JP4833991B2 - 哺乳動物細胞のための無血清細胞培養培地 - Google Patents
哺乳動物細胞のための無血清細胞培養培地 Download PDFInfo
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Description
アミノ酸:例えば米国特許第6,048,728号(Inlow等)は、以下のアミノ酸が細胞培養培地中で使用され得ることを開示する。アラニン、アルギニン、アスパラギン酸、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、プロリン、セリン、トリプトファン、チロシン、スレオニンおよびバリン。
ビタミン:例えば、米国特許第2003/0096414号(Clccarone等)または米国特許第5,811,299号(Renner等)が、以下のビタミンが細胞培養培地中で使用され得ることを開示する。ビオチン、パントテン酸、塩化コリン、葉酸、ミオ−イノシトール、ナイアシンアミド、ピリドキシン、リボフラビン、ビタミンB12、チアミン、プトレシン。
塩:例えば、米国特許第6,399,381号(Blum等)は、CaCl2、KCl、MgCl2、NaCl、一塩基リン酸ナトリウム、二塩基リン酸ナトリウム、亜セレン酸ナトリウム、CuSO4、ZnCl2を含む培地を開示する。培養培地中で使用され得る無機塩を開示している文書の他の例は、米国特許第2003/0153042号(Arnold等)であり、CaCl2、KCl、MgCl2、NaCl、一塩基リン酸ナトリウム、二塩基リン酸ナトリウム、CuCl2・2H2O、ZnCl2を含む培地を開示する。
脂肪酸:培地中で使用されることが公知の脂肪酸は、アラキドン酸、リノール酸、オレイン酸、ラウリル酸、ミリスチン酸、ならびにミリスチル−βシクロデキストリンであり、例えば米国特許第5,045,468号(Darfler)を参照のこと。シクロデキストリンは本質的に脂質ではないが、脂質と複合体を形成する能力があるので、細胞培養培地中で脂質を可溶化するために使用されることに留意すべきである。
特に無血清細胞培養培地の枠において使用される更なる成分は、グルコース、グルタミン、Na−ピルビン酸、インスリンまたはエタノールアミン等の化合物(例えば欧州特許第274445号)、またはPluronic F68等の保護剤である。Pluronic(商標)F68(Poloxamer 188としても知られている)は、エチレンオキシド(EO)およびプロピレンオキシド(PO)のブロックコポリマーである。
本発明は、動物血清に由来する成分を含まず、同時に培養中の哺乳動物細胞の細胞成長および維持に非常に有効であり、特に組換えタンパク質の産出を可能にする、細胞培養培地の開発に基づく。
本発明は、動物血清を含まない細胞培養培地の開発に基づく。
本発明による動物血清を含まない細胞培養培地には、
0.2〜1.75μMの範囲の濃度にある亜鉛(Zn)、および/または
10〜75nMの範囲の濃度にある銅(Cu)、および/または
3〜10μMの範囲の濃度にある鉄イオン(Fe)
が含まれる。
約0.2、0.25、0.30、0.35、0.40、0.45、0.5、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1、1.05、1.1、1.15、1.2、1.25、1.3、1.35、1.4、1.45、1.5、1.55、1.6、1.65、1.7、1.75μMでの亜鉛。
好適には、亜鉛は約0.5μMまたは約1.5μMで含まれる。また亜鉛が硫酸亜鉛として含まれることも好適である。
約10、15、20、25、30、35、40、45、50、55、60、65、70または75nMでの銅。
好適には、銅は約25nMで含まれる。銅が硫酸銅として含まれることも好適である。
鉄イオンは、約1、1.5、2、2.5、3、3.5、4、4.5、4.8、5、5.5、6、6.5、7、7.5、8、8.5、9、9.5または10μMで含まれる。
好適には、鉄イオンは、約5または6μMにて含まれる。鉄イオンは、好適にはクエン酸鉄および/または硝酸鉄として含んでもよく、クエン酸鉄が細胞培養培地中に含まれる鉄イオンのほとんどを占めることがさらに好適である。培地は例えば、約5μMのクエン酸鉄と約1μMの硝酸鉄を含み得る。
1.イントロダクション
本研究は、微量金属元素の添加による、産出培養培地(DMEM、「ダルベッコ改変イーグル培地」)の開発に関する実験的作業を発表する。本開発の結果として、C127細胞培養中のr−hGH産出の顕著な増加が得られた。
試薬および溶液
すべての化学試薬を、メルク(Merck)(商標)より得た:硫酸亜鉛(ZnSO4:7H2O)、硫酸銅(CuSO4・5H2O)、塩化バリウム(BaCl2・2H2O)、塩化コバルト(CoCl2・6H2O)、硫酸カリウムクロム(K[Cr(SO6H4)2(H2O)2]・6H2O)、硝酸ニッケル(Ni(NO3)2・6H2O)、亜セレン酸ナトリウム(Na2SeO3・5H2O)、クエン酸鉄(FeC6H5O7 シグマ(Sigma)(商標)カタログ番号F3388)を鉄供給源として使用した。
遺伝的に修飾したC127マウス細胞(ATCC CRL1616)を、組換えヒト成長ホルモン(rhGH)の発現のために使用した。ベクターは、pBR322多重クローニング部位、およびマウス メタトロチオネイン−1(MT−1)プロモーターの制御下で、1.6kbのrhGHミニ遺伝子を含むBPV69Tに基づく。異なるrhGH産出バッチから得た、1つのWorking Cell Bankに由来する培養を実験に使用した。
rhGH産出段階のために使用した培養培地は、重炭酸ナトリウム(3.7g/L)で緩衝させた4.5g/Lグルコースを含むDMEMであった。
培養培地中のrhGHの測定を、逆相HPLC滴定によって毎日実施した:
材料
Synchropak RP4、100×4.6mm i.d.、300Å カタログ番号C4R103−10(エイクロム(Eichrom))
Resource RPC 1mL、30mm×6.4mm i.d.、15μm、art 17−1181−01、アマシャム バイオサイエンセズ(Amersham Biosciences)
Symmatry300、50mm×4.6 i.d.、C4 5μm、P/N186000287(ウォーターズ(Waters))
試薬
トリフルオロ酢酸(TFA)(ピアス(Pierc)、カタログ番号28904または同等物)
アセトニトリル(ACN)(メルク(Merck)1.00030または同等物)
精製水、PW(例えばMilliQ水、、または同等物)
ヘリウム
溶液
移動相A:TFA 水中0.08%(v/v)
PW水の容積を目盛り付きフラスコ中で測定し、以下の表にしたがってTFAを加える。攪拌し標識する。
勾配による溶出:混合相A:相B 60/40にて開始し、相A/相B 20/80にて終了する。勾配は5分間で完了する(使用する器具によってわずかに変わる)
注入量 50マイクロリットル
検出:215nmでのUV吸収
較正曲線:10、50、100、120および150μg/mlでのr−hGH標準
生産性を、rhGHのmg/ローラーボトルとして示す。生データは、(HPLCによって測定したような)回収中のrhGH濃度であり、回収したローラーボトルの総数である。典型的には、回収相の間のローラーボトルには、約109細胞が含まれる。
第一の一連の実験にて、断続的に培養培地に加えた高コバルト濃度(20μM CoCl2・6H2O)の効果をアッセイした。添加は、1つのバッチの産出相の初期段階(リンスおよびPM=産出培地、すなわち回収相の0ポイント)および中間段階(回収6および7)中、2回の培地変更の間に実施した。結果(図示せず)によってプロモーターが活性であり、調節可能であることが示唆された。
DMEMに、以下の表2で報告した濃度で、微量元素Zn、Cu、SeおよびCoを加えた。これらの濃度は、増殖培地中の金属元素の濃度に相当する。微量元素をDMEMに加えることによって達成されたrhGH生産性の増加を表2に示す。
hGH産物の生産性における銅および亜鉛の効果に基づき、要因設計実験を実施して、金属の可能性ある組み合せ効果をアッセイした。
アミノ酸解析を、hGH生産性の増加が、任意のアミノ酸の利用能によって制限されるかどうかを決定するために実施した。表4は、培地中に亜鉛および銅を添加した、及び亜鉛および銅を添加しない培養中での、2日後の回収されたアミノ酸の割合を示す。
銅の最適濃度を測定するために、実験を実施し、クエン酸鉄濃度(4.8μM)および亜鉛濃度(0.5μM)定数を維持し、銅濃度を変化させた(図5)。
図7は、鉄イオンと一緒の、または単独での微量濃度にあるZnおよびCuイオンで得られた結果を要約する。
亜鉛 1.5μM:10.3%±5.0%、亜鉛 0.5μM:16.8%±1.6%
銅 0.02μM:32.1%±9.4%
亜鉛 1.5μM+銅 0.02μM:66.3%±16%
亜鉛 0.5μM+銅 0.02μM:61.2%(±10%)
亜鉛 0.5μM+銅 0.02μM+クエン酸鉄 4.8μM:69.4%±19%
・25nMにて硫酸銅(CuSO4・5H2O)としての銅
・50nM〜1500nMの間の硫酸亜鉛(ZnSO4・7H2O)としての亜鉛、好適には200〜500nMの範囲の濃度
・濃度4.8μM〜約6μMのイオンの最終濃度でのクエン酸鉄、硝酸鉄はすでにDMEM中に存在する。
DMEM培地へのサプリメントとして微量の銅、亜鉛および鉄イオンの利用が、標準DMEMと比較して50%を上回るまでrhGH生産性を増加させた。
Claims (16)
- 動物血清に由来する成分を含まない細胞培養培地中で成長ホルモンを発現する細胞株の細胞を培養する段階を含み、前記培地が、5または6μMの鉄イオンと、0.2μM〜0.5μMの範囲の濃度の亜鉛と、25nMの濃度の銅を含む、成長ホルモンの産出のための方法。
- 前記培地が、硫酸亜鉛として亜鉛を含む、請求項1に記載の方法。
- 前記培地が、硫酸銅として銅を含む、請求項1又は2に記載の方法。
- 前記培地が、クエン酸鉄および/または硝酸鉄として鉄イオンを含む、請求項1〜3のいずれか1項に記載の方法。
- 前記培地がさらに、基礎培地の成分を含む、請求項1〜4のいずれか1項に記載の方法。
- 前記基礎培地が、ダルベッコ改変イーグル培地(DMEM)である、請求項5に記載の方法。
- 前記成長ホルモンが、メタロチオネイン(MT)プロモーターの制御下で発現している、請求項1〜6のいずれか1項に記載の方法。
- 前記メタロチオネインプロモーターがマウスMT−1プロモーターである、請求項7に記載の方法。
- 細胞培養から成長ホルモンを回収する段階をさらに含む、請求項1〜8のいずれかに1項に記載の方法。
- さらに成長ホルモンを精製することを含む、請求項1〜9のいずれか1項に記載の方法。
- 精製成長ホルモンを、医薬的に許容され得る担体と共に製剤化し、医薬組成物を得ることをさらに含む、請求項1〜10のいずれか1項に記載の方法。
- 前記成長ホルモンがヒト成長ホルモンである、請求項1〜11のいずれか1項に記載の方法。
- 成長ホルモンの産出のための、請求項1〜6のいずれか1項に記載の培地の使用。
- 成長ホルモンの産出段階の間、培養中で細胞を維持するための、請求項1〜6のいずれか1項に記載の培地の使用。
- 前記成長ホルモンが、ヒト成長ホルモンである、請求項13または14に記載の使用。
- 前記細胞がマウスC127細胞である、請求項13または14に記載の使用。
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2005
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Also Published As
Publication number | Publication date |
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CA2583027A1 (en) | 2006-10-19 |
KR101196103B1 (ko) | 2012-11-01 |
AU2005330353B2 (en) | 2010-10-14 |
EP1807504A1 (en) | 2007-07-18 |
US20080064644A1 (en) | 2008-03-13 |
ATE499434T1 (de) | 2011-03-15 |
CN101052708B (zh) | 2012-08-29 |
DK1807504T3 (da) | 2011-03-21 |
ZA200702434B (en) | 2008-08-27 |
EP1807504B1 (en) | 2011-02-23 |
NO341236B1 (no) | 2017-09-25 |
PL1807504T3 (pl) | 2011-07-29 |
WO2006108455A1 (en) | 2006-10-19 |
JP2008518592A (ja) | 2008-06-05 |
CN101052708A (zh) | 2007-10-10 |
PT1807504E (pt) | 2011-03-07 |
SI1807504T1 (sl) | 2011-05-31 |
AU2005330353A1 (en) | 2006-10-19 |
NO20072719L (no) | 2007-05-29 |
ES2361559T3 (es) | 2011-06-20 |
DE602005026548D1 (de) | 2011-04-07 |
RS51913B (en) | 2012-02-29 |
US7709229B2 (en) | 2010-05-04 |
KR20070073780A (ko) | 2007-07-10 |
AR052028A1 (es) | 2007-02-28 |
UA92157C2 (ru) | 2010-10-11 |
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