁液および第2の実験試行の細胞懸濁液を取得した。精製CD16+細胞集団の最初のバッチは合計35日間培養され、精製CD16+細胞集団の2番目のバッチは少くとも202日目まで長期間培養された。
実施形態3.1において異なる時点で取得された細胞懸濁液の各サンプルを遠心分離した。上清を除去し、細胞をバッファーに再懸濁する。次に、1μLのヨウ化プロピジウム(PI)と混合する。セルソーター又はフローサイトメーターを使用して、細胞がヨウ化プロピジウムで染色されているかどうかを検出し、アポトーシスを起こしている、又は死んだ細胞の割合を決定した。
実施形態3.1において異なる時点で取得された細胞懸濁液の各サンプルを遠心分離した。上清を除去し、細胞をバッファーに再懸濁する。次に、1μLのCD56蛍光標識抗体 (Cat. No. 318304, Biolegend, USA)、1μLのCD3蛍光標識抗体 (Cat. No. 300410, Biolegend, USA)、および1μLのCD2蛍光標識抗体(Cat. No. 300222, Biolegend, USA)と混合して、CD56分子、CD3分子、および/又はCD2分子を発現する細胞を同時に標識する。最後に、セルソーター又はフローサイトメーターを使用して、細胞がCD56分子、CD3分子、および/又はCD2分子を示すかどうかを分析し、さまざまな細胞表面メーカーを持つ細胞の割合を計算した。
溶解された標的細胞の割合(%)=1-[(実験ウェルの細胞指数-標的細胞の最大溶解コントロールウェルの細胞指数)÷(対照ウェルの細胞指数-標的細胞の最大溶解コントロールウェルの細胞指数)]×100 %
表1および表2を参照すると、表1は最初の実験的試行で取得された細胞懸濁液の結果を示し、表2は2番目の実験的試行で取得された細胞懸濁液の結果を示す。
ステップ(a1) 第1の一本鎖DNAが得られ、第1の一本鎖DNAの配列は配列番号:5、配列番号:6、又は配列番号:7であった。
ステップ(b1)第2の一本鎖DNAが得られ、第2の一本鎖DNAの配列は配列番号:8、配列番号:9、又は配列番号:10であり、第2の一本鎖DNAの配列は第1の一本鎖DNAの相補鎖である。
この実施形態の実験方法は、以下の点を除いて、実施形態3.5の実験方法とほぼ同じである:(1) 本実施形態で使用するエフェクター細胞は、<i>実施形態2.1に開示する培養方法で55日間培養して取得された細胞懸濁液(55日培養oNK懸濁液と呼ばれる)であり、又は、<ii>ACE-oNK-HER2細胞を用いた細胞懸濁液(「55日培養oNK懸濁液」の総細胞を、実施形態4に記載のように相補的な細胞リンカーおよびトラスツズマブリンカーを使用してトラスツズマブと連結させた)である。そして、(2)SK-OV-3細胞(標的細胞)の数に対するエフェクター細胞(55日培養oNK懸濁液又はACE-oNK-HER2細胞懸濁液における総細胞)の数の比率は1:1 (ET1), 2:1 (ET2), 又は5:1 (ET5)であり、(3)55日間培養oNK懸濁液の実験用ウェルにおいて、E:T比が1(0.55 ng)、2(1.10 ng)、および5(2.75 ng)のACE-oNK-HER2細胞懸濁液中の細胞に結合したトラスツズマブの総量と同等のトラスツズマブが添加された。詳細な手順は以下のとおりである。
実施形態8.1 液滴デジタルPCR(ddPCR)によるCD16受容体をコードするDNA配列の検出。
TCTGAAGACACATTTTTACTCCCAA[C/A]AAGCCCCCTGCAGAAGTAGGAGCCG(配列番号:41)、https://www.thermofisher.com/order/genome-database/details/genotyping/C_25815666_10?CID=&ICID=&subtype=)と混合し、最終容量は20μLである。
含む陽性液滴は陰性液滴と比較して蛍光の増加を示す。
この実施形態の実験方法は、以下の点を除いて、実施形態3.5の実験方法とほぼ同じである:(1)この実施形態で使用されるエフェクター細胞はCtrl oNK細胞、Ctrl yNK細胞、ACE-oNK細胞、又はACE-yNK細胞であり、(2)SK-OV-3細胞(標的細胞)の数に対するエフェクター細胞の数の比率は2:1(ET2),又は5:1(ET5)である。
ステップ(a1)第1の一本鎖DNAが取得され、第1の一本鎖DNAの配列は、配列番号:5、配列番号:6、又は配列番号:7であった。
ステップ(b1)第2の一本鎖DNAが得られ、第2の一本鎖DNAの配列は配列番号:8、配列番号:9、又は配列番号:10であり、第2の一本鎖DNAの配列は第1の一本鎖DNAの相補鎖である。
この実施形態の実験方法は、以下の点を除いて、実施形態2.1の実験方法とほぼ同じである:(1)ステップS22’において、実施形態2.1に開示された培養方法で9日間培養(9日間培養oNK懸濁液と呼ばれる)することによって取得された細胞懸濁液中のすべての細胞がこの実施形態において培養され、ステップS22’の最初容器の細胞数は5×106であった。そして、(2)細胞培地は、500 IU/mLのIL-2と<i>2.5%のヒト血小板溶解物、<ii>5.0%ヒト血小板溶解物、<iii>10.0%ヒト血小板溶解物、又は<iv>5.0%ヒト血清(ヒト血小板溶解物を含有しない)を含有する。
この実施形態では、出願者は少なくとも外因性標的化ユニットが複合体を形成した外因性標的化ユニット複合oNK細胞を調製する。外因性標的化ユニットは標的細胞上の生物学的マーカーへの特異的結合を発現する標的化部分を含有する。そして、標的化部分は、癌抗原、糖脂質、糖タンパク質、造血系統の細胞に存在する分化抗原のクラスター、ガンマ-グルタミルトランスペプチダーゼ、接着タンパク質、ホルモン、成長因子、サイトカイン、リガンド受容体、イオンチャネル、免疫グロブリンμ.鎖の膜結合型、アルファ-フェトプロテイン、C反応性タンパク質、クロモグラニンA、上皮ムチン抗原、ヒト上皮特異的抗原、ルイス(a)抗原、多剤耐性関連タンパク質、Neu癌遺伝子タンパク質、ニューロン特異的エノラーゼ、P糖タンパク質、多剤耐性関連抗原、p170、多剤耐性関連抗原、前立腺特異抗原、NCAM、ガングリオシド分子、MART-1、熱ショックタンパク質、シアリルTn、チロシナーゼ、MUC-1、HER-2/neu、KSA、PSMA、p53、RAS、EGF-R、VEGF、又はMAGEから選択された生物学的マーカーに結合する可能性がある。標的化部分は核酸ではなく、外因性標的化ユニット複合oNK細胞によって生成されない。
ステップ(a1)第1の一本鎖DNAが取得され、第1の一本鎖DNAの配列は、配列番号:5、配列番号:6、又は配列番号:7であった。
ステップ(b1)第2の一本鎖DNAが得られ、第2の一本鎖DNAの配列は配列番号:8、配列番号:9、又は配列番号:10であり、第2の一本鎖DNAの配列は第1の一本鎖DNAの相補鎖である。
標的抗原に対する標的結合一本鎖可変フラグメント(scFv)を含有するキメラ抗原受容体(CAR)をコードする合成、遺伝子改変および/又は意図的に導入されたポリヌクレオチドを含有するoNK細胞を調製するための方法がこの実施形態において開示され、キメラ抗原受容体は、CD2、CD3デルタ、CD3イプシロン、CD3ガンマ、CD4、CD7、CD8a、CD8、CD1 1a(ITGAL)、CD1 1b(ITGAM)、CD1 1c(ITGAX)、CD1 1d(ITGAD)、CD 18(ITGB2)、CD 19(B4)、CD27(TNFRSF7)、CD28、CD29(ITGB1)、CD30(TNFRSF8)、CD40(TNFRSF5)、CD48(SLAMF2)、CD49a(ITGA1)、CD49d(ITGA4)、CD49f(ITGA6)、CD66a(CEACAM1)、CD66b(CEACAM8)、CD66c(CEACAM6)、CD66d(CEACAM3)、CD66e(CEACAM5)、CD69(CLEC2)、CD79A(B細胞抗原受容体複合体関連アルファ鎖)、CD79B(B細胞抗原受容体複合体関連ベータ鎖)、CD84(SLAMF5)、CD96(触覚)、CD100(SEMA4D)、CD103(ITGAE)、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD158A(KIR2DL1)、CD158B1(KIR2DL2)、CD158B2(KIR2DL3)、CD158C(KIR3DP1)、CD158D(KIRDL4)、CD158F1(KIR2DL5A)、CD158F2(KIR2DL5B)、CD158K(KIR3DL2)、CD160(BY55)、CD162(SELPLG)、CD226(DNAM1)、CD229(SLAMF3)、CD244(SLAMF4)、CD247(CD3-ゼータ)、CD258(LIGHT)、CD268(BAFFR)、CD270(TNFSF14)、CD272(BTLA)、CD276(B7-H3)、CD279(PD-1)、CD314(NKG2D)、CD319(SLAMF7)、CD335(NK-p46)、CD336(NK-p44)、CD337( NK-p30)、CD352(SLAMF6)、CD353(SLAMF8)、CD355(CRTAM)、CD357(TNFRSF18)、誘導性T細胞共刺激因子(ICOS)、LFA-1(CD1 1a/CD18)、NKG2C、DAP-10、ICAM-1、NKp80(KLRF1)、IL-2Rベータ、IL-2Rガンマ、IL-7Rアルファ、LFA-1、SLAMF9、LAT、GADS(GrpL)、SLP-76(LCP2)、PAG1/CBP、CD83リガンド、Fcガンマ受容体、MHCクラス1分子、MHCクラス2分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、活性化NK細胞受容体、Toll様受容体、HER2、BCMA、PD-L1、およびその組み合わせからから選ばれる。
本発明の実施形態から、本発明の方法によって取得されたすべての非トランスジェニックヒトCD16+ナチュラルキラー細胞株、本発明の外因性標的化ユニット複合ナチュラルキラー細胞、および本発明のキメラ抗原受容体(CAR)発現oNK細胞はADCC様プロセスを介して実際に標的細胞(例えば、癌細胞)を殺すことができることを示す。従って、本発明の培養法によって得られる非トランスジェニックヒトCD16+ナチュラルキラー細胞株の適用可能な分野には、これらに限定されないが、癌治療、自己免疫疾患治療、神経疾患治療、ヒト免疫不全ウイルス(HIV)根絶 、造血細胞関連疾患、代謝症候群治療、病原性疾患治療、ウイルス感染症の治療、および細菌感染症の治療が含まれる。
http://www.pathologyoutlines.com/topic/cdmarkerscd3.html
http://www.pathologyoutlines.com/topic/cdmarkerscd2.html
http://www.pathologyoutlines.com/topic/cdmarkerscd16.html
参考文献6: Rezvani KおよびRouce RH、2015年。癌治療のためのナチュラルキラー細胞免疫療法の適用。Front Immunol. 6:578。
Claims (11)
- NPMDに寄託され、寄託番号NITE BP-03017を有する、ヒトナチュラルキラー細胞。
- ヒトCD16+ナチュラルキラー細胞が実質的に濃縮された組成物を得る方法であり、
(a)寄託番号ATCC CRL-2407を有するヒト末梢血ナチュラルキラー細胞の集団を取得し、
(b)ヒト末梢血ナチュラルキラー細胞の集団をCD16受容体に特異的な抗体と接触させ、そして
(c)抗体によって特異的に結合される細胞を分離し、それによってヒトCD16+ナチュラルキラー細胞が実質的に濃縮された組成物を得、
前記ステップ(c)が以下のサブステップを含有し:
(c1)前記抗体によって特異的に結合される細胞を分離し、
(c2)容器内で、前記抗体が特異的に結合している細胞をヒト血小板溶解物およびIL-2を含有する培地と接触させ、および
(c3)前記細胞を複数日間培養することにより、ヒトCD16+ナチュラルキラー細胞が実質的に濃縮された組成物が得られ、
前記ヒトCD16+ナチュラルキラー細胞は、
(A)NPMDに寄託され、寄託番号NITE BP-03017を有する、又は
(B)以下の特徴を有する:
i)CD16受容体を発現していること、および
ii)x)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まない、又はy)ddPCRシステムを使用して細胞のゲノムDNAを分析し、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子との比率は1以上であり、前記CD16 F176Fプローブの配列は配列番号:11であり、前記CD16 F176Vプローブは配列番号:12である、方法。 - 前記容器が細胞を播種するための底部を含有し、前記底部が空気透過性および水不透過性である、請求項2に記載の方法。
- 前記培地中の溶解グルコースの濃度が1500~5000mg/Lである、請求項2に記載の方法。
- 前記組成物におけるヒトCD16+ナチュラルキラー細胞数が少なくとも5×105であり、前記ヒトCD16+ナチュラルキラー細胞が組成物における細胞の総数を100%として、数で5%以上の量である、請求項2に記載の方法。
- ヒトCD16+ナチュラルキラー細胞を培養および増殖させる方法であり、以下を含有する:
(x)容器内で前記ヒトCD16+ナチュラルキラー細胞を0.5-10vol%ヒト血小板溶解物および100-3000IU/mL IL-2を含有する培地と接触させ、および
(y)前記細胞を複数日間培養し、
前記ヒトCD16+ナチュラルキラー細胞が、CD16+細胞の集団を培養するステップおよび分離するステップを含むプロセスを通して、寄託番号ATCC CRL-2407を有する細胞集団から得られたものであり、
前記培養するステップが、ヒト血小板溶解物およびインターロイキン2(IL-2)を
含む培養培地において実施され、
さらに以下の特徴を有する、方法:
a)合成、遺伝子改変、および/又は意図的に導入されたCD16受容体をコードするポリヌクレオチドを含まない、又はb)ddPCRシステムを使用して細胞のゲノムDNAを分析することにより、CD16 F176Fプローブで検出可能なDNA分子とCD16 F176Vプローブで検出可能なDNA分子の比率は1以上であり、CD16 F176Fプローブの配列は配列番号:11であり、CD16 F176Vプローブは配列番号:12である。 - 前記容器が細胞を播種するための底部を含有し、前記底部が空気透過性および水不透過性である、請求項6に記載の方法。
- 前記ステップ(y)が以下のサブステップを含有する:
(y1)前記細胞を少なくとも1日間培養し、および
(y2)前記細胞を少なくとも1ヶ月継代培養する、請求項6に記載の方法。 - 前記ヒトCD16+ナチュラルキラー細胞が少なくとも3ヶ月継代培養した後に増殖能力を保持することができる、請求項6に記載の方法。
- 前記ヒトCD16+ナチュラルキラー細胞が
(A)NPMDに寄託され、寄託番号NITE BP-03017を有する、又は
(B)NPMDに寄託され、寄託番号NITE BP-03017である細胞から得られた、請求項6に記載の方法。 - ヒトCD16+ナチュラルキラー細胞が実質的に濃縮された組成物であって、前記組成物中の前記ヒトCD16+ナチュラルキラー細胞の数が少なくとも5×105であり、前記ヒトCD16+ナチュラルキラー細胞が、前記組成物中の細胞の総数を100%として、数で5%以上の量であり、前記ヒトCD16+ナチュラルキラー細胞がNPMDに寄託され、寄託番号NITE BP-03017を有する、組成物。
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