JP2017160264A - 癌治療用医薬組成物の製造方法及びその方法によって製造された癌治療用医薬組成物 - Google Patents
癌治療用医薬組成物の製造方法及びその方法によって製造された癌治療用医薬組成物 Download PDFInfo
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Abstract
Description
また、低酸素環境は、多数の遺伝子発現を調整し、細胞の増殖、分化、アポトーシスなどの細胞応答などを制御する。
従来技術1は、通常の酸素濃度条件の下で培養した、血管内皮増殖因子(VEGF)、肝細胞増殖因子(HGF)、インシュリン様成長因子(IGF)、血小板由来成長因子(PDGF)、形質転換成長因子−ベータ(TGF-β)からなる群より選択された少なくとも2のサイトカインを含む幹細胞の培養上清が、種々の疾病によって損傷を受けた組織、例えば、中枢神経組織、皮膚組織、歯周組織、骨組織、脳組織、網膜組織の治療に使用できることを見出し、主要な死因のひとつである、心疾患や脳血管疾患によって損傷した組織の治療剤を開発したという点では優れた技術である。しかし、主要な死因のひとつである腫瘍(癌)については検討がされていない。
また、前記コンディション培地は、トランスフォーミング因子β(TGF-β1)を、酸素濃度を20%とした以外は同じ条件の下で培養した場合に比べて、少なくとも5倍以上の含有量で含むことが好ましい。さらに、前記コンディション培地は、ストロマ細胞由来因子(SDF-1)を、酸素濃度を20%とした以外は同じ条件の下で培養した場合に比べて、少なくとも3倍の含有量で含む、ことが好ましい。
本願発明の不死化幹細胞を得るには、まず、哺乳類の間葉系細胞、初期発生胚及び体細胞から幹細胞を単離する。上記哺乳類としては、ヒト、ブタ、ウマ、及びサルからなる群から選ばれるものであることが、ヒト細胞との遺伝的類似性が高いこと、及び感染の危険性が低いことから好ましい。
まず、脱落乳歯を、例えば、クロロヘキシジン、イソジン溶液その他の消毒薬で消毒した後、歯冠部を分割し、歯科用リーマーにて歯髄組織を回収する。
上記の基本培地は、後述する細胞選別用の培養、及び選別後の細胞の培養に使用することもできる。
継代培養は、例えば、肉眼で観察してサブコンフレント又はコンフレントに達したときに、上述のように、トリプシンとEDTAとを用いて細胞を培養容器から剥離させて回収し、再度、培養液を入れた培養容器に播種する。
こうした遺伝子の導入は、以下のようにして行うことができる。
以上の手順によって、歯髄由来の不死化幹細胞を得ることができる。
(実施例1)不死化細胞の調製
(1)ウイルス導入用ベクターの作製
(1−1)プラスミド抽出用試薬等
カナマイシン(Kan)、アンピシリン(Amp)、LB液体培地及びLB寒天培地、グリコーゲン、アガロース、滅菌水、酢酸アンモニウム、酢酸ナトリウム、ドデシル硫酸ナトリウム及びRNase Aを使用した。50mg/mLのカナマイシン及びアンピシリンを調製し、ストック溶液として−20℃で保存した。グリコーゲンは20mg/mLに調製した。10mg/mLのRNase Aを調製し−20℃で保存した。10M(飽和)酢酸アンモニウム(NH4OAc)、3Mの酢酸ナトリウム(NaOAc;pH5.2)を調製した。
大腸菌コンピテントセル(Supercharge EZ10 Electrocompetent Cells、製品コード 636756)、Swa I(製品コード 1111A、Smi Iが同等品)、Xho I(製品コード 1094A)、T4 DNA Ligase(製品コード 2011A)、NucleoBond Xtra Midi(製品コード 740410.10/.50/.100)、NucleoSpin Plasmid(製品コード 740588 10/50/250)は、いずれもタカラバイオ(株)より購入した。Pac IはNew England Biolabs社より購入した。
1xTE Buffer(1mMのEDTAを含む10mM Tris-HCl [pH8.0])、100mM Tris-HCl(pH8.0)で飽和したフェノール:クロロホルム:イソアミルアルコール(25:24:1、以下、「PCI混液」という。)を調製した。エタノールは、100%及び70%で使用した。ミニスケールでの組換えで使用するpAdeno-X プラスミドDNAの精製用に、以下のバッファー1〜4を調製した。
(オートクレーブ後、4℃で保存)
バッファー2:1%SDSを含む0.2M NaOH(使用直前に用時調製、密封し、室温保存)
バッファー3:5M KOAc(オートクレーブ後、4℃で保存)
バッファー4:1mM EDTA、20μg/mL RNaseを含む10mM Tris-HCl(pH8.0)
(使用直前にRNaseを添加し、−20℃で保存)
ヒト5型アデノウイルスで形質転換したヒトHEK293細胞(ATCC #CRL1573)を使用した。HEK293細胞は完全培地で培養した。完全培地の組成は、100 unit/mLのペニシリンGナトリウムと100μg/mLのストレプトマイシン、4mMのL-グルタミン及び10%FBSを添加したDMEM(Dulbecco’s Modified Eagle’s Medium、基本培地)とした。ペニシリンGナトリウム溶液は10,000units/mL、硫酸ストレプトマイシン溶液は10,000μg/mLで調製し、ストック溶液として保存した。
(3−1)lac Zを含む組換えアデノウイルス(pAdeno-X-lac Z)の構築
10mLの上述した完全培地に、解凍後、DMSOを除去したHEK293細胞を再懸濁し、全量を100mmの培養プレートに移した。HEK293細胞が付着した後に培養液を除去し、細胞を滅菌PBSで1度洗浄し1mLのトリプシン-EDTA溶液を加えて約2分間処理した。
組換えpShuttle2 Vector(以下、「rpShuttle2 Vector」という。)の構築前に、キットに含まれているpShuttle2 Vector及びpShuttle2-lac Z VectorでDH5α大腸菌を形質転換した。50μg/mLのカナマイシンを含有するLB寒天プレート(以下、「LB/Kan」という。)上で形質転換体を選択し、単一コロニーからとった菌体を新しいLB/Kanに画線し、37℃で一晩インキュベートした。
上記のようにして作製したrpShuttle2プラスミドDNAから、導入した遺伝子の発現カセットをPI-Sce I及びI-Ceu Iで切り出した。キットに添付されたプロトコルに記載されたin vitroライゲーション法に従って、切り出した発現カセットをAdeno-X Viral DNAに組み込んだ。rpShuttle2プラスミドDNAのPI-Sce I/I-Ceu I二重消化液を30μL調製し、下記の表1に記載した試薬を1.5mLの滅菌済みマイクロ遠心チューブに入れて混合した。
1kbラダー(DNA サイズマーカー)と共に上記二重消化後の反応液(5μL)を1%アガロース/EtBrゲルで泳動した。
遠心チューブに、上述した二重消化液の残り(25μL)に、70μLの1xTE Buffer(pH8.0)と100μLのPCI混液とを添加し、ボルテックスで十分に撹拌した。次いで、微量遠心機を用いて、4℃にて14,000rpmで5分間遠心し、水層を清浄な1.5mLのマイクロ遠心チューブ移した。ここに、400μLの95%エタノール、25μLの10M酢酸アンモニウム、及び1μLのグリコーゲン(20mg/mL)を添加し、ボルテックスで十分に撹拌した。
(4−1)Adeno-X ウイルスゲノムへの発現カセットのサブクローニング
下記の表2に示す試薬を、順番通りに1.5mLの滅菌済マイクロ遠心チューブに入れ、穏やかに混和し、軽く遠心した後に、16℃にて一晩インキュベートした。
ペレットが乾燥した後に、これを15μLの滅菌脱イオン水に溶解した。
下記表3に示す消化液を調製し、遠心チューブに入れた各サンプルに加えて、2時間、25℃にて、インキュベートした。
電気的にコンピテントにした大腸菌を、Supercharge EZ10Electrocompetent Cell(製品コード 636756)を使用して、上記(4−2)で得たSwa I消化産物で形質転換した。
対数増殖にある培養液5mLを、14,000rpmで30秒間遠心し、上清を除去した。ペレットを再度10,000rpmで1分間遠心し、マイクロピペットを用いて、上清を除去した。
PI-Sce I及びI-Ceu Iを用いて解析を行った。下記の表4に示す試薬を、1.5mLの滅菌済みマイクロ遠心チューブに入れ、30μLのPI-Sce I/I-Ceu I二重消化反応液を加えて、十分に撹拌し、軽く回転させて内容物を集めた。
(6−1)HEK293細胞トランスフェクト用rAdeno-X プラスミドDNAの調製
下記表5に示す試薬等を、1.5mLの滅菌済み遠心チューブに入れて混合し、微量遠心機で軽く遠心した。その後、37℃にて2時間、インキュベートし、rAdeno-X プラスミドDNAのPac I制限酵素処理を行った。
上記プラスミドDNAのトランスフェクションの24時間前に、60mmの培養プレートあたりの細胞数が1〜2x106(およそ100cells/mm2)になるよう、HEK293細胞を接種し、37℃、5%CO2存在下でインキュベートした。
この力価測定を始める約24時間前に、HEK293細胞をT75フラスコに接種し、37℃、5%CO2存在下で一夜培養し、50〜70%コンフルエントになっていることを確認した。翌日、ウイルスを含む新しい培地と交換し、MOI=10で感染させた。37℃、5%CO2存在下で90分間培養した後にフラスコを取り出し、10mLの培地を加えた。
(7−1)標的細胞への感染
感染の24時間前に6−ウェルプレートに1x106個のSHEDを接種した。接種の翌日に培地を取り除き、ウイルスを含む1.0mLの培地を各プレートの中心に添加した。この溶液をSHEDが形成した単層全体に均一に広げた。
(7−2)感染細胞のβ-ガラクトシダーゼ発現の解析
Adeno-X-lac Zを感染させた接着性細胞におけるβ-ガラクトシダーゼの発現は、Luminescent β-galDetection Kit II(製品コード 631712、クロンテック社製)を使用してアッセイした。
(1)乳歯幹細胞の分離
10歳の健常男児から得られた脱落乳歯を使用した。この脱落乳歯をイソジン溶液で消毒した後、歯科用ダイヤモンドポイントを用いて、歯冠を水平方向に切断し、歯科用リーマーを用いて歯髄組織を回収した。得られた歯髄組織を、3mg/mLのI型コラゲナーゼ及び4mg/mLのディスパーゼの溶液中で37℃にて1時間消化した。ついで、この溶液を70mmの細胞ストレーナ(Falcon社製)を用いて濾過した。
上述したように、bmi-1, E6, E7及びhTERTの4つの遺伝子をアデノウイルスベクターに組み込み、これらの遺伝子産物を発現するウイルスベクターを作製した。対照として、これらの遺伝子を組み込んでいない対照ベクターを作製した。
SHEDを100mmφのコラーゲンコートディッシュに1x106個を播種し、10%FBSを添加したDMEMを加えてサブコンフレントまで培養した。この培地を吸引除去して上記培地で希釈したウイルス溶液500μLを加え(MOI=10)、37℃にて、5%CO2インキュベータ中で1時間培養し、上記ウイルスベクターを感染させた。感染48時間後、感染細胞をピューロマイシン(1pg/mL)を加えた上記の培地中で10日間培養して選択し、500〜600個の耐性クローンをプールした。3〜4日ごとに約0.5x105個のSHEDを100mmφの培養シャーレに播種し、継代した。遺伝子が導入されたSHEDをSHED-T、遺伝子が導入されないSHEDをSHED-Cとした。
(1)SHED-C及びSHED-Tの成長速度の測定
SHED-T(遺伝子導入をしたSHED)の個体数の倍加状態を、図1に示した。図中、縦軸は個体数倍加回数(細胞分裂回数、回)、横軸は時間(培養日数)である。また、培養中のSHEDが1ヶ月間分裂しない状態を、細胞の老化の判断基準とした。
単一細胞を含む懸濁液を得るため、接着性の単層細胞をトリプシン/EDTAで消化した。2x105個の細胞に抗STRO-1モノクローナル抗体(1:100)を加えて放置し、FACSCaliburフローサイトメーター(Becton Dickinson社製)を使用して分析した。対応するアイソタイプが同一の対照抗体と比較し、99%以上の割合で蛍光レベルが高い場合に発現が陽性とした。SHED-T及びSHED-Cともに、初期及び後期の継代細胞を固定し、FITC結合STRO-1抗体で染色した。その後、フローサイトメトリーで分析した。試験はそれぞれ2回行なった。SHED-CではSTRO-1陽性細胞の割合がPD20で27%であり、PD30では15%まで減少した(図2(A)及び(B))。SHED-TではSTRO-1陽性細胞の割合が、それぞれPD20で46%、PD40で41%であった(図2(C)及び(D))。
PD0、PD10及びPD20におけるSHED-C及びSHED-Tの分化能を、新生骨量の形成能及び組織染色で調べた。まず、2.0x106個のSHED-C又はSHED-Tを、40mgのヒドロキシアパタイト/三カルシウムリン酸(HA/TCP)セラミック粉末(オリンパス工業(株)製)に混合し、10週齢の免疫無防備状態マウス(NIH-bgnu-xid, 雌、Harlan Sprague Dawley社製)の背側表面の皮下に移植した。
新生骨量=新生骨面積/視野面積x100
SHED-C及びSHED-T細胞を、免疫無防備状態マウスの皮下組織に1x106個移植した。移植後、30日以上観察を行ったが、この期間中、上記の細胞を移植したいずれのマウスにおいても、腫瘍は形成されなかった。また、SHED-T細胞では、40〜200PDの培養細胞のすべてのクローンの形態に変化はなかった。
以上より、SHED-Tには、癌化活性はないことが示された。
SEHD-Tは、260PDを超えても分化能力を保ったまま増殖する能力を有していることが示されたが、SHED-Cは、分化能力を有するものの30PD以下で老化した。
実施例1で調製した不死化SHEDを、酸素濃度を20%、10%、5%、1%とした下記の条件で48時間、無血清培地で培養し、その上清を回収した。
マウス扁平上皮癌株SCCVII(近畿大学医学部、西村氏より提供を受けた)を、10%FBS(ギブコ社製)を含むDMEM中で、37℃で1週間培養し、0.5%トリプシンを含むPBSバッファーを用いて、細胞をバラバラにした。トリパンブルーで染色して生細胞数を計数し、1x106個/mLの懸濁液を1mLのPBSバッファーを用いて調製した。
対照群(バッファーのみ)、グループI〜グループIV(以下、「GI〜GIV」ということがある。)の培養上清を、各群のマウスに1mLずつ、尾静脈から投与した。
癌細胞を注入した後に、各群のマウスをそれぞれ上記と同じ時条件飼育した。
癌組織に対するマクロファージの挙動を、in vivoイメージングで測定した。5mLのチオグリコレート溶液(2%のBrewer's チオグリコレート培地(Difco社製))をマウスの腹腔内に注入し、4日後に、PBSを用いて腹腔洗浄を行い、107個のマクロファージを得た。得られたマクロファージのうち、3x106個を、3.5μg/mLの色素(MolecularTracer DiR(住商ファーマインターナショナル(株)製))及び0.5%エタノールと混合してラベルした。
CH3/Heマウスに、5x105個のSCCVIIを注入し、1週間後、15週間後に周辺組織を含めて腫瘍を切除し、組織学的に検索した。15週で、治療群(GIV)において、腫瘍壊死を認めた例があった(図6)。
図10に、対照群と治療群とにおける、マウスの腫瘍組織のエオシン−ヘマトキシリン染色による染色像を示す。拡大率が低い対照群(A)と治療群(B)の染色像を対比すると、治療群の染色像で腫瘍組織に若干の死滅している部分があることがわかる。拡大率を上げると、その相違が明確に観察された(図10(C)及び(D))。
Claims (8)
- 哺乳類の歯髄から得た乳歯歯髄幹細胞に、hTERT、bmi−1、E6、及びE7という4種類の遺伝子を導入して不死化幹細胞とする幹細胞作製工程と;
前記不死化幹細胞を、無血清培地中で所定の時間、酸素濃度が0.5%以上20%未満の低酸素濃度下で23〜27℃で培養し、所定の濃度以上の複数の再生因子を含むコンディション培地を調製する、コンディション培地調製工程と;を備え、
前記コンディション培地調整工程では、酸素濃度を20%とした以外は同じ条件の下で培養したときに調製されるコンディション培地に比べて、インスリン様成長因子(IGF-1)及び血管内皮細胞増殖因子(VEGF)の双方を1.5倍以上の含有量で含有するコンディション培地が製造される、癌治療用医薬組成物の製造方法。 - 前記コンディション培地は、インスリン様成長因子(IGF-1)、血管内皮細胞増殖因子(VEGF)、トランスフォーミング因子β(TGF-β1)及びストロマ細胞由来因子(SDF-1)から成る群から選ばれる再生因子を、酸素濃度を20%とした以外は同じ条件の下で培養した場合に比べて少なくとも1.5倍の含有量で含む、ことを特徴とする請求項1に記載の癌治療用医薬組成物の製造方法。
- 前記コンディション培地は、トランスフォーミング因子β(TGF-β1)を、酸素濃度を20%とした以外は同じ条件の下で培養した場合に比べて、少なくとも5倍以上の含有量で含む、ことを特徴とする請求項2に記載の癌治療用医薬組成物の製造方法。
- 前記コンディション培地は、ストロマ細胞由来因子(SDF-1)を、酸素濃度を20%とした以外は同じ条件の下で培養した場合に比べて、少なくとも3倍の含有量で含む、ことを特徴とする請求項2又は3に記載の癌治療用医薬組成物の製造方法。
- 前記所定の時間が40〜56時間である、請求項1〜4のいずれかに記載の癌治療用医薬組成物の製造方法。
- 前記低酸素濃度は、酸素濃度5%以下である、請求項1又は5に記載の癌治療用医薬組成物の製造方法。
- 前記低酸素濃度は、酸素濃度1%以下である、請求項6に記載の癌治療用医薬組成物の製造方法。
- 請求項1〜7に記載の癌治療用医薬組成物の製造方法で製造された、癌治療用医薬組成物。
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CN106102754A (zh) | 2016-11-09 |
CA2937522C (en) | 2022-08-23 |
JP6166388B2 (ja) | 2017-07-19 |
KR102297734B1 (ko) | 2021-09-03 |
JPWO2015111712A1 (ja) | 2017-03-23 |
EP3093023A1 (en) | 2016-11-16 |
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JP6351799B2 (ja) | 2018-07-04 |
EP3093023B1 (en) | 2020-11-04 |
US20170007677A1 (en) | 2017-01-12 |
CA2937522A1 (en) | 2015-07-30 |
WO2015111712A1 (ja) | 2015-07-30 |
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