JP5837476B2 - 組換えil−18結合タンパク質の生産 - Google Patents
組換えil−18結合タンパク質の生産 Download PDFInfo
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- JP5837476B2 JP5837476B2 JP2012247547A JP2012247547A JP5837476B2 JP 5837476 B2 JP5837476 B2 JP 5837476B2 JP 2012247547 A JP2012247547 A JP 2012247547A JP 2012247547 A JP2012247547 A JP 2012247547A JP 5837476 B2 JP5837476 B2 JP 5837476B2
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Description
a) 生産処理の全体に渡り、不変値でかん流量を固定すること。
このアプローチは、堅実且つ継続的に操作するためにより簡便であるから、一般に工業生産工程において好適である。また処理間のかん流量にばらつきがないため、工程の中間コストを定めるのに利点を有する。
b) 細胞数及び/またはグルコース(Oh等. 1994) (Dowd等. 2001) (Gorenflo等. 2003)、グルタミン(Gorenflo等. 2002)、または酸素(Kyung等. 1994)等の栄養消費量に応じて、かん流量を調整すること。
このアプローチは、かん流量を調整するためのより科学的な論拠を提供するが、過剰発育培養及びかん流量の“制御不能”な増加をもたらし得る。細胞を懸濁様式で培養する場合は、"培養流出(culture bleed)"をして培養の過剰発育を回避するが、細胞を担体上に固定する場合はこれを回避できない。ゆえに一般にこのアプローチは、堅実且つ継続的な方法で操作することが困難であり、また毎日培地かん流量の再調整を行う必要があるような製造操作には向かない。
c) a)とb)の両戦略を初期細胞増殖期(または"成長期")と組み合せること。
ここでは細胞代謝を比較的低い不変レベルで安定化し保持するために、温度及び/またはpH等の培養条件を移行した後の成長期の間に、かん流量を細胞成長の要求に従って徐々に増加させる。この段階でのかん流量は生産期の間の細胞の減少した要求に合致する固定値まで減少させることができる。
本発明は、無血清の培養条件下にあるバイオリアクター中の哺乳動物細胞において組換えインターロイキン-18結合タンパク質(IL-18BP)を生産するための方法の開発に関し、約37℃での細胞増殖期、及び約29℃〜約34℃の範囲の温度での生産期を含んで成る。
a) 37℃で一定のかん流量(100%)での細胞増殖期;
b) 33.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期I;
c) 32.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期II、を含んで成る。
a. 37℃での細胞増殖期;
b. 任意に33℃での間期;
c. 29℃での生産期、を含んで成る。
本発明は、無血清の細胞培養条件下にあるバイオリアクター中で組換えIL-18BPを生産するための効率的な方法の開発に基づく。したがって本発明は、無血清の培養条件下にあるバイオリアクター中の哺乳動物細胞において組換えインターロイキン-18結合タンパク質(IL-18BP)を生産するための方法に関し、約37℃での細胞増殖期、及び約29℃〜約34℃の範囲の温度での生産期を含んで成る。
a) 37℃で一定のかん流量(100%)での細胞増殖期;
b) 33.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期I;
c) 32.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期II、を含んで成る。
a. 37℃での細胞増殖期;
b. 任意に33℃での間期;
c. 29℃での生産期、を含んで成る。
本実施例は、充填層バイオリアクター中での組換えCHO細胞の高細胞密度培養に基づく方法を発表する。ここでのかん流量は、成長期の間は細胞成長の要求に伴い調整し、その後の生産期の間は方法の生産性またはタンパク質の品質を落とさずに顕著に減少させた。
細胞培養−実験系
Fibra-Cel(商標)担体(Bibby Sterilin, 英国)を有する充填層バイオリアクター(Ducommun等. 2002a; Ducommun等. 2002b)を、CHO細胞(Laboratoires Serono S.A., Corsier-sur-Vevey, スイス)を培養するために使用し、無血清培地(Sigma C-9486)中でIL-18BPを発現及び分泌させた。かん流量の減少を調査するために用いた小規模系では、バイオリアクターと充填層は、15リットル及び5リットルの処理容量をそれぞれ有した。
培養中は、サンプルを毎日取り除いた。グルコースと乳酸塩の濃度はEML 105分析器(Radiometer Medical A/S, Bronshoj, デンマーク)で定量した。
かん流量の減少
最初の試みは、生産期の間のかん流量を2.6 vvdから2.0 vvd及び1.3 vvdに減少させること(図1)、及びその細胞代謝への影響、体積生産性、及び製品の品質を追跡することであった。
図5A、B及びCに示した結果は、参照処理-100と減少した培地かん流での処理において生産した組換えタンパク質の比較を示す(体積生産性、全生産量、および滴定濃度)。
2.6 vvdから2.0 vvd及び1.3 vvdまでのかん流量の減少について、処理-100、処理-75、及び処理-50に関して試験した。組換えタンパク質の滞留時間(t)は、それぞれ0.4日から0.5日及び0.8日に増加した(t=1/D)。
生産された組換えIL-18BPのサンプルは、注目のタンパク質の多様なシアル化形態の比率を定量するために、上記で示した方法に従いN-グリカンマッピングに供した。N-グリカンマッピングの結果は、比較可能なN-グリカンの比率が試験された全てのかん流量で得られたことを示す表2に要約した。これは図6に示した対応のHPLCプロファイルによっても説明されている。
本研究では、Fibra-Cel(商標)ディスク担体でできている充填層バイオリアクター中での組換えCHO細胞株の連続培養に使用される最適な培地かん流量を決定した。
小規模で得られた結果から、かん流量の−25%の減少は、生産性の最大化の利益と−25%の培地消費の節約の利益が組み合されたことが明白である。
懸濁培養における組換えヒトIL-18発現細胞による流加方法も同様に開発された。合計で3つの処理を5 L (n=2)または300 L (n=1)の標準容量のバイオリアクターを用いて実行した。
表3:流加製造方法スキーム
2) 5Lと300Lのバイオリアクターは、それぞれ小規模(5L)とパイロット規模(300L)のの操作用である。
3) 供給-1の最初の付加は、c(グルコース)<1.0 g/L (+80 g/kg)のときに起こる。
4) 供給-1のその後の付加は、c(グルコース)<5.5 g/L (+30 g/kg)のときに起こる。
* WD=処理日数
** VCs=生存細胞
IL-18BPを生産するための更なるかん流方法を設定した。かん流処理は、4.4 kgのFibracel(商標)-ディスクでパックした160 Lの総容量(40 Lの外部カラムを含む)を含むバイオリアクター中で、33.5または32.5℃の生産温度で、2.75 vvdのかん流量で実施した。
Z=A (中性)×0+A (モノ)×1+A (ジ)×2+A (トリ)×3+A (テトラ)×4+A (ペンタ)×5。
CZE溶液
- 5 mMのホスフェートCZE洗浄/処理緩衝液:
50 mMのホスフェート貯蔵溶液pH 7.0を1:10に希釈して調製する。0.22 μmのフィルターを通しろ過する。新たに調製する。
- 0.5 MのNaOH (CZE洗浄液):
26.2 μlの50%のNaOHを水に付加し、1 mLの総容量とする。新たに調製する。
- 1 MのNaOH (CZE再生液):
52.4μlの50%のNaOHを水に付加し、1 mLの総容量とする。新たに調製する。
- 中性マーカー(1:10000に希釈)
10 μlの中性マーカー貯蔵溶液を水に付加し、1 mLの総容量とする。10 μLのこの中性マーカー1:100希釈物を水に付加し、1 mlの総容量とする。3ヶ月間、4℃で貯蔵する。
≧20 μLのサンプル/参照を1/10の容積の中性マーカーを含むPCRバイアル中に移して、泡を立てずにリバースピペッティングで混合する。
極性 陽性対陰性(前進)
温度 キャピラリー=25±2℃
サンプル台 =10±2℃
検出 214 nm
キャピラリー調整の目的のために、少なくとも3つの標準参照物質を注入すべきである。
標準参照1(開始)
サンプル1の単回注入
サンプル2の単回注入
サンプル3の単回注入
サンプル4の単回注入
標準参照2(終了)
注:再生産能を増加させるために、参照1と参照2の間の1順で、同一のCZE処理緩衝剤を用いて最大で4つのサンプルを分析することができる。
標準参照(開始1)
サンプル1の単回注入
標準参照(終了1/開始2)
サンプル2の単回注入
標準参照反復(終了2/開始3)
サンプル3の単回注入
標準参照反復(終了3)
標準参照物質はサンプルデータの比較のために使用される。重層され、また積み重ねられたエレクトロフェログラムのサンプルと両括弧内の参照標準(開始/終了)はプリントアウトして保管される。
参照標準(開始)の−3と+3のピークの左と右の谷間で移行時間MT2及びMT3が決定される。0ピークは、参照の主要ピークである。
IL-18BP糖タンパク質の強い酸性プロファイルによって、MT2とMT3の間のアイソフォームは"酸性アイソフォーム"と名付けられた。MT3よりも長い移行時間を有するアイソフォームは"強酸性アイソフォーム"と名付けられた。MT2よりも短い移行時間を有するアイソフォームは"弱酸性アイソフォーム"と名付けられた。
参照とそれぞれのサンプルを、MT1-M2、MT2-MT3及びMT3-MT4の間のマニュアルピーク;5分と28分の間のマニュアルベースライン、並びに0とMT1の間、及びMT4と30分の間のインテグレーションオフの機能を用いて分析した。マニュアル的に幅(Width)と基準点(Threshold)の機能を改変して、上記の参照標準と類似するMT1-M2(より弱酸性のアイソフォーム)、MT2-MT3(酸性アイソフォーム)及びMT3-MT4(より強酸性のアイソフォーム)の間の3つのピークの群の統合を得る。
本CZE法は粗採取物サンプル、並びにかん流方法及び流加方法の両方の精製サンプルに適用された(図9)。前処理された採取物サンプルで多少の相違が観察されたが(例えばかん流方法による塩基性アイソフォームの高い比率)、これらの塩基性アイソフォームは精製工程の間のイオン交換クロマトグラフィーでうまく除去された(データは示されていない)。したがって精製生産物に関しては、比較可能なアイソフォームプロファイルが両方法で得られた(図10)。
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Claims (7)
- 無血清の培養条件下、バイオリアクター中で、チャイニーズハムスター卵巣(CHO)細胞において組換えインターロイキン-18結合タンパク質(IL-18BP)を生産するための方法であって、以下のステップ:
a. 37℃での細胞増殖期;
b.任意に33℃での間期;
c. 29℃での生産期、
を含んで成る流加方法である、前記方法。 - 前記生産期における総細胞密度が、少なくとも10日間の細胞培養で、1日あたり、1mlあたり、4〜8×106個の細胞の範囲である、請求項1に記載の方法。
- 少なくとも10日間の細胞培養で、生存能が100〜80%の範囲である、請求項1または2に記載の方法。
- タンパク質生産性が150 mgより高い、請求項1〜3のいずれか1項に記載の方法。
- 細胞培養の上澄みを収集するステップを更に含んで成る、請求項1〜4のいずれか1項に記載の方法。
- IL-18BPを精製するステップを更に含んで成る、請求項1〜5のいずれか1項に記載の方法。
- IL-18BPを医薬組成物に製剤化するステップを更に含んで成る、請求項1〜6のいずれか1項に記載の方法。
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Also Published As
Publication number | Publication date |
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WO2006128908A1 (en) | 2006-12-07 |
ATE517917T1 (de) | 2011-08-15 |
AU2006254103B2 (en) | 2012-09-06 |
CA2609060A1 (en) | 2006-12-07 |
EP2267024B1 (en) | 2012-05-09 |
PT1885753E (pt) | 2011-10-06 |
SI2267024T1 (sl) | 2012-09-28 |
PT2267024E (pt) | 2012-06-01 |
US20100137195A1 (en) | 2010-06-03 |
PL2267024T3 (pl) | 2012-10-31 |
JP2008541748A (ja) | 2008-11-27 |
JP2013048633A (ja) | 2013-03-14 |
US20080199913A1 (en) | 2008-08-21 |
CY1111969T1 (el) | 2015-11-04 |
CA2609060C (en) | 2014-07-15 |
EP2267024A1 (en) | 2010-12-29 |
ATE557038T1 (de) | 2012-05-15 |
SI1885753T1 (sl) | 2011-12-30 |
DK1885753T3 (da) | 2011-10-03 |
NO20076672L (no) | 2008-02-22 |
IL187838A (en) | 2011-07-31 |
DK2267024T3 (da) | 2012-06-25 |
JP5199073B2 (ja) | 2013-05-15 |
ES2385639T3 (es) | 2012-07-27 |
CY1113056T1 (el) | 2016-04-13 |
AU2006254103A1 (en) | 2006-12-07 |
IL187838A0 (en) | 2008-03-20 |
EP1885753A1 (en) | 2008-02-13 |
EP1885753B1 (en) | 2011-07-27 |
NO342802B1 (no) | 2018-08-06 |
ES2370417T3 (es) | 2011-12-15 |
PL1885753T3 (pl) | 2011-12-30 |
US7691611B2 (en) | 2010-04-06 |
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