JP4638151B2 - 高分子コンジュゲート及びその製造方法 - Google Patents
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- JP4638151B2 JP4638151B2 JP2003570764A JP2003570764A JP4638151B2 JP 4638151 B2 JP4638151 B2 JP 4638151B2 JP 2003570764 A JP2003570764 A JP 2003570764A JP 2003570764 A JP2003570764 A JP 2003570764A JP 4638151 B2 JP4638151 B2 JP 4638151B2
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- 229940033134 talc Drugs 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
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- 239000000196 tragacanth Substances 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Description
従来の高分子コンジュゲートの形成方法においてはコンジュゲート形成過程が十分に制御されていない。従って、従来の高分子コンジュゲートは、通常、該コンジュゲートを構成するモノマー間のような空間的関係が均一でなく、ランダムであり、制御されておらず、前記高分子コンジュゲートは架橋反応の制御されていない組合せの原因となっている。本発明は特にコンジュゲート形成過程に高度の制御を与える。本発明は、改良されたコンジュゲート形成方法を用いる方法によりコンジュゲート形成過程を改良し、本発明の方法により製造された生成物(すなわち、コンジュゲート)を改良する。本発明の方法を水性条件下で実施することが好ましく、全体を水性条件下で実施することがより好ましい。好ましくは、水性条件はコンジュゲート形成される高分子の所望活性を維持するように選択される。本発明方法の実施態様では、ウシ胃腸アルカリホスファターゼの触媒活性を維持するように水性条件を選択する。
第1ステップ(1S)で、0.200ナノモルのSATA活性化RPEを得た。このステップのpHは反応を遅らすために後続のステップよりも低くし、RPEを連結前に支持体中に分散するようにした。各コンジュゲートの結合を最小限とし、均質産物を得るために前記コアタンパク質の固定化分子間の距離を長くすることが望ましい。0.200ナノモルの添加SATA活性化RPEのうち、0.168〜0.178ナノモルがEMCH活性化支持体に結合した。
生理学的緩衝食塩液中2.69mg/mlの抗体(500μl)に対して100mM トリエタノールアミン(pH7.7)(100ul)及びDMF中100mM GMBS(10ul)を添加した。室温で50分間後、混合物を5mM EDTAを含有する生理学的緩衝食塩液中に脱塩して、1.2mlを収集した。
100mM トリエタノールアミン(pH7.7)中10mg/mlのR−フィコエリトリン(200ul)に対して500mM EDTA(10μl)及び水中100mM 2−イミノチオラン(40μl)を添加した。室温で55分間後、混合物を5mM EDTAを含有する生理学的緩衝食塩液中に脱塩して、1.2mlを収集した。
フリットを取り付けたカラム中の酸化アガローススラリー(2.0ml)を10mMリン酸ナトリウム、150mM 塩化ナトリウム、0.2% CHAPS、5mM EDTA(pH7.2)(PCE)で洗浄した。カラムに蓋を被せ、PCE(500μl)及びDMF中100mM EMCH(50μl)を添加し、混合物を撹拌し、室温で70分間放置した。次いで、カラムを排水し、PCE(2ml)及びTC8E(100mM トリス,0.2% CHAPS,5mM EDTA;pH8.0)(6ml)で洗浄し、氷浴中に置いた。ここにRS(566μl,4.0ナノモル)を添加し、混合物を渦巻き撹拌し、氷に置いた。時々渦巻き撹拌しながら15分間後、100mM MESNA(100μl)を添加した。混合物を渦巻き撹拌し、氷に置いた。5分間後カラムを排水し、TC8E(10ml)で洗浄した。カラムに蓋を被せ、AbM(1.0ml,9.4ナノモル)を添加した。混合物を渦巻き撹拌し、氷に置いた。時々渦巻き撹拌しながら15分間後、カラムを排水し、冷TC8E(5.5ml)で洗浄した。
Claims (15)
- a)反応性表面を用意するステップ、
b)前記反応性固体表面と安定な破壊性結合を形成し得る第1高分子を用意するステップ、
c)前記第1高分子を前記反応性固体表面と接触させて表面結合第1高分子複合体を形成するステップ、
d)固体表面を、第1高分子と非反応性とするステップ、
e)必要ならば、第1高分子及び/または第2高分子を活性化するステップ、
f)前記表面結合第1高分子を反応性第2高分子と接触させて固体表面:第1高分子:第2高分子安定複合体を形成するステップ、
g)液体媒体中で固体表面と第1高分子コンジュゲートとの間の安定な結合を破壊して第1高分子及び第2高分子を含む懸濁または可溶性高分子コンジュゲートを得るステップ
を含み、前記第1高分子は第2高分子と相互作用し得る反応性部分を複数含み、および前記第2高分子は第1高分子と相互作用し得る反応性部分を複数含む、懸濁または可溶性高分子コンジュゲートの製造方法であって、
第1高分子を第2高分子と結合させる反応をしない第1高分子上の残存反応性部分または第2高分子上の残存反応性部分をキャッピング化合物を用いて失活させる、前記方法。 - 第1高分子が破壊性共有結合を介して固体表面に結合している、請求の範囲第1項に記載の方法。
- 第2高分子が二官能性リンカーを介して第1高分子に結合している、請求の範囲第1項に記載の方法。
- 二官能性リンカーがN−スクシンイミジルS−アセチルチンプロピオネート、N−スクシンイミジルS−アセチルチオアセテート、2−イミノチオラン(Trauts試薬)、4−スクシンイミジルオキシカルボニル−メチル−(2−ピリジルジチオ)−トルエンスルホスクシンイミジル、4−[N−マレイミドメチル]−シクロヘキサン−1−カルボキシレート、N−[γ−マレイミドブチリルオキシ]スルホスクシンイミドエステル、N−(K−マレイミドウンデカノイルオキシ)スルホスクシンイミドエステル、マレイミド酢酸N−ヒドロキシスクシンイミドエステル、N−(ε−マレイミドカプロン酸)ヒドラジド、N−(K−マレイミドウンデカン酸)ヒドラジド、N−(β−マレイミドプロピオン酸)ヒドラジド及び3−(2−ピリジルジチオ)プロピオニルヒドラジドからなる群から選択される請求の範囲第3項に記載の方法。
- 第1高分子がタンパク質であり、前記タンパク質が反応性スルフヒドリル部分を含み、固体表面がヒドラゾン結合を介して該表面に結合したマレイミド部分を含む、請求の範囲第4項に記載の方法。
- 更に、結合した固体表面:第1高分子:第2高分子を、前記第2高分子と反応性の第3高分子と接触させて、第2高分子を介して第1高分子に連結させた少なくとも1単位の第3高分子を含む表面結合複合体を形成することを含み、前記第1高分子及び前記第3高分子は同一でも異なっていてもよい、請求の範囲第3項に記載の方法。
- 更に、第2高分子を、第3高分子と接触させた後、複合体中の第2高分子上の反応しなかった反応性部分を第3高分子上の使用した反応性部分に対して非反応性とするような、十分な失活試薬を添加するかまたは充分な条件下に表面結合複合体を置くこと、
反応に添加した追加高分子上の反応性部分が失活しないように過剰量の失活試薬を除去するか上記条件を変化させること、および
第3高分子と第4高分子間に結合を形成するのに十分な条件下に表面結合複合体と第4高分子を接触させること
を含み、前記第2高分子及び前記第4高分子は同一でも異なっていてもよい、請求の範囲第6項に記載の方法。 - 更に、高分子を1回またはそれ以上逐次添加することを含む、請求の範囲第6項に記載の方法。
- 固体表面がアガロース、ポリアクリルアミド及びポリスチレンからなる群から選択され、前記固体支持体上の反応性部分がヒドラゾン基を介して前記支持体に連結されたマレイミドであり、第1高分子がスルフヒドリル基とマレイミド基の反応により形成されたチオエーテル基を介して固体支持体上のマレイミドに連結されている、請求の範囲第1項に記載の方法。
- 固体表面と第1高分子コンジュゲート間の安定結合が、該結合を破壊性結合に対して特異的な試薬と接触させることにより破壊され、それによって前記コンジュゲートが固体表面から遊離させる、請求の範囲第1項に記載の方法。
- 結合の破壊により高分子コンジュゲートの第1高分子上にヒドラジドを生成させ、前記ヒドラジドをコンジュゲートの特性を変化させるための化合物と反応させることを更に含む、請求の範囲第10項に記載の方法。
- キャッピング化合物が双イオン性である、請求の範囲第1項に記載の方法。
- キャッピング化合物がデキストラン、ポリエチレングリコール及びポリサッカライドからなる群から選択するポリマーである、請求の範囲第1項に記載の方法。
- キャッピング化合物がポリペプチド及び核酸からなる群から選択されるポリマーである、請求の範囲第1項に記載の方法。
- 第1高分子を、固体表面と反応するが第2高分子と反応しない第2分子を含む組成物の形態で用意する請求の範囲第1項に記載の方法。
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US10/062,131 US20030149246A1 (en) | 2002-02-01 | 2002-02-01 | Macromolecular conjugates and processes for preparing the same |
PCT/US2002/040285 WO2003072017A2 (en) | 2002-02-01 | 2002-12-16 | Macromolecular conjugates and processes for preparing same |
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GB0314209D0 (en) * | 2003-06-19 | 2003-07-23 | Amersham Biosciences Ab | Novel MS reagents |
WO2005095331A1 (ja) * | 2004-03-31 | 2005-10-13 | Shionogi & Co., Ltd. | 糖鎖-ペプチド結合剤 |
US20060135459A1 (en) * | 2004-11-09 | 2006-06-22 | Epstein Alan L | Targeted innate immunity |
EP1877101B1 (en) | 2005-04-28 | 2016-11-16 | Ventana Medical Systems, Inc. | Enzymes conjugated to antibodies via a peg heterobifuctional linker |
EP1951316B1 (en) | 2005-11-23 | 2015-08-19 | Ventana Medical Systems, Inc. | Molecular conjugate |
FR2909881A1 (fr) * | 2006-12-14 | 2008-06-20 | Inst Nat Sante Rech Med | Nouveaux conjugues, utilisables a des fins therapeutiques, et/ou a titre d'agent de diagnostic et/ou d'imagerie et leur procede de preparation |
WO2010006604A1 (en) * | 2008-07-16 | 2010-01-21 | Radiometer Medical Aps | High capacity solid phase |
CN102216779B (zh) * | 2008-10-13 | 2013-11-27 | 泽普塔根股份公司 | 免疫缀合物的制备方法及其应用 |
US9910040B2 (en) | 2012-07-09 | 2018-03-06 | Sevident, Inc. | Molecular nets comprising capture agents and linking agents |
US9733242B2 (en) | 2012-10-07 | 2017-08-15 | Sevident, Inc. | Devices for capturing analyte |
AU2014236090B2 (en) * | 2013-03-14 | 2019-09-12 | Inoviq Inc. | Molecular nets on solid phases |
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NZ212437A (en) * | 1985-06-17 | 1992-06-25 | Mark Philip Best | Site-directed antibody conjugates, and their preparation |
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US5057313A (en) * | 1986-02-25 | 1991-10-15 | The Center For Molecular Medicine And Immunology | Diagnostic and therapeutic antibody conjugates |
ES2073394T3 (es) * | 1987-06-10 | 1995-08-16 | Dana Farber Cancer Inst Inc | Constructos de anticuerpos bifuncionales y su utilizacion para destruir selectivamente las poblaciones celulares. |
ATE192465T1 (de) * | 1987-10-28 | 2000-05-15 | Florey Howard Inst | Oligonucleotid-polyamid konjugate |
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US5474765A (en) * | 1992-03-23 | 1995-12-12 | Ut Sw Medical Ctr At Dallas | Preparation and use of steroid-polyanionic polymer-based conjugates targeted to vascular endothelial cells |
SE9503380D0 (sv) * | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
US5876995A (en) * | 1996-02-06 | 1999-03-02 | Bryan; Bruce | Bioluminescent novelty items |
US6759036B1 (en) * | 1997-03-28 | 2004-07-06 | The Picower Institute For Medical Research | Fibrocyte-base vaccine formulations |
JP3524401B2 (ja) * | 1998-09-16 | 2004-05-10 | 株式会社ニチレイ | 酵素抗体複合体およびその製造方法 |
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US7985601B2 (en) * | 2002-03-08 | 2011-07-26 | The Regents Of The University Of California | Tunable, semi-interpenetrating polymer networks (sIPNS) for medicine and biotechnology |
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- 2002-12-16 WO PCT/US2002/040285 patent/WO2003072017A2/en active Search and Examination
- 2002-12-16 EP EP02799950A patent/EP1478927A4/en not_active Ceased
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WO2003072017A3 (en) | 2004-09-23 |
US20090203842A1 (en) | 2009-08-13 |
WO2003072017A2 (en) | 2003-09-04 |
US20030149246A1 (en) | 2003-08-07 |
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