JP7429713B2 - 免疫細胞の製造方法及びその使用 - Google Patents
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Description
上記「CD56+」及び「CD3+」とは、NKT細胞の表面にある指標であり、本発明ではCD56+、CD3+及びこれらの組み合わせの発現をフローサイトメトリー(Flow Cytometry)を通じて分析してNKT細胞が製造されたことを確認した(図1B、図2、図4、図10~12)。
分離された末梢血液単核細胞(Peripheral Blood Mononuclear Cell: PBMC)を培養液で2日に1回ずつ培地を交換して4日間培養した。
PBMCを構成するT細胞の亜型のNKT製造効率を分析するために、FACSAriaII(BD)を用いてPBMCをCD3+CD8-、CD3+CD8+、CD3-CD8-、CD3-CD8+細胞群に分離した後、実施例1の方法で直接リプログラミングを実施した。直接リプログラミング後、24日目、実施例1の方法でFACS分析を実施した結果、CD3+CD8-細胞から直接リプログラミングを通じて約94.1%の効率でCD56+CD3+ NKT細胞が製造されることを確認した(図2)。
3-1:iNKT第1培地及び第2培地の組成最適化
実施例1のiNKT第1培地及び第2培地の組成でCHIR99021(CT)、SR1(SR)、FICZ添加有無によるNKT生産効率を確認した。具体的には、図3の表のようにiNKT第1培地及び第2培地内CHIR99021(CT)、SR1(SR)の添加有無をそれぞれ異にした培地A~Fを製造した。培地C及びFの場合、SR1(SR)の代わりにAHR作用剤であるFICZを添加した。PBMC細胞を互いに異なる培地組成で製造したiNKT第1培地及び第2培地を用いて実施例1の方法で直接リプログラミングを実施し、NKT細胞の製造効率を分析した。
実施例1のiNKT第2培地の組成でAHR作用剤であるFICZまたはビオカニンA、抗-CD3抗体であるOKT3またはUCHT1を添加した時のNKT生産効率を確認した。具体的には、iNKT第2培地にAIHR作用剤または抗-CD3抗体を添加した場合、添加していない場合に比べてNKT生産効率が3.7~4.7倍以上増加すること(無添加時に10.0%→FICZ添加時に42.9%、ビオカニンA添加時に39.6%、OKT3添加時に47.7%、UCHT1添加時に36.9%)を確認した(図4)。
実施例1で製造されたiNKT細胞の癌細胞殺傷能を検証するために、iNKT細胞を癌細胞と共培養した後に発現される、癌細胞溶解能を有するCD107a+細胞の頻度を定量分析した。具体的には、癌細胞であるHCT116(Human Colon Cancer cells)、NIC-H460(Human Lung Cancer Cells)、HepG2(Human Liver Hepatocellular Carcinoma Cells)、Mia-paca-2(Human Pancreas Ductal Adenocarcinoma cells)それぞれ1×106個の細胞/mlとiNKT細胞1×106個の細胞/mlを6-ウェルプレートにそれぞれ1mlずつ分注した後、400gで1分間遠心分離し、これを2時間または16時間37℃、5% CO2存在下で細胞インキュベーターで培養した後、フローサイトメトリーを通じてCD107a+細胞の頻度を確認した。具体的には、CD107a+細胞の頻度はiNKT細胞を蛍光が付着されたCD56-PE、CD3-APC及びCD107a-FITC抗体が添加されたFACS緩衝液で常温で20分間反応させた後、FACSでCD56+CD3+細胞群をゲーティング(Gating)して分析した。
実施例1で製造されたiNKT細胞の癌細胞殺傷能を測定するために、カルセイン-AM(Calcein-AM)を用いた細胞殺傷能の測定を行った。具体的には、癌細胞である Raji(Raji B, Human B Lymphocyte; Burkitt's Lymphoma), SNU-817(Human B-lymphoblastoid Cells), K562(Human Immortalised Myelogenous Leukemia Cells), HCT116, PC3(Human Prostate Cancer Cells), HepG2, NIC-H460, Mia-paca-2を10%のウシ胎児血清を含むDMEM培地でそれぞれ1×105個の細胞/mlになるように希釈した後、25μMになるようにカルセイン-AMを添加し、37℃で1時間培養後にDMEM培地で洗浄し、カルセイン標識標的癌細胞を作製した。
生後8週目のヌードマウス(Balb/c-nude Mouse、平均重量20-25g)の背中にルシフェラーゼ(Luciferase)を発現するCFPAC-1(Human Huctal Pancreatic Adenocarcinoma Cells) 2×106個の細胞/ml5mlを皮下注入(Subcutaneous Injection)し、膵臓癌細胞異種移植マウス動物モデルを製造した。翌日、陰性対照群としてPBS 200 ulまたは実験群としてiNKT(1×107個の細胞/200 ul PBS)を注入した後、7日間の間隔で腫瘍の大きさをIVIS 100(PerkinElmer)を通じて確認した。
CAR(Chimeric Antigen Receptor)をコードする二重シストロンレンチウイルスベクターを製作するために、CD19、HER2(Human Epidermal Growth Factor Receptor 2)またはMSLN(Mesothelin)にそれぞれ結合する4種のCAR遺伝子を作製した。上記各CAR遺伝子は、抗体ドメイン(scFv)を含む細胞外ドメイン、細胞膜貫通ドメイン及び細胞内ドメインをコードする遺伝子を含めて構成された。具体的には、上記各CAR遺伝子は下記の通り構成された(図8)。
ii)CD8リーダ(配列番号1)、CD19 scFv(配列番号2)、CD8ヒンジ(配列番号5)、CD8膜貫通ドメイン)(配列番号6)、CD28細胞内(Intracellular)ドメイン(配列番号8)、CD3ζ(Zetta)(配列番号9)、IRES(Internal Ribosome Entry Site)(配列番号10)及びGFP(配列番号11)を含むCD19-CAR2遺伝子;
iii)CD8リーダ(配列番号1)、MSLN(Mesothelin) scFv(配列番号3)、CD8ヒンジ(配列番号5)、CD8膜貫通ドメイン(配列番号6)、CD28細胞内ドメイン(配列番号8)、CD3ζ(配列番号9)、IRES(配列番号10)及びGFP(配列番号11)を含むMSLN-CAR遺伝子;及び
iV)CD8リーダ(配列番号1)、HER2(Human Epidermal Growth Factor Receptor 2)scFv(配列番号4)、CD8ヒンジ(配列番号5)、CD8膜貫通ドメイン(配列番号6)、CD28細胞内ドメイン(配列番号8)、CD3ζ(配列番号9)、IRES(配列番号10)及びGFP(配列番号11)を含むHER2-CAR遺伝子。
PBMCを培養液(2.5% StemPro-34 Nutrient Supplement, 2 mM Glutamax I, 1% Penicillin/Streptomycin, 20 ng/ml ヒトIL-6、100ng/mlヒトSCF、100ng/mlヒトFLT3を含むStempro SFEM II)で2日に1回ずつ培地交換して4日間培養した。
実施例1のiNKT細胞及び実施例8のCD19-CAR2が導入されたiNKT細胞(CD19-CAR2-iNKT細胞)をそれぞれ0.25×105個の細胞/mlまたは1×105個の細胞/mlの細胞数密度になるように培養液で希釈した後、96-ウェルプレートにそれぞれ100ulずつ分注した。癌細胞であるRaji(Raji B)、SNU-817を用いて実施例5の方法でカルセイン標識標的癌細胞を製作した。カルセイン標識標的癌細胞1×105個の細胞/mlを100ul/wellずつ96-ウェルプレートに添加した後、実施例5の方法で癌細胞殺傷能を測定した。
実施例1のiNKT細胞、実施例8のMSLN-CARが導入されたiNKT細胞(MSLN-CAR-iNKT細胞)及び実施例8のHER2-CARが導入されたiNKT細胞(HER2-CAR-iNKT細胞)をそれぞれ0.25×105個の細胞/ml又は1×105個の細胞/mlの細胞数密度になるように培養液で希釈した後、96-ウェルプレートにそれぞれ100ulずつ分注した。癌細胞であるPC3(PC-3)、CFPAC-1、HepG2を用いて実施例5の方法でカルセイン標識標的癌細胞を製作した。カルセイン標識標的癌細胞1×105個の細胞/mlを100ul/wellずつ96-ウェルプレートに添加した後、実施例5の方法で癌細胞殺傷能を測定した。
Claims (11)
- I)リプログラミング因子(Reprogramming Factor)又はII)リプログラミング因子(Reprogramming Factor)及びCAR(Chimeric Antigen Receptor)遺伝子が導入された分離された細胞を、a) SCF(Stem Cell Factor)、FLT3(FMS-like Tyrosine Kinase)、IL(Interleukin)-3、IL-6及びCHIR99021を含む第1培地;並びにb)(1)SCF、FLT3、IL-2、IL-7、IL-15、FICZ及びビオカニンAを含む培地、又は(2)SCF、FLT3、IL-2、IL-7、IL-15、OKT3及びUCHT1を含む第2培地で、段階的に培養してNKT細胞に直接リプログラミングさせる段階を含む、iNKT(induced Natural Killer T)細胞の製造方法。
- 上記a)の第1培地又はb)の第2培地は、FBS(Fetal Bovine Serum)、抗生剤及びこれらの組み合わせからなる群から選択されるいずれか一つ以上をさらに含む、請求項1に記載のiNKT細胞の製造方法。
- リプログラミング因子が導入された分離された細胞は、上記a)の第1培地で4~8日間培養した後、上記b)の第2培地で12日間以上培養する、請求項1に記載のiNKT細胞の製造方法。
- 上記リプログラミング因子は、Lin28、Asc11、Pitx3、Nurr1、Lmx1a、Nanog、Oct4、Oct3、Sox2、Klf4、Myc及びこれらの組み合わせからなる群から選択されるいずれか一つ以上である、請求項1に記載のiNKT細胞の製造方法。
- 上記リプログラミング因子は、Oct4、Sox2、Klf4及びMycである、請求項4に記載のiNKT細胞の製造方法。
- 上記リプログラミング因子が導入される分離された細胞は、NKT細胞を除く体細胞である、請求項1に記載のiNKT細胞の製造方法。
- 上記CAR遺伝子は、上記リプログラミング因子導入の際、上記a)の第1培地で培養時又は上記b)の第2培地で培養時から選択されるいずれか一つの時点で上記分離された細胞に導入される、請求項1に記載のiNKT細胞の製造方法。
- 上記CAR遺伝子は、
i)CD8リーダ(Leader)、CD19 scFv、CD8ヒンジ(Hinge)、CD8膜貫通ドメイン及びFc-γ受容体を含むCAR遺伝子;
ii)CD8リーダ、CD19 scFv、CD8ヒンジ、CD8膜貫通ドメイン、CD28細胞内ドメイン、CD3ζ及びIRES(Internal Ribosome Entry Site)を含むCAR遺伝子;
iii)CD8リーダ、MSLN(Mesothelin)scFv、CD8ヒンジ、CD8膜貫通ドメイン、CD28細胞内ドメイン、CD3ζ及びIRESを含むCAR遺伝子;並びに
iV)CD8リーダ、HER2(Human Epidermal Growth Factor Receptor 2)scFv、CD8ヒンジ、CD8膜貫通ドメイン、CD28細胞内ドメイン、CD3ζ及びIRESを含むCAR遺伝子;からなる群から選択されるいずれか一つである、請求項1に記載のiNKT細胞の製造方法。 - 上記CAR遺伝子は、GFP(Green Fluorescent Protein)をさらに含む、請求項8に記載のiNKT細胞の製造方法。
- 上記製造されたiNKT細胞は、CD56+、CD3+及びこれらの組み合わせからなる群から選択されるいずれか一つ以上を発現する、請求項1に記載のiNKT細胞の製造方法。
- a)SCF(Stem Cell Factor)、FLT3(FMS-like Tyrosine Kinase)、IL(Interleukin)-3、IL-6及びCHIR99021を含む第1培地を含有する第1容器;並びにb)(1)SCF、FLT3、IL-2、IL-7、IL-15、FICZ及びビオカニンAを含む培地、又は(2)SCF、FLT3、IL-2、IL-7、IL-15、OKT3及びUCHT1を含む第2培地を含有する第2容器;を含むiNKT細胞製造用直接リプログラミング培地キット。
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KR102298639B1 (ko) | 2021-09-07 |
JP2022527932A (ja) | 2022-06-07 |
KR20200115358A (ko) | 2020-10-07 |
KR102298640B1 (ko) | 2021-09-07 |
EP3950935A1 (en) | 2022-02-09 |
CN113874492A (zh) | 2021-12-31 |
CN113874492B (zh) | 2024-03-19 |
JP2023179554A (ja) | 2023-12-19 |
US20220184128A1 (en) | 2022-06-16 |
CN113874493B (zh) | 2024-05-10 |
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