JP5448010B2 - 細胞を培養する改善された方法 - Google Patents
細胞を培養する改善された方法 Download PDFInfo
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- JP5448010B2 JP5448010B2 JP2012133156A JP2012133156A JP5448010B2 JP 5448010 B2 JP5448010 B2 JP 5448010B2 JP 2012133156 A JP2012133156 A JP 2012133156A JP 2012133156 A JP2012133156 A JP 2012133156A JP 5448010 B2 JP5448010 B2 JP 5448010B2
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Description
cerevisiae)、クリヴェロミセス・ラクチス(Kluyveromyces
lactis)、ファフィア・ロドチマ(Phaffia rhodozyma)などの酵母と、例えばピチア・パストリス(Pichia pastoris)などのピチア(Pichia)属からの酵母などの真核生物、または例えば大腸菌(Escherichia coli)、例えばB.リチェニホルミス(licheniformis)、枯草菌(B.subtilis)、B.アミロリケファシエンス(amyloliquefaciens)、B.アルカロフィルス(alcalophilus)(alkalophilus)などのバシラス(Bacillus)種と、ストレプトミセス(Streptomyces)種、コリネバクテリウム・グルタミカム(Corynebacterium glutamicum)、シュードモナス(Pseudomonas)種などの原核生物であってもよい。真核細胞の例についてはまた、例えばChu,L.、Robinson,D.K.(2001年)Curr.Opinion Biotechn.、第12巻、180〜187頁でも記載されている。好ましくは本発明の方法で使用される細胞は、動物細胞、特に哺乳類細胞である。哺乳類細胞の例としては、CHO(チャイニーズハムスター卵巣)細胞と、ハイブリドーマと、BHK(幼若ハムスター腎臓)細胞と、骨髄腫細胞と、例えばHEK−293細胞、ヒトリンパ芽球腫細胞、E1不死化HER細胞などのヒト細胞と、例えばNS0細胞などのマウス細胞とが挙げられる。より好ましくはE1不死化HER細胞、最も好ましくはPER.C6細胞が使用される。
KW、Gallimore PH、1982年、「クローン化アデノウィルス12DNAによるヒト胚網膜芽細胞の悪性形質転換(Malignant transformation of human embryo retinoblasts by cloned adenovirus 12 DNA)」Nature 298:69〜71頁;Byrd PJ、Grand RJA、Gallimore PH、1988年、「アデノウィルスE1領域とE1A+rasの組み合わせとによる初代ヒト胚網膜細胞の異なる形質転換(Differential transformation of primary human embryo retinal cells by adenovirus E1 regions and combinations of E1A
+ ras)」Oncogene 2:477〜484頁)。初代細胞は、数代にわたり継代培養すると死滅する。本発明の目的のためのE1−不死化HER細胞は、アデノウィルスE1AおよびE1Bタンパク質をコードするDNAをその中で発現させて初代HER細胞から誘導することにより、不死化細胞が得られる。このような不死化細胞は、100代以上の継代培養ができる。E1−不死化HER細胞を得るための方法については、例えば次で記載されている。米国特許第5,994,128号明細書、Byrd P、Brown KW、Gallimore PH、1982年、「クローン化アデノウィルス12DNAによるヒト胚網膜芽細胞の悪性形質転換(Malignant transformation of human embryo retinoblasts by cloned adenovirus 12 DNA)」Nature 298:69〜71頁;Byrd PJ、Grand RJA、Gallimore PH、1988年、「アデノウィルスE1領域とE1A+rasの組み合わせとによる初代ヒト胚網膜細胞の異なる形質転換(Differential transformation of primary human embryo retinal cells by adenovirus E1 regions and combinations of E1A + ras)」Oncogene 2:477〜484頁;およびGallimore,P.H.、Grand,R.J.A.、およびByrd,P.J.(1986年)「シミアンウイルス40、アデノウィルス、およびras発癌遺伝子によるヒト胚網膜芽細胞の形質転換(Transformation of human embryo retinoblasts with simian virus 40,adenovirus and ras oncogenes)」AntiCancer Res.6、499〜508頁。例えばPER.C1、PER.C3、PER.C4、PER.C5、PER.C6、PER.C8、およびPER.C9細胞をはじめとする不死化HER細胞が、ヒトホスホグリセリン酸キナーゼ(「PGK」)プロモーターの制御下にあるアデノウィルス血清型5(Ad5)E1A−およびE1B−コード配列(Ad5ヌクレオチド459〜3510)を含有するプラスミドを使用した、初代HER細胞の形質移入によって作り出された(米国特許第5,994,128号明細書参照)。
供給速度=SFR×(総細胞培養物容積)×(生存細胞密度) (1)に従った供給速度で添加され、供給速度は一日当たりリットル数で表現されて、SFRは比供給速度、すなわち単位時間あたり生存細胞毎に添加される培地の容積として表現される細胞培養液が細胞培養物に供給される速度であり、生存細胞密度は単位容積あたりの生存細胞数である。生存細胞数は、例えばトリパンブルー排除法を通じて、当業者によって判定されることができる。比供給速度は、好ましくは0.01〜0.3nL/細胞/日の間、より好ましくは0.01〜0.2nL/細胞/日の間で選択される。
biopharmaceutical proteins)」779〜807頁を参照されたい)などの生物学的物質を生成するために使用できる。
[実施例1:バッチ工程、流加工程、および本発明に従った工程間の比較]
この実施例では、本発明に従った方法の性能をバッチおよび流加工程と比較した。
ザルトリウスB5容器内で、4Lの作業容積でバッチ工程を実行した。6mMのL−グルタミン(glutamin)を添加したSAFCからのVPRO培地に細胞を3×10e5細胞/mLで接種し、続いて17日間培養した。
ザルトリウスB5容器内で、4Lの作業容積で流加工程を実行した。6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地に細胞を3×10e5細胞/mLで接種した。培養中にグルコースおよびグルタミンを添加して、上の濃度をそれぞれ15mMおよび1mMに保った。5日目からアミノ酸およびペプチドを添加して、消費されたアミノ酸を補給した。
2Lアプリコン容器内で、本発明の工程を実施した。Refine TechnologyからのATF−2システムを用いて、ATFフローモードで操作される、ゼネラル・エレクトリック(GE)から得られた分画分子量(MWCO)100kDaの中空繊維膜を使用して、細胞およびIgG生成物を保持した。6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地中で、3×10e5細胞/mLで培養を開始した。0.05〜0.2nL/細胞/日の間の比流速(SFR)を使用して、懸濁細胞培養物を通して、6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地を灌流した。得られた最大生成物濃度は1.4g/Lであった。
この実施例では、本発明に従った方法を再度バッチおよび流加工程と比較し、工程C2ではCO2圧力を制御して50kDa分離システムを使用した。
ザルトリウスB5容器内で、4Lの作業容積でバッチ工程を実行した。6mMのL−グルタミン(glutamin)を添加したSAFCからのVPRO培地に細胞を3.105細胞.mL−1で接種し、続いて17日間培養した。
ザルトリウスB5容器内で、4Lの作業容積で流加工程を実行した。6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地に細胞を3.105細胞.mL−1で接種した。培養中にグルコースおよびグルタミンを添加して、上の濃度をそれぞれ15mMおよび1mMに保った。5日目からアミノ酸およびペプチドを添加して、消費されたアミノ酸を補給した。
2Lアプリコン容器内で、本発明の工程を実施した。Refine TechnologyからのATF−2システムを用いて、ATFフローモード内で操作される、GEからの分画分子量(MWCO)50kDaの中空繊維膜を使用して、細胞およびIgG生成物を保持した。6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地中で、3×10e5細胞/mLで培養を開始した。0.05〜0.2nL.細胞−1.日−1の間のSPRを使用して、懸濁細胞培養物を通して、6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地を灌流した。CO2圧力を15%未満に制御した。
図3および図4から分かるように、本発明に従った工程は、等しいかそれ以下の時間で(バッチ時間の100%;流加時間の81%)、顕著な生存細胞密度の増大および生成物濃度の増大をもたらした(2415%×バッチ収率;690%×流加収率)。
この実施例では、細胞培養物除去を伴う本発明に従った方法の性能を再度バッチおよび流加工程と比較する。工程C3では細胞培養物が除去された。
ザルトリウスB5容器内で、4Lの作業容積でバッチ工程を実行した。6mMのL−グルタミン(glutamin)を添加したSAFCからのVPRO培地に細胞を3.105細胞.mL−1で接種し、続いて17日間培養した。
ザルトリウスB5容器内で、4Lの作業容積で流加工程を実行した。6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地に細胞を3.105細胞.mL−1で接種した。培養中にグルコースおよびグルタミンを添加して、上の濃度をそれぞれ15mMおよび1mMに保った。5日目からアミノ酸およびペプチドを添加して、消費されたアミノ酸を補給した。
2Lアプリコン容器内で、本発明の工程を実施した。Refine TechnologyからのATF−2システムを用いて、ATFフローモード内で操作される、GEからの分画分子量(MWCO)100kDaの中空繊維膜を使用して、細胞およびIgG生成物を保持した。6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地中で、3×10e5細胞/mLで培養を開始した。0.05〜0.2nL.細胞−1.日−1の間のSPRを使用して、懸濁細胞培養物を通して、6mMのL−グルタミン(Glutamin)を添加したSAFCからのVPRO培地を灌流した。10.106細胞.mL−1を超えたら1日あたり作業容積の10%、生存細胞密度が30.106細胞.mL−1を超えたらそれ以降は1日あたり作業容積の30%の細胞培養を除去する。
図5から分かるように、本発明の工程によってより高い生存細胞密度が迅速に達成される。さらに細胞密度が非常に高くても保持装置の目詰まりが起こらなかったため、工程C3は40日間近い期間にわたり作動を維持されたので、図5はまた、本発明の工程によって細胞生存度がより長く維持できることも示す。
この実施例では、IgG産生CHO細胞系に、本発明に従った方法を実施して温度低下を含めて細胞生育を低下させた。
2Lアプリコン容器内で、本発明の工程を実施した。細胞および生成物保持装置は、Refine TechnologyからのATF−2システムを用いて、ATFフローモードで操作されるゼネラル・エレクトリックからの50kD分画分子量(MWCO)中空繊維膜である。ハイクローンからのMTCM−49培地中で、5.106細胞.mL−1で培養を開始した。0.1〜0.4nL.細胞−1.日−1の間のSPRを使用して、懸濁細胞培養物を通して培地を灌流した。CO2圧力は15%未満に制御された。
データは、本発明の工程が、タンパク質産生CHO細胞系を使用した場合にも機能することを示す。達成された細胞密度および生成物濃度は、バッチ培養と比較して増大する。データはまた、本発明に従った方法で(例えば温度低下によって)細胞生育を抑止できる一方、培養システム中の生成物蓄積が継続することも示す。
本発明に従った方法はまた、骨髄腫細胞系にも適用できる。この目的でザルトリウスバイオスタットBコントローラーを使用して、温度を36.5℃に、pHを7.2〜6.8の間に、およびDOを40%空気飽和率に調節して、100rpmで発酵を実施する。5Lザルトリウス容器内のハイクローンからのSFM4Mab培地に、骨髄腫細胞を3×10e5細胞/mlで接種して細胞培養を開始する。細胞および生成物保持装置は、Refine TechnologyからのATF−4システムを用いて、ATFフローモード内で操作されるゼネラル・エレクトリックからの30kD分画分子量(MWCO)中空繊維膜である。0.1〜0.4nL.細胞−1.日−1の間のSPRを使用し、懸濁細胞培養物を通して、ハイクローンからのSFM4Mab培地を灌流させる。CO2圧力は15%未満に制御される。
本発明に従った方法はまた、懸濁状態の形質転換MDCK細胞系に適用できる。この目的でザルトリウスバイオスタットBコントローラーを使用して、温度を36.5℃に、pHを7.2〜6.8の間に、およびDOを40%空気飽和率に調節して、100rpmで発酵を実施する。5Lザルトリウス容器内のインビトロジェンからのVP−SFM培地に、形質転換MDCK細胞を3×10e5細胞/mlで接種して細胞培養を開始する。細胞および生成物保持装置は、Refine TechnologyからのATF−4システムを用いて、ATFフローモード内で操作されるゼネラル・エレクトリックからの30kD分画分子量(MWCO)中空繊維膜である。0.1〜0.4nL.細胞−1.日−1の間のSPRを使用し、懸濁細胞培養物を通して、インビトロジェンからのVP−SFM培地を灌流させる。CO2圧力は15%未満に制御される。
Claims (14)
- 細胞が、形質移入された少なくとも1つの遺伝子によってコードされる所望の生物学的物質を産生することができ、少なくとも1つの細胞培養液成分が細胞培養物に供給され、
細胞、所望の生物学的物質、および細胞培養液を含んでなる細胞培養物が、液体流出および流れをもたらす分離システム上で循環され、前記流れの内容物が反応器内に保持されまたは反応器の中に送り戻され、
分離システムが、所望の生物学的物質よりも低い分子量を有する物質から所望の生物学的物質が分離されるフィルターを有し、
フィルターからの液体流出物は、本質的に所望の生物学的物質よりも低い分子量の成分のみを含み、
前記流れは、本質的に、生物学的物質の分子量と少なくとも等しいかそれ以上の分子量を有する成分のみを含有し、
前記反応器が、撹拌タンク容器、気泡ポンプ容器、または、揺動、振盪運動若しくは撹拌によって混合できる使い捨てバッグであり、
前記細胞が前記所望の生物学的物質を産生することによって、前記培養液中に前記所望の生物学的物質が溶解し、前記所望の生物学的物質の濃度が増大する、反応器内で細胞培養液中の懸濁状態の真核細胞を培養する方法。 - 前記フィルターが、前記生物学的物質の分子量の2分の1以下の分画分子量を有するフィルターである、請求項1に記載の方法。
- 前記フィルターが、30kDa〜100kDaの分画分子量を有するフィルターである、請求項1又は2に記載の方法。
- 所望の生物学的物質よりも低い分子量の物質の一部が細胞培養物から連続的に除去される、請求項1〜3のいずれか一項に記載の方法。
- 所望の生物学的物質が組み換えタンパク質である、請求項1〜4のいずれか一項に記載の方法。
- 所望の生物学的物質が抗体である、請求項1〜5のいずれか一項に記載の方法。
- 分離システムが薄膜フィルターである、請求項1〜6のいずれか一項に記載の方法。
- 分離システムが中空繊維フィルターである、請求項1〜6のいずれか一項に記載の方法。
- 細胞培養物が交互のタンジェンシャルフローで、フィルター上で循環される、請求項7又は8に記載の方法。
- 細胞培養物が反応器から少なくとも1回除去され、液体が反応器に添加されて細胞培養物の除去を代償する、請求項1〜9のいずれか一項に記載の方法。
- 細胞培養物が反応器から少なくとも1回除去され、細胞培養液が反応器に添加されて細胞培養物の除去を代償する、請求項1〜9のいずれか一項に記載の方法。
- 細胞培養条件が、細胞培養液成分の少なくとも1つの濃度が一定のままであるように選択される、請求項11に記載の方法。
- 枯渇栄養素を反応器に供給することで、これらの栄養素が少なくとも部分的に補給される、請求項1〜12のいずれか一項に記載の方法。
- 所望の生物学的物質が細胞からおよび/または細胞培養物から収集される、請求項1〜13のいずれか一項に記載の方法。
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