JP2007504863A - アフェレーシス装置 - Google Patents
アフェレーシス装置 Download PDFInfo
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- JP2007504863A JP2007504863A JP2006525566A JP2006525566A JP2007504863A JP 2007504863 A JP2007504863 A JP 2007504863A JP 2006525566 A JP2006525566 A JP 2006525566A JP 2006525566 A JP2006525566 A JP 2006525566A JP 2007504863 A JP2007504863 A JP 2007504863A
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- apheresis
- nucleic acid
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Abstract
Description
a)カラム (内部) にAPP (等)をロードし、APP (等)をカラムに固定化する;
b) カラムの第一の末端からカラムの第二の末端へと移動する所定の体積流量のキャリア物質を供給して核酸混合物をカラムの第一の末端にアプライする;
c)核酸を結合させ固定化させる、ここでカラムの第一末端からの距離が大きくなると核酸のAPP (等)に対する親和性が低下する;
d)体積流量のキャリア物質のカラムの通過を規定の移動時間後に完了する;
e)カラムをいくつかに区切って分離しカラムセグメントを得る、ここで各セグメントは関連ランパス座標(an associated run-path coordinate)を付与される;
f)少なくとも1つのセグメントから、固定化核酸が非特異的に脱離し、そのセグメントに関連していたランパス座標(run-path coordinate)の分配により回収される。
「カラム内部に」という表現は、広い意味での内腔を意味する。「カラム」という表現は全てのタイプの固体担体システムを含み、完全に閉鎖していない担体システムでもよい。
図1はAβ42のペプチド 1208 (BSAに結合しており、ELISA プレートを被覆している)に対する結合を示す;
図2はペプチド 1208 (および1208-BSA)のAβ42 (ELISA プレートを被覆している)に対する結合を示す;
図3は、Aβ42の1208-BSAへの競合的結合を示す。
1.1 モノリシック構造カラム
CIM(登録商標)エポキシモノリシック構造カラム (BIA Separations、SI)を製造業者の指示にしたがって0.5 m Na リン酸バッファー (pH 8.0)で平衡化し、Aβペプチドに対するモノクローナル抗体を製造業者の指示にしたがって活性化し、CIM カラムに結合させる。カラムをリン酸バッファー (+ 1 M NaCl)で数回洗浄し、過剰のエポキシ基を所望によりブロックする。
アガロースバルク材料(セファロース CL4B)を無菌環境下で、無菌かつパイロジェン不含有容器に満たし、材料を無菌環境下で洗浄し、ゲル材料を各洗浄工程の間に減圧下で完全に乾燥する。次いで、セファロースをオートクレーブ中で30 分115℃で蒸気滅菌する。
糖尿病研究所(the institute for diabetes)において、「Gerhardt Katsch」という、小型化した体外のシステムが、小動物モデルラットにおいてアフェレーシス療法を適用するために開発されている。世界中で、かかるアフェレーシス試験システムは非常に限られた程度でしか利用できない。同じ被験動物に対する繰り返しのアフェレーシス治療および次いで療法の成功を評価するための追跡期間における実験は非常に新規であり、今まで世界中の文献に記載されたことはない。
3.1 トレシルクロリドによるシリカゲルカラムの活性化
カラムをアセトンですすぐ。活性化のために、無水溶液 (2 mlのアセトン、1 mlのトレシルクロリド、数滴のピリジン)をカラムに通し(カラム容積の10倍)、それを氷上で一晩インキュベートする。次いで、カラム容積の20倍の100% アセトン (無水)でカラムをすすぐ。活性化したカラムは1 mM HCl中で保存できる。
室温で、ポリエチレンチューブをカラム容積の20倍の溶液 (濃硫酸 (H2SO4)中の2% 過マンガン酸カリウム (KMnO4) (w/v))、次いで蒸留水ですすぐ。カラム表面でのさらなる結合(coupling)のために、二価または多価分子を架橋に用いることが出来、それは少なくとも1つの反応性アルデヒド基を含む (例えば、1% グルタルアルデヒド)。それらをカラムに4℃で1時間通す。次いで、反応を還元条件下で(例えば、 pH 3.9の0.15 M NaCl中のシアノホウ化水素ナトリウム (0.00025% w/v)によって)安定化する。
トレシルクロリド-活性化カラムを0.1 M Na2CO3 (pH 8.5)ですすぐ。結合(coupling)のために、ペプチドまたはタンパク質 (2 mg/ml 0.1 M Na2CO3、pH 8.5) をカラムに、37℃2時間、次いで氷上で4時間、数回通す。カラムの遊離結合部位をブロックするために、過剰の0.2 M グリシン、pH 8をカラムに通す。
活性化したカラムを0.1 M Na2CO3 (pH 8.5)ですすぐ。結合(coupling)の目的で、Aβ42 (2 mg/ml、0.1 M Na2CO3、pH 8.5) をカラムに37℃2時間、次いで氷上で4時間、数回通す。カラムの遊離結合部位をブロックするために、過剰の0.2 M グリシン、pH 8をカラムに通す。反応を促進するために、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド(EDC)、5% w/v、を添加してもよい。
トレシルクロリド-活性化カラムを0.1 M Na2CO3 (pH 8.5)ですすぐ。1または数個の一級または二級アミンを有する分子を排除の対象とする場合は、この分子、または混合物 (2 mg/ml 0.1 M Na2CO3、pH 8.5) を一晩室温で数回カラムに通す。カラムの遊離結合部位をブロックするために、さらに過剰の0.2 M グリシン、pH 8をカラムに通す。特定の1以上の一級または二級アミンを有する分子の排除が望ましくない場合は、カラムのすべての結合部位をグリシンでブロックする。
被覆されたカラムを漏出が起こらないように順番に連結する:第一は望ましくない分子の排除用のカラムであり、次はAβ42 カラムである。平衡化の目的で、好適なバッファー、例えば、バッファー溶液 (10 mM Tris-HCl、50 mM KCl、1.5 mM MgCl2およびゼラチン 0.001% (w/v) pH 8.3)を氷上で1時間カラムに通す。コンビナトリアル核酸ライブラリーの核酸を1 mlの同バッファー中に取り出し、95℃で10分間加熱して二本鎖を解離させ、その後それらを数回(4-30回)カラムに通す。次いでカラムを分離し、選択したバッファー(前記)で一晩氷上で洗浄する。流れ方向におけるカラムの分離は好適な切断道具で行った。
ペプチド 1208へのアミロイド-β-結合の分析のために、まずペプチドを担体タンパク質 (BSA)にペプチド濃度500 μMol (およそ1 mg/ml)で結合(coupling)させた。1208-BSA コンジュゲートをELISA プレートに結合させ、ここでウェルあたり100 ngのペプチドが結合した。ELISA プレートをPBS、1% BSAで満たし、その後、アミロイド-β(1-42)の結合を濃度範囲8-100ng/ウェルにて分析した。結合したアミロイド-βを特異的マウス抗体で検出した。最後に、結合したアミロイド-βの量を、ビオチン化抗-マウス抗体とストレプトアビジン結合ペルオキシダーゼを用いて定量した。基質としてABTSを用い、分析は405 nmの波長でELISA リーダーで行った(図1)。
Claims (4)
- 血液または血漿の流れと接触することが出来る固体担体を含むアフェレーシス装置であって、固体担体がアミロイド-β-前駆タンパク質(APP)-結合性受容体を含むことを特徴とする装置。
- APP-結合性受容体が、抗-APP 抗体、抗-Aβ40 抗体、抗-Aβ42 抗体、APP-結合性タンパク質、特にゲルゾリン、apoJまたはapoE、APP-結合性ペプチド、APP-結合性ガングリオシド、特に GM1、またはAPP-結合性核酸、特に アプタマー、またはこれら受容体の混合物から選択されることを特徴とする請求項1の装置。
- 担体が無菌パイロジェン不含有カラムであることを特徴とする請求項1または2の装置。
- アルツハイマー病の治療または予防を提供するための請求項1〜3のいずれかの装置の使用。
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JP2017523165A (ja) * | 2014-07-10 | 2017-08-17 | アフィリス・アクチェンゲゼルシャフトAffiris Ag | ハンチントン病の予防および/または処置における使用のための薬剤および方法 |
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US20100030196A1 (en) * | 2008-07-29 | 2010-02-04 | Medtronic, Inc. | Apheresis of a target molecule from cerebrospinal fluid |
US20100158893A1 (en) * | 2008-12-19 | 2010-06-24 | Baxter International Inc. | Systems and methods for obtaining immunoglobulin from blood |
US20110033463A1 (en) * | 2009-08-06 | 2011-02-10 | Medtronic, Inc. | Apheresis, administration of agent, or combination thereof |
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PT2579042E (pt) | 2011-10-04 | 2014-09-09 | Affiris Ag | Método para detecção de anticorpos específicos para a numa amostra biológica. |
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ATE382383T1 (de) | 2008-01-15 |
EP1663347B1 (de) | 2008-01-02 |
US20070026029A1 (en) | 2007-02-01 |
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AU2004271651A1 (en) | 2005-03-24 |
DE502004005851D1 (de) | 2008-02-14 |
CA2538305A1 (en) | 2005-03-24 |
AT413336B (de) | 2006-02-15 |
US7935252B2 (en) | 2011-05-03 |
PT1663347E (pt) | 2008-03-28 |
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CA2538305C (en) | 2011-05-24 |
ES2298789T3 (es) | 2008-05-16 |
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CN1867365A (zh) | 2006-11-22 |
PL1663347T3 (pl) | 2008-06-30 |
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