JP4688092B2 - 活性型TGF−βが濃縮されたタンパク質画分を得る方法、タンパク質画分および治療的適用 - Google Patents
活性型TGF−βが濃縮されたタンパク質画分を得る方法、タンパク質画分および治療的適用 Download PDFInfo
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- JP4688092B2 JP4688092B2 JP2003512270A JP2003512270A JP4688092B2 JP 4688092 B2 JP4688092 B2 JP 4688092B2 JP 2003512270 A JP2003512270 A JP 2003512270A JP 2003512270 A JP2003512270 A JP 2003512270A JP 4688092 B2 JP4688092 B2 JP 4688092B2
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Description
a)陽イオン交換クロマトグラフィーによって日常製品の基礎画分を回収し;
b)工程a)で得られた画分をヒドロキシアパタイトカラムに通し;さらに
c)例えば実質的にIGF-1を含まないTGF-β画分が得られるよう選択した好適な溶出剤を用いてヒドロキシアパタイトカラムから溶出すること;
を含んでなるものである。
a)精製した可溶性タンパク質を5および30g/溶液1リットルの間の濃度に調節し;
b)このように得た溶液の55℃および68℃の間にわたる温度での4および5.5の間にわたるpHへの酸処理によって乳漿タンパク質の一部を沈殿させ;
c)処理した溶液のダイアフィルトレーションを伴う精密濾過を実施して、それぞれ精密濾過残留物および精密濾過液を得て;
d)TGFβが高度に濃縮されたタンパク質画分を含有する精密濾過残留物を回収し;さらに
e)ダイアフィルトレーションに付された精密濾過残留物を乾燥させてTGFβが高度に濃縮された粉末を得ること;
を含んでなる。
a)精製した乳漿タンパク質を5および30g/溶液1リットルの間の濃度に調節し;
b)この液体溶液の4および5.5の間にわたるpHおよび55℃および68℃の間にわたる温度での酸処理によって乳漿タンパク質の一部を沈殿させ;
c)処理した溶液のダイアフィルトレーションを伴う精密濾過を実施して、それぞれ精密濾過残留物および精密濾過液を得て;
d)TGFβが高度に濃縮されたタンパク質画分を含有する精密濾過残留物を回収し;さらに
e)ダイアフィルトレーションされた精密濾過残留物を乾燥させてTGFβが高度に濃縮された粉末を得る;
という工程を含んでなる。
総窒素性物質:10g/Kg
乾燥抽出物:10.4g/Kg
を有することが好ましい。
従って、タンパク質の96%が乾燥抽出物中にある。
本方法の工程a)
本方法の工程a)は、好ましくは溶液1キログラム当たり5〜30gタンパク質の濃度を得るためのタンパク質の浸透水での希釈工程からなる。
本プロセスの工程b)
工程b)は最初に乳漿タンパク質の豊富な液体、例えば、WPIに含まれていたTGF-βのほとんどすべてを含有するタンパク質画分の選択的沈殿を可能にする操作条件における乳漿タンパク質の分画沈殿工程からなる。
本プロセスの工程c)
工程b)で得られた沈殿していない乳漿タンパク質の溶液中にTGF-βを含有するタンパク質懸濁液をダイアフィルトレーションを伴って精密濾過する。
一方では、TGF-βが高度に濃縮された残留物;および
他方では、可溶性乳漿タンパク質を含有する精密濾過液
である。
・精密濾過残留物の回収
ダイアフィルトレーションを伴う精密濾過工程後、精密濾過残留物を回収し、これはTGF-βが高度に濃縮されたタンパク質画分となる。
・乳漿タンパク質の豊富な開始溶液を調製するための好ましい実施形態
本発明の有利な実施形態では、乳漿タンパク質の豊富な開始溶液は以下の工程:
i)均一な膜透過圧を可能にする装置において平均ポアサイズが0.1μmの膜でスキムミルクをクロスフロー精密濾過して精密濾過液を回収し;
ii)工程i)で得られた精密濾過液を、乳漿からタンパク質濃縮物を調製するために当業者によって頻繁に用いられるものなどの、5000ダルトンおよび20000ダルトンの間からなるカットオフを有する膜でダイアフィルトレーションを伴う限外濾過で濃縮し;さらに
iii)ダイアフィルトレーションされた限外濾過残留物を回収すること
によって得る。
・TGF-βが高度に濃縮されたタンパク質画分
本発明のもう1つの目的は、5μg/全タンパク質1gより高い活性型TGF-β2の濃度を含んでなることを特徴とする、TGF-βが高度に濃縮されたタンパク質画分からなることである。
・本発明の医薬組成物
本発明のもう1つの目的は、前記のとおりのTGF-βが高度に濃縮されたタンパク質画分を、必要に応じて1種以上の生理学上適合する賦形剤と組み合わせて含んでなる医薬組成物からなる。
50℃にて、乾物で92.9g/Kgの含有物およびN×6.38で35.4g/Kgの含有物を含む10,000Kgのスキムミルクを4.6m2および0.1μmのMembralox(登録商標)膜(アルミン-ジルコン)を含んでなり、0.6〜0.7バールの均一な膜透過圧などを得るための精密濾過液の同時循環機能を有する精密濾過装置に注入した。
実施例2 乳漿タンパク質の豊富な溶液から出発するTGF-βが高度に濃縮された画分の調製:
攪拌羽根装置を備えたタンクにおいて、20℃の温度にて200kgの実施例I、に従って得たダイアフィルトレーションされた残留物を浸透水で2000lに希釈した。
実施例3 本発明のTGF-βが高度に濃縮されたタンパク質画分の定量および定性分析:
実施例2で得た1mgの凍結乾燥粉末を1mlのミリQ水に溶解し、次いで、バッファーAで5倍希釈した。用いた分析装置は「source RPC3ml」カラム(Pharmacia(登録商標))を用いるWaters600E HPLCクロマトグラフであった。
バッファーB:アセトニトリル90%中のTFA0.09%。
Claims (19)
- 乳漿から活性型TGFβが濃縮されたタンパク質画分を得る方法であって、
a)前記乳漿のタンパク質を5および30g/溶液1リットルの間の濃度に調節し、
b)前記溶液の、4および5.5の間にわたるpHおよび55℃および68℃の間にわたる温度での酸処理によって前記乳漿の一部を沈殿させ;
c)沈殿した懸濁液を、0.8μmおよび1.6μmの間の平均ポアサイズを有する精密濾過膜で精密濾過して、精密濾過残留物を得て;
d)精密濾過残留物にダイアフィルトレーションを実施して、ダイアフィルトレートされた精密濾過残留物を得て、
e)TGFβが高度に濃縮されたタンパク質画分を含んでなる精密濾過残留物を回収し;さらに
f)前記のダイアフィルトレートされた精密濾過残留物を乾燥させてTGFβが濃縮された粉末を得る;
という工程を含んでなる方法。 - 前記沈殿工程b)を4および5の間からなるpHで、好ましくは、pH 4.6で実施する請求項1に記載の方法。
- 前記沈殿工程b)を63℃の温度で実施する請求項1または2に記載の方法。
- 前記沈殿工程b)を30秒および10分の間、最も好ましくは約2分で実施する請求項1〜3に記載の方法。
- 工程b)の最後に前記液体溶液を1分から20分で迅速に冷却する請求項1〜4に記載の方法。
- 前記の工程d)のダイアフィルトレーションを浸透または鉱質除去濾過水を用いて実施する請求項1〜5に記載の方法。
- 前記の精密濾過およびダイアフィルトレーションを4および5.5の間のpH、好ましくは約4.6で実施する請求項1〜6に記載の方法。
- 前記の乳漿を、工程a)の前に以下の工程:
均一な膜透過圧を得ることができる装置において0.1μmの平均ポアサイズを有する精密濾過膜で乳漿のクロスフロー精密濾過を実施して精密濾過液を得、そしてこの精密濾過液を限外濾過およびダイアフィルトレーションによって濃縮して濃縮残留物を得ること、
で処理する請求項1〜7のいずれか1項に記載の方法。 - 請求項1〜8のいずれか1項に記載の方法によって得られたTGFβが濃縮されたタンパク質画分であって、全乳漿タンパク質1グラム当たり5μgより高い活性型のTGFβ2含量を含んでなるタンパク質画分。
- その他の乳漿タンパク質が主にα-ラクトアルブミンからなる請求項9に記載のタンパク質画分。
- 前記画分の全重量に対して45〜80重量%の間のα-ラクトアルブミンを含んでなる請求項10に記載のタンパク質画分。
- TGFβが濃縮されたタンパク質画分であって、この画分の全タンパク質1グラム当たり5μgより高い活性型のTGFβ2と、45〜80重量%の間のα-ラクトアルブミンと、10〜25重量%の間の免疫グロブリンと、11重量%以下のβ-ラクトグロブリンとを含有するタンパク質画分。
- 請求項9〜12のいずれか1項に記載のタンパク質画分を、必要に応じて1種以上の生理学的に適合する賦形剤と組み合わせて含んでなる医薬組成物。
- 紅斑性狼瘡、乾癬およびクローン病から選択される自己免疫疾患の治療または予防のための医薬品調合のための請求項9〜12に記載のタンパク質画分の使用。
- 関節リウマチ、骨関節炎、筋無力症またはブドウ膜炎の治療または予防のための医薬品調合のための請求項9〜12に記載のタンパク質画分の使用。
- 治癒促進のための医薬品調合のための請求項9〜12に記載のタンパク質画分の使用。
- 骨粗鬆症の治療または予防のための医薬品調合のための請求項9〜12に記載のタンパク質画分の使用。
- オンコスタチン様薬組成物の調合のための請求項9〜12に記載のタンパク質画分の使用。
- 移植片拒絶の予防または治療のための医薬品調合のための請求項9〜12に記載のタンパク質画分の使用。
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PCT/FR2002/002489 WO2003006500A1 (fr) | 2001-07-13 | 2002-07-12 | Procede d'obtention d'une fraction proteique enrichie en tgf-beta sous forme activee, fraction proteique et applications therapeutiques |
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JP2005506316A (ja) | 2005-03-03 |
US8937043B2 (en) | 2015-01-20 |
DE60210304D1 (de) | 2006-05-18 |
WO2003006500A1 (fr) | 2003-01-23 |
FR2827290B1 (fr) | 2004-07-09 |
GB0324873D0 (en) | 2003-11-26 |
AU2002329364B2 (en) | 2008-07-24 |
DK1409539T3 (da) | 2006-07-31 |
ATE321781T1 (de) | 2006-04-15 |
NZ529180A (en) | 2005-05-27 |
US20050250698A1 (en) | 2005-11-10 |
US20050250697A1 (en) | 2005-11-10 |
CA2434303A1 (fr) | 2003-01-23 |
ES2258154T3 (es) | 2006-08-16 |
DE60210304T2 (de) | 2006-12-07 |
EP1409539B1 (fr) | 2006-03-29 |
FR2827290A1 (fr) | 2003-01-17 |
US7141262B2 (en) | 2006-11-28 |
US20040097714A1 (en) | 2004-05-20 |
AU2002329364B8 (en) | 2008-12-04 |
EP1409539A1 (fr) | 2004-04-21 |
CA2434303C (fr) | 2013-05-14 |
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