JP5872902B2 - 新規な流加培養法 - Google Patents
新規な流加培養法 Download PDFInfo
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- JP5872902B2 JP5872902B2 JP2011551921A JP2011551921A JP5872902B2 JP 5872902 B2 JP5872902 B2 JP 5872902B2 JP 2011551921 A JP2011551921 A JP 2011551921A JP 2011551921 A JP2011551921 A JP 2011551921A JP 5872902 B2 JP5872902 B2 JP 5872902B2
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- 230000005865 ionizing radiation Effects 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
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- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
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- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
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- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- 229960001471 sodium selenite Drugs 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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- 229960001727 tretinoin Drugs 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
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- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- C12P21/00—Preparation of peptides or proteins
- C12P21/005—Glycopeptides, glycoproteins
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/303—Liver or Pancreas
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
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- C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
- C12M41/24—Heat exchange systems, e.g. heat jackets or outer envelopes inside the vessel
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
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- C07K2317/00—Immunoglobulins specific features
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- C07K2317/41—Glycosylation, sialylation, or fucosylation
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- C12N2510/00—Genetically modified cells
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Description
(1)所望のポリペプチドを発現し得る細胞を、流加培養法を用いて培養し、発現したポリペプチドを細胞培養液から採取することにより当該ポリペプチドを製造する方法であって、本培養槽に流加する前の流加培地を流加培地槽において低温に保存することを特徴とする方法。
(2)低温が0度から20度の範囲内である(1)に記載の方法。
(3)低温が2度から15度の範囲内である(1)に記載の方法。
(4)低温が4度から10度の範囲内である(1)に記載の方法。
(5)工場生産レベルの培養槽で行われる製造方法である(1)から(4)に記載の方法。
(6)初発培地の液量が100L以上のスケールであることを特徴とする(5)に記載の方法。
(7)流加培地槽が本培養槽に連結されていることを特徴とする(1)から(6)に記載の方法。
(8)流加培地を追加調製せず、培養開始時に調製された流加培地のみを流加培養槽中で保存して用いる(7)に記載の方法。
(9)細胞が動物細胞である(1)から(8)に記載の方法。
(10)動物細胞が哺乳類動物細胞である(9)に記載の方法。
(11)哺乳類動物細胞がチャイニーズハムスター卵巣細胞である(10)に記載の方法。
(12)細胞が所望のポリペプチドをコードするDNAを導入した細胞である、(1)から(11)に記載の方法。
(13)ポリペプチドが糖タンパク質である、(1)から(12)に記載の方法。
(14)糖タンパク質が抗体である、(13)に記載の方法。
(15)抗体のクラスがIgGまたはIgMである、(14)に記載の方法。
(16)ポリペプチドが医薬の有効成分である、(1)から(12)に記載の方法。
(17)宿主細胞を流加法により培養して組換え抗体を製造する際に、抗体の物性を改善する方法であって、本培養槽に流加する前の流加培地を流加培地槽において低温で保存することを特徴とする方法。
(18)流加培地槽が本培養槽に連結されていることを特徴とする(17)に記載の方法。
(19)流加培地槽を低温に制御する冷却手段を具備することを特徴とする、(1)に記載の方法を実施するための装置。
(20)冷却手段が、冷却水を通水する冷却手段、電気による冷却手段、冷蔵庫に保管する手段、低温室に保管する手段、冷却材を使用する手段、吸熱材を使用する手段、保冷材を使用する手段、吸熱反応を利用した手段、冷風をあてる手段、ドライアイスを使用する手段、氷水につける手段のいずれかの手段である、(19)に記載の装置。
(21)さらに、流加培地中のアンモニアの生成が抑制されることを特徴とする(1)に記載の方法。
(22)さらに、流加培地中のグルタミンの分解が抑制されることを特徴とする(1)に記載の方法。
培地組成、細胞及び調製法は以下のとおりである。
初発培地:市販の哺乳動物由来成分不含培地1を用いた。
流加培地:初発培地に用いた哺乳動物由来成分不含培地1の成分を、初発培地に対し3倍濃縮し、流加培地として用いた。培養開始時に低温(摂氏4度)または室温(約22−23度)に保存し、室温保存をコントロールとした。
細胞:組換え型抗グリピカン-3ヒト化抗体(国際公報第WO2006/006693号パンフレットの実施例24に記載の方法でヒト化し、実施例25の方法でL鎖が改変された抗体)を産生するCHO細胞株を用いた。抗体のクラスはIgG1。
培地組成、細胞及び調製法は以下のとおりである。
初発培地:市販の哺乳動物由来成分不含培地1を用いた。
流加培地:初発培地に用いた哺乳動物由来成分不含培地1の成分を、初発培地に対し3倍濃縮し、流加培地として用いた。培養開始時に低温(摂氏5度)または室温(約22−23度)に保存し、室温保存をコントロールとした。
細胞:組換え型抗IL-6レセプターヒト化抗体(トシリツマブ、hPM-1抗体)を産生するCHO細胞株を用いた。抗体のクラスはIgG1。
培地組成、細胞及び調製法は以下のとおりである。
初発培地:市販の哺乳動物由来成分不含培地1を用いた。
流加培地:初発培地に用いた哺乳動物由来成分不含培地1の成分を、初発培地に対し3倍濃縮し、流加培地として用いた。培養開始時に低温(摂氏5度)または室温(約22−23度)保存し、室温保存をコントロールとした。
細胞:実施例2と同じ組換え型抗IL-6レセプターヒト化抗体(トシリツマブ、hPM-1抗体)を産生するCHO細胞株を用いた。抗体のクラスはIgG1。
図3に示したように、低温に保たれた流加培地を添加した場合の抗体タンパク質の主成分(糖鎖修飾が成熟)の割合は培養10日目で68.3%、14日目で65.6%であった。これに対して、室温保存の流加培地を添加した場合の抗体タンパク質の主成分の割合は培養10日目で66.1%、14日目で60.8%であった。
培地組成、細胞及び調製法は以下のとおりである。
初発培地:市販の哺乳動物由来成分不含培地1を用いた。
流加培地:完全合成培地IS CHO FEED-CD XP (IS社,Cat No. 91122)を流加培地として用いた。培養開始時に低温(摂氏4度)または室温(約22−23度)に保存し、室温保存をコントロールとした。
細胞:実施例1と同じ組換え型抗グリピカン-3ヒト化抗体を産生するCHO細胞株を用いた。抗体のクラスはIgG1。
図12に示したように、低温に保たれた流加培地を添加した場合の抗体タンパク質の主成分2(糖鎖修飾が成熟)の割合は培養14日目で45.0%であった。これに対して、室温保存の流加培地を添加した場合の抗体タンパク質の主成分2の割合は培養14日目で41.9%であった。
培地組成、実験方法は以下のとおりである。
初発培地に用いた哺乳動物由来成分不含培地1の成分を、初発培地に対し3倍濃縮し、流加培地として用いた。一定温度(4℃、10℃、15℃、室温22-23℃、25℃、37℃)保存下 14日後の流加培地中のグルタミン、アンモニア濃度を測定した。流加培地調製時のサンプル(Day0)をコントロールとした。
培地組成、細胞及び調製法は以下のとおりである。
初発培地:市販の哺乳動物由来成分不含培地1を用いた。
流加培地:初発培地に用いた哺乳動物由来成分不含培地1の成分を、初発培地に対し3倍濃縮し、コントロールの流加培地(FM Ctrl.)として用いた。またその流加培地に10mMアンモニアを添加した培地(FM+10mM NH3)、20mMアンモニアを添加した培地(FM-20mM NH3)を調製した。全て低温(摂氏4度)で保存した。
細胞:実施例2と同じ組換え型抗IL-6レセプターヒト化抗体(トシリツマブ、hPM-1抗体)を産生するCHO細胞株を用いた。抗体のクラスはIgG1。
Claims (16)
- 所望の抗体を発現し得る動物細胞を、流加培養法を用いて培養し、発現した抗体を細胞培養液から採取することにより当該抗体を製造する方法であって、該方法が工場生産レベルの培養槽で行われる製造方法であり、当該培養槽は流加培地槽が本培養槽に連結されており、流加培地を追加調製せず、培養開始時に調製された流加培地のみを流加培養槽中で保存して用い、当該流加培養は7日間以上行われ、当該流加培地が哺乳動物由来成分不含培地または完全合成培地であって、本培養槽に流加する前の流加培地を流加培地槽において低温に保存することを特徴とする方法。
- 低温が0度から20度の範囲内である請求項1に記載の方法。
- 低温が2度から15度の範囲内である請求項1に記載の方法。
- 低温が4度から10度の範囲内である請求項1に記載の方法。
- 初発培地の液量が100L以上のスケールであることを特徴とする請求項4に記載の方法。
- 動物細胞が哺乳類動物細胞である請求項1から5のいずれか一項に記載の方法。
- 哺乳類動物細胞がチャイニーズハムスター卵巣細胞である請求項6に記載の方法。
- 細胞が所望の抗体をコードするDNAを導入した細胞である請求項1から7のいずれか一項に記載の方法。
- 抗体のクラスがIgGまたはIgMである、請求項1から8のいずれか一項に記載の方法。
- 抗体が医薬の有効成分である、請求項1から9のいずれか一項に記載の方法。
- 宿主動物細胞を流加法により培養して組換え抗体を製造する際に、抗体の物性を改善する方法であって、製造が工場生産レベルの培養槽で行われる製造であり、当該培養槽は流加培地槽が本培養槽に連結されており、流加培地を追加調製せず、培養開始時に調製された流加培地のみを流加培養槽中で保存して用い、当該流加培養は7日間以上行われ、当該流加培地が哺乳動物由来成分不含培地または完全合成培地であって、本培養槽に流加する前の流加培地を流加培地槽において低温で保存することを特徴とする方法。
- 流加培地槽を低温に制御する冷却手段を具備することを特徴とする、請求項1に記載の方法を実施するための装置。
- 冷却手段が、冷却水を通水する冷却手段、電気による冷却手段、冷蔵庫に保管する手段、低温室に保管する手段、冷却材を使用する手段、吸熱材を使用する手段、保冷材を使用する手段、吸熱反応を利用した手段、冷風をあてる手段、ドライアイスを使用する手段、氷水につける手段のいずれかの手段である、請求項12に記載の装置。
- さらに、流加培地中のアンモニアの生成が抑制されることを特徴とする請求項1に記載の方法。
- さらに、流加培地中のグルタミンの分解が抑制されることを特徴とする請求項1に記載の方法。
- 所望の抗体を発現し得る動物細胞を、流加培養法を用いて培養して当該抗体を製造する際に生じるハイマンノース型抗体の生成を抑制する方法であって、該方法が工場生産レベルの培養槽で行われる方法であり、当該培養槽は流加培地槽が本培養槽に連結されており、流加培地を追加調製せず、培養開始時に調製された流加培地のみを流加培養槽中で保存して用い、当該流加培養は7日間以上行われ、当該流加培地が哺乳動物由来成分不含培地または完全合成培地であって、本培養槽に流加する前の流加培地を流加培地槽において低温に保存することを特徴とする方法。
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