JP5345532B2 - Lct中毒に対する医薬品 - Google Patents
Lct中毒に対する医薬品 Download PDFInfo
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- C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
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Description
本発明は、大クロストリジウム細胞毒(Large Clostridial Cytotoxins、LCTs)、特にクロストリジウムディフィシレ細胞毒素A及びB(TcdA及びTcdB)、クロストリジウムソルデリィラテレス毒素(TcsL)及びクロストリジウムノヴィα毒素(Tcnα)による中毒の回避又は軽減のための医薬品に関する。
TcdBアミノ酸配列P18177番(SwissProt/TrEMBL)の1665位のDXGモチーフ、
TcdBアミノ酸配列P18177番(SwissProt/TrEMBL)のアミノ酸位置AS1653〜AS1678、
TcdBアミノ酸配列P18177番(SwissProt/TrEMBL)のアミノ酸位置AS1500〜AS1800、
TcdAアミノ酸配列P16154番(SwissProt/TrEMBL)の1662位のDXGモチーフ、
TcdAアミノ酸配列P16154番(SwissProt/TrEMBL)のアミノ酸位置AS1651〜AS1675、
TcsLアミノ酸配列Q46342番(SwissProt/TrEMBL)の1666位のDXGモチーフ、
TcsLアミノ酸配列Q46342番(SwissProt/TrEMBL)のアミノ酸位置AS1654〜AS1679、
Tcnαアミノ酸配列Q46149番(SwissProt/TrEMBL)のアミノ酸位置AS1641〜AS1665、
本発明は、以下において、実施例及び図に基づきより詳細に説明される。図は、以下のことを示す:
図1:
a:Cy3標識化したTcdB10463及びブタ脾臓抽出物からの混合物(実施例1A)、
b:Cy3標識化したTcdB10463及びタンパク質不含のブタ脾臓抽出物からの混合物(実施例1B)、
c:Cy3標識化したTcdB10463及びイノシトールリン酸からの混合物、
d:標識化していないTcdB10463及びイノシトールリン酸からの混合物、
e:標識化していない(親和性クロマトグラフィにより精製した)TcdB10463及びイノシトールリン酸からの混合物;を用いて実施した、SDS−PAGEにおけるTcdB10463(270kDa)ホロトキシンの、トランスロケーション/リガンドドメイン(207kDa)及びN末端の触媒性ドメイン(63kDa)への開裂、
a−eはそれぞれ、室温で1時間のインキュベーションに関連する。
レーン1:EPNPを用いた前処理後、かつ、IP6無しのTcdB10463、63kDaの範囲中にバンドを検出できない、
レーン2:EPNPを用いた前処理後及びIP6を用いたインキュベーション後の前処理後のTcdB10463、この典型的な63kDaのバンドはわずかにのみ見える:
レーン3:EPNPを用いた前処理無しそしてIP6でのインキュベーション後のTcdB10463、これは、63kDaの分子量範囲中で顕著に際だったバンドが認識可能である;
レーン4:EPNPを用いた前処理無し、そしてIP無しでのTcdB10463、63kDa中にバンドは検出可能でない。
参照株VPI 10463のクロストリジウム細胞毒B(270kDa)、以下において短縮してTcdB10463と呼ぶ、をまずCy3で蛍光標識化した。このためには、200〜400μgのTcdB10463(tgcBIOMICS, Mainz, Germany)を着色剤Cy3で、この毒素をジメチルホルムアミド中に溶解した着色剤と一緒に1時間4℃でインキュベーションすることにより、製造者の指示(Amersham Biosciences)に応じて標識化した。結合していない着色剤を引き続き、サイズ排除クロマトグラフィ(Size Exclusion Chromatographie = SEC)を用いて取り除き、その際10mMのTris−HCl、pH8.5を展開緩衝液として使用した。着色剤とCy3標識化したTcdB10463のモル比は、0.8〜1.6であった。標識化したTcdB10463をアリコート採取し、−80℃で更なる使用まで貯蔵した。
TcDB10463を実施例1(D)中に記載したとおりにアフィニティクロマトグラフィを用いて、モノクローナル抗体2CVを使用して精製し、引き続き(i)プロテアーゼ阻害剤EPNP(10mM 1,2−エポキシ−3−(ニトロフェノキシ)−プロパン)を用いて又は(ii)対照として緩衝液(50mM HEPES、1M NaCl、1mM EDTA、pH8.0)を用いて、60分間室温で前処理した。
TcdB10463を、実施例1(C)中に記載されたのと同様に100μMのIP6でインキュベーションした。このインキュベーションに引き続き、このプロテアーゼ活性により分解されるより小さいな63kDaの毒素タンパク質の断片を、このバッチをマイクロコン管(Millipore, 排除サイズ100kD)を用いて精製することにより分離した。この63kDaのTcdB10463の断片を、引き続き実施例2中に記載された、Moos et al. (2000)に応じたCHO試験において細胞の丸み付けについて試験した。この際、このタンパク質を未希釈で、及び、希釈段階において細胞へと添加した。
EPNP不活性化した(参照、実施例2)及び未処理のTcdB10463を、SDSゲルを用いて分離し、かつ、亜鉛染色を用いて示した。引き続き、このタンパク質に相当するバンドを切断し、小さな破片に分解した。これらから着色剤を取り除き、乾燥させ、引き続き2mMのDTT中で還元し、20mMのヨードアセトアミドでアルキル化した。このゲル断片の洗浄及び新規の乾燥後に、この断片を、トリプシンを用いて一晩37℃で消化させた。この生じるペプチドを引き続きHPLC(NanoAcquity Ultraperformance Liquid Chromatography, Waters, Milford, USA)を介して分離した。このために2μlの試料を2%の移動相B緩衝液(アセトニトリル中0.1%ギ酸)中の逆相カラム(NanoEase BEH C18(75μm×10cm)、Waters, Milford, USA)に設けた。移動相A緩衝液は、H2O中に0.1%ギ酸を含有した。引き続きこの断片を3〜40%の移動相B緩衝液(300nl/分で90分間)の勾配によりカラムを通じて溶出した。
TcdBの細胞毒性効果に対する保護を誘導するために、以下のTcdB調製物を製造し、かつ、免疫化のためにウサギにおいて使用した。
調製物A:TcdB、ホルマリンで不活性化、
調製物B:TcdB、EPNPで不活性化(参照、実施例2)、
調製物C:TcdB断片AS1601〜1716(DSGモチーフ)、
調製物D:TcdB断片AS1508〜1601(イノシン結合性モチーフの部分)、
調製物E:TcdB断片AS1508〜2157
(DSGモチーフ及び全体のイノシン結合性モチーフ)。
文献:
Claims (4)
- 作用物質として、LCT(大クロストリジウム細胞毒)の自己触媒性プロテアーゼ活性の、少なくとも1種の活性化剤を含有し、その際、前記活性化剤が、イノシトール1,3,4−三リン酸(Ins(1,3,4)P3)、イノシトール1,3,4,5−四リン酸(Ins(1,3,4,5)P4)、イノシトール3,4,6−三リン酸(Ins(3,4,6)P3)、イノシトール1,2,3,4−四リン酸(Ins(1,2,3,4)P4)、イノシトール1,2,3,4,5−五リン酸(Ins(1,2,3,4,5)P5)、イノシトール1,2,3,5,6−五リン酸(Ins(1,2,3,5,6)P5)、イノシトール1,3,4,5,6−五リン酸(Ins(1,3,4,5,6)P5)、イノシトール3,4,5,6−四リン酸(Ins(3,4,5,6)P4)、イノシトール2,3,4,5,6−五リン酸(Ins(2,3,4,5,6)P5)、イノシトール1,4,5,6−四リン酸(Ins(1,4,5,6)P4)およびイノシトール六リン酸(IP6)からなる群から選択される、LCTによる中毒を回避又は軽減するための医薬品。
- 活性化剤が、イノシトール六リン酸(IP6)であることを特徴とする、請求項1記載の医薬品。
- LCTが、TcdA及び/又はTcdB及び/又はTcsL及び/又はTcnαであることを特徴とする、請求項1または2記載の医薬品。
- LCTによる中毒を回避又は軽減するための医薬品をスクリーニングする方法であって、LCTの自己触媒性プロテアーゼ活性を活性化する物質を同定する工程を含む、前記スクリーニング法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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DE102006036373.6 | 2006-08-02 | ||
DE102006036373A DE102006036373A1 (de) | 2006-08-02 | 2006-08-02 | Arzneimittel gegen LCT-Vergiftungen |
DE102007004938.4 | 2007-01-26 | ||
DE102007004938A DE102007004938A1 (de) | 2007-01-26 | 2007-01-26 | Arzneimittel gegen LCT-Vergiftungen |
PCT/DE2007/000957 WO2008014733A1 (de) | 2006-08-02 | 2007-05-26 | Arzneimittel gegen lct-vergiftungen |
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JP2012248267A Division JP5777594B2 (ja) | 2006-08-02 | 2012-11-12 | Lct中毒に対する医薬品 |
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JP5345532B2 true JP5345532B2 (ja) | 2013-11-20 |
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JP2012248267A Expired - Fee Related JP5777594B2 (ja) | 2006-08-02 | 2012-11-12 | Lct中毒に対する医薬品 |
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EP (1) | EP2054044B1 (ja) |
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AU2007280861B2 (en) * | 2006-08-02 | 2013-02-07 | Johannes Gutenberg-Universitat Mainz | Medicament for LCT poisoning |
EP2373332A1 (en) * | 2008-12-03 | 2011-10-12 | Boehringer Ingelheim Vetmedica GmbH | Process for production of vaccines |
CN105949234B (zh) * | 2011-09-29 | 2018-07-10 | 苏黎世联邦理工学院 | 用于治疗艰难梭菌感染的药物化合物 |
ES2704069T3 (es) | 2011-12-08 | 2019-03-14 | Glaxosmithkline Biologicals Sa | Vacuna basada en toxinas de Clostridium difficile |
RU2017127772A (ru) * | 2012-03-02 | 2019-02-04 | Регенерон Фармасьютикалз, Инк. | Человеческие антитела к токсинам clostridium difficile |
GB201206070D0 (en) | 2012-04-04 | 2012-05-16 | Health Prot Agency | Clostridium difficile antigens |
CN111499738B (zh) * | 2020-06-03 | 2022-04-05 | 郑州师范学院 | 一种抗艰难梭菌肠毒素a的抗体 |
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Also Published As
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EP2054044B1 (de) | 2014-07-23 |
RU2465893C2 (ru) | 2012-11-10 |
JP2013067630A (ja) | 2013-04-18 |
RU2009107138A (ru) | 2010-09-10 |
JP2009545536A (ja) | 2009-12-24 |
EP2054044A1 (de) | 2009-05-06 |
UA96768C2 (uk) | 2011-12-12 |
AU2007280861A1 (en) | 2008-02-07 |
JP5777594B2 (ja) | 2015-09-09 |
CA2659684A1 (en) | 2008-02-07 |
US20150344531A1 (en) | 2015-12-03 |
WO2008014733A9 (de) | 2009-01-29 |
US20090311258A1 (en) | 2009-12-17 |
ES2507553T3 (es) | 2014-10-15 |
US20130280286A1 (en) | 2013-10-24 |
AU2007280861B2 (en) | 2013-02-07 |
US9066961B2 (en) | 2015-06-30 |
WO2008014733A1 (de) | 2008-02-07 |
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