JP2008263991A - 修飾されたアネキシン蛋白質および血栓症を防ぐための方法 - Google Patents
修飾されたアネキシン蛋白質および血栓症を防ぐための方法 Download PDFInfo
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Abstract
【解決手段】血栓症を変調させる修飾アネキシン蛋白質をスクリーニングする方法であって、a)血栓症試験システムを、血栓症を許容する条件下で、少なくとも一つの修飾されたアネキシン蛋白質に接触させ;b)上記試験修飾アネキシン蛋白質の存在下で抗血栓活性を評価し;そしてc)試験修飾アネキシン蛋白質の存在下での抗血栓活性を、試験修飾アネキシン蛋白質の不在下での抗血栓活性と比較し、試験修飾アネキシン蛋白質の存在下での抗血栓活性の変化が血栓症を変調させる修飾アネキシン蛋白質の指標である、上記方法が提供される。
【選択図】 図1
Description
本発明は、一般に、血栓症を治療するための方法及び組成物に関する。特定すれば、本発明は、修飾されたアネキシン蛋白質およびそれらの使用方法に関する。
血栓症は、血管の中の血液クロット(血栓)の形成、成長又は存在であり、最も共通の重度の医学上の障害である。動脈の血栓症の最も頻繁な例は冠動脈の血栓症であり、冠動脈の閉塞を導いて、しばしば心筋梗塞(心臓発作)を導く。130万人より多い患者が北米において毎年心筋梗塞のために病院に入院する。標準の治療は点滴による血栓溶解蛋白質はの投与である。急性の心筋梗塞の血栓溶解治療は治療された1000人の患者あたり30人の生命を救うと見積もられる;にもかかわらず、この障害の30日の死亡率が実在したままである(Mehta et al.,Lancet 356:449−454(2000)、引用により本明細書に編入される)。全量一回投与(bolus)の注射による抗血栓剤及び血栓溶解剤の投与が便利なのは、付加的な利益を伴う病院への入院の前に使用されるかもしれないからである(Rawles,J.Am.Coll.Cardiol.30:1181−1186(1997)、引用により本明細書に編入される)。しかしながら、全量一回投与(bolus)は(より漸次の静脈内点滴とは対照的に)、大脳の出血の危険を顕著に増加させる(Mehta et al.,2000)。出血なしに血栓症を防ぐか及び/又は血栓溶解を増加させることができる薬剤の開発が望まれる。
発明の概要
本発明は、出血を増加させることなく動脈又は静脈の血栓症を防ぐための組成物及び方法を提供する。組換えヒトアネキシン、好ましくはアネキシンVを、血管区画内でのその半減期を延長させるように修飾する。これは様々な様式により達成できる;3つの好ましい態様は、ポリエチレングリコールにカップリングさせたアネキシン、アネキシンのヘテロポリマー又はホモポリマー、及びアネキシンと別の蛋白質(例えば、イムノグロブリンのFc部分)との融合蛋白質である。修飾されたアネキシンは高い親和性をもって、活性化された血小板又は損傷した細胞の表面上のホスファチジルセリンに結合し、それにより、Gas6並びに前凝血蛋白質の結合及びプロトロンビナーゼ複合体の形成を防ぐ。修飾されたアネキシンは、よって、血小板の凝固が増幅される細胞機構及び体液機構の両方を阻害して、それにより血栓症を防ぐ。
発明の詳細な説明
本発明は、出血を増加させることなく哺乳類において血栓症を防ぐための化合物及び方法を提供する。発明は、血小板凝集の主要な機構が動脈と静脈の血栓の形成に必要な血小板凝集を増幅させる機構とは異なるという認識に一部基づく。血栓の形成は阻害するが主要な血小板の凝集は阻害しないことにより、血栓症が出血の増加なしに防ぐことができる。
別の態様において、アネキシン遺伝子は、配列番号:1に類似であるが同一ではない配列を含む全ての対立遺伝子バリアントであり得る。配列番号:1を含むアネキシン遺伝子の全ての対立遺伝子バリアントは、配列番号:1を含むが、例えば変異又は組換えにより引き起こされる天然の変化により類似ではあるが同一ではない配列を有する遺伝子として、ゲノム内の同じ位置(又は座)にて本質的に生じる遺伝子である。対立遺伝子バリアントは、典型的には、それらが比較される遺伝子によりコードされる蛋白質と類似の活性を有する蛋白質をコードする。蛋白質バリアントは、遺伝子の5’又は3’未翻訳領域内の変化も含み得る(例えば、制御調節領域中)。対立遺伝子バリアントは、当業者にはよく知られており、既知の(given)ヒトにおいて見いだされることが予測されるはずであるが、ゲノムが二倍体であり、及び又は、2人又はそれ以上のヒトを含む集団の間の中にあるからである。
修飾されたアネキシン核酸分子又は遺伝子
本発明の別の態様は、アネキシンVのホモダイマーのような修飾されたアネキシン蛋白質をコードする遺伝子にストリンジェントな条件下でハイブリダイズできる、単離された核酸分子である。そのような核酸分子は、修飾されたアネキシン核酸分子とも呼ばれる。特に好ましいのは、ストリンジェント条件下で修飾されたアネキシン遺伝子とハイブリダイズする単離された核酸分子である。そのような遺伝子の特性は、本明細書に開示される。本発明によれば、単離された核酸分子は、その天然環境から取り出された核酸分子である(即ち、人の操作に供された)。そいうものとして、「単離された」は、上記核酸分子が精製された程度を反映しない。単離された核酸分子は、DNA、RNA,又はDNA又はRNAの何れかの誘導体を含み得る。
天然野生型細菌細胞及び組換え分子及び細胞
本発明は、上記核酸分子を宿主細胞へ送達することができるあらゆるベクターに挿入された本発明の修飾されたアネキシン核酸分子を含む、組換えベクターも含む。そのようなベクターは、異種核酸配列、即ち本発明の修飾されたアネキシン核酸分子に隣接した、天然では見いだされない核酸配列を含む。当該ベクターは、RNA又はDNAの何れか、原核又は真核の何れか、そして典型的にはウイルス又はプラスミドであり得る。組換えベクターは、本発明の修飾されたアネキシン核酸分子のクローン化、配列決定、及び/又は他の操作において使用することができる。本明細書において組換え分子と呼ばれて以下に詳細に説明される一つの種類の組換えベクターを、本発明の核酸分子の発現において使用することができる。好ましい組換えベクターは、形質転換された細胞中で複製することができる。本発明の組換えベクター中に含まれる好ましい核酸分子は、本明細書に開示される。
抗体
本発明は、単離された抗−修飾アネキシン蛋白質及びそれらの用途も含む。抗−修飾アネキシン抗体は、修飾されたアネキシン蛋白質に選択的に結合できる抗体である。単離された抗体は、それらの天然の環境から取り出された抗体である。用語「単離された」は、そのような抗体の精製の状態を意味しない。そういうものとして、単離された抗体は、そのような抗体を含む抗体血清、又は程度を変えて精製された抗体を含む。本明細書にて使用されるとおり、用語「選択的に結合する」は、抗体を生じさせた蛋白質に好適に結合するそのような抗体の能力を意味する(即ち、混合物中の無関係の成分からその蛋白質を識別することができる)。結合親和性は、平衡結合定数として共通に表現されるが、典型的には、約103M-1から約1012M-1の範囲である。結合は、当業者に知られている様々な方法を用いて測定することができ、例えば、イムノブロットアッセイ、免疫沈殿アッセイ、放射免疫アッセイ、酵素免疫アッセイ(例えば、ELISA)、免疫蛍光抗体アッセイ及び免疫電子顕微鏡を含み;例えば、Sambrook et al.,1989を参照されたい。
治療方法
上記の修飾されたアネキシン蛋白質の何れもが、発明の方法において使用することにより、あらゆる医療上の手法又は条件により引き起こされる動脈又は静脈の血栓症を治療する。一般的に、発明において使用され治療剤は、有効量にて動物に投与される。一般的に、有効な量は、(1)治療されることが求められる疾患の兆候を軽減するか又は(2)治療されることが求められる疾患を治療することに関連して薬学上の変化を誘導するかの何れかに有効な量である。
実施例1:修飾されたアネキシンの製造
アネキシンは、ヒトの組織から精製するか又は組換え技術により生産することができる。例えば、アネキシンVは、Funakoshi et al(1987)により記載されたとおりにヒト胎盤から精製することができる。組換え生成物の例は、Escherichia coli中のアネキシンIIとアネキシンVの発現である(Kang,H.−M.,Trends Cardiovasc.Med.9:92−102(1999);Thiagarajan and Benedict,1997,2000)。組換えVの迅速かつ有効な精製方法は、ホスファチジルセリン含有リポソームへのCa2+−増強結合に基づき、EDTAによるBerger,FEBS Lett.329:25−28(1993)に記載された。この手法は、固相支持体にカップリングされたホスファチジルセリンの使用により改善され得る。
アネキシンVは以下のアミノ酸配列を有する:
MALRGTVTDFSGFDGRADAEVLRKAMKGLGTDEDSILNLLTARSNAQRQQIAEEFKTLFGRDLVNDMKSELTGKFEKLIVALMKPSRLYDAYELKHAKLGAGTDEKVLTEILASRTPEELRAIKQAYEEEYGSNLEDDVVGDTSGYYQRMLVVLLQANRDPDTAIDDAQVELDAQALFQAGELKWGTDEEKFITILGTRSVSHLRRVFDKYMTISGFQIEETIDRETSGNLENLLLAVVKSIRSIPAYLAETLYYAMKGAGTDDHTLIRVIVSRSEIDLFNIRKEFRKNFATSLYSMIKGDTSGDYKKALLLLCGGEDD(*停止)(配列番号:3)。
ATGGCCCTGCGCGGCACCGTGACCGACTTCTCCGGCTTCGACGGCCGCGCCGACGCCGAGGTGCTGCGCAAGGCCATGAAGGGCCTGGGCACCGACGAGGACTCCATCCTGAACCTGCTGACCGCCCGCTCCAACGCCCAGCGCCAGCAGATCGCCGAGGAGTTCAAGACCCTGTTCGGCCGCGACCTGGTGAACGACATGAAGTCCGAGCTGACCGGCAAGTTCGAGAAGCTGATCGTGGCCCTGATGAAGCCCTCCCGCCTGTACGACGCCTACGAGCTGAAGCACGCCAAGCTGGGCGCCGGCACCGACGAGAAGGTGCTGACCGAGATCATCGCCTCCCGCACCCCCGAGGAGCTGCGCGCCATCAAGCAGGCCTACGAGGAGGAGTACGGCTCCAACCTGGAGGACGACGTGGTGGGCGACACCTCCGGCTACTACCAGCGCATGCTGGTGGTGCTGCTGCAGGCCAACCGCGACCCCGACACCGCCATCGACGACGCCCAGGTGGAGCTGGACGCCCAGGCCCTGTTCCAGGCCGGCGAGCTGAAGTGGGGCACCGACGAGGAGAAGTTCATCACCATCCTGGGCACCCGCTCCGTGTCCCACCTGCGCCGCGTGTTCGACAAGTACATGACCATCTCCGGCTTCCAGATCGAGGAGACCATCGACCGCGAGACCTCCGGCAACCTGGAGAACCTGCTGCTGGCCGTGGTGAAGTCCATCCGCTCCATCCCCGCCTACCTGGCCGAGACCCTGTACTACGCCATGAAGGGCGCCGGCACCGACGACCACACCCTGATCCGCGTGATCGTGTCCCGCTCCGAGATCGACCTGTTCAACATCCGCAAGGAGTTCCGCAAGAACTTCGCCACCTCCCTGTACTCCATGATCAAGGGCGACACCTCCGGCGACTACAAGAAGGCCCTGCTGCTGCTGTGCGGCGGCGAACGACTGA(配列番号:1)。
インビトロアッセイは、修飾されたアネキシン蛋白質が活性化された血小板に結合する能力を決定する。アネキシンVは血小板に結合し、この結合は血栓による血小板の活性化によりインビトロにおいて顕著に増加する(Thiagarajan and Tait,1990;Sun et al.,1993)。好ましくは、本発明の修飾されたアネキシン蛋白質は、それらが血小板に結合して蛋白質Sが血小板に結合するのを防ぐことにおいて、アネキシンの機能を果たすような方法で製造される(Sun et al.,1993)。修飾されたアネキシン蛋白質は、未修飾のアネキシン蛋白質が呈するのと同じ抗凝血活性をインビトロにて呈する機能も果たす。クロット形成時間を測定する方法は、活性化された部分的なトロンボプラスチン時間である(Fritsma,in Hemostasis and thrombosis in the clinical laboratory(Corriveau,D.M.and Fritsma,G.A.,編纂)J.P.Lipincott Co.,Philadelphia(1989),pp.92−124,引用により本明細書に編入される)。
ヒト組換えアネキシンV及びペギル化ヒト組換えアネキシンVの抗凝血能力をインビトロにて比較した。
アネキシンV生産。ポリメラーゼ鎖反応を用いて、ヒト胎盤cDNAライブラリーからの特定のオリゴヌクレオチドプライマーを用いて、イニシエーターメチオニンから停止コドンまでのcDNAを増幅した。フォワードプライマーはACCTGAGTAGTCGCCATGGCACAGGTTCTC(配列番号:7)であり、そしてリバースプライマーはCCCGAATTCACGTTAGTCATCTTCTCCACAGAGCAG(配列番号:8)であった。増幅された1.1kbの断片をNcoIとEcoRIにより消化して、原核発現ベクターpTRC99Aに連結した。連結生成物を用いて、コンピテントなEscherichia coli株JM105を形質転換して、配列決定した。
抗−凝血アッセイ。
アネキシンV及びペギル化されたアネキシンVにより誘導されたクロット形成時間(活性化された部分的なトロンボプラスチン時間)の延長を比較した。活性化された部分的なトロンボプラスチン時間を、Fritsma,1989において記載されたとおりに、クエン酸化された正常なプールされた血漿とアッセイした。異なる濃度の上記のとおりに生成されたアネキシンV及びペギル化されたアネキシンVを用いて、クロット形成時間の延長に関する用量応答曲線を得た。結果を図2に示すが、クロット形成時間対アネキシンV及びペギル化されたアネキシンVのプロットである。当該図面において示されるとおり、組換えヒトアネキシンVとペギル化組換えヒトアネキシンVの抗凝血能力は実質等価であった。観察された小さな違いは、ペギレーション後の分子量の変化に帰する。この実験は、アネキシンVのペギレーションがその抗凝血作用を実質上減じることなしに達成できるという、本明細書になされた主張を確認する。
Claims (5)
- 血栓症を変調させる修飾アネキシン蛋白質をスクリーニングする方法であって、
a)血栓症試験システムを、血栓症を許容する条件下で、少なくとも一つの修飾されたアネキシン蛋白質に接触させ;
b)上記試験修飾アネキシン蛋白質の存在下で抗血栓活性を評価し;そして
c)試験修飾アネキシン蛋白質の存在下での抗血栓活性を、試験修飾アネキシン蛋白質の不在下での抗血栓活性と比較し、試験修飾アネキシン蛋白質の存在下での抗血栓活性の変化が血栓症を変調させる修飾アネキシン蛋白質の指標である、上記方法。 - 血栓症試験システムが、活性化された部分的なトロンボプラスチン時間を測定するシステムである、請求項1記載の方法。
- 請求項1記載の方法により同定された、血栓症を変調させる、修飾されたアネキシン蛋白質。
- アネキシン活性に関して修飾アネキシン蛋白質を同定する方法であって、
a)活性化された血小板を、結合を許容する条件下で、少なくとも一つの修飾されたアネキシン蛋白質に接触させ;
b)上記血小板の試験修飾アネキシン蛋白質−結合活性を評価し;
c)上記試験修飾アネキシン蛋白質の存在下での蛋白質S−結合活性を評価し;そして
d)試験修飾アネキシン蛋白質の存在下での試験修飾アネキシン−結合活性と蛋白質−S結合活性を、未修飾のアネキシン蛋白質の存在下での未修飾アネキシン−結合活性と蛋白質S−結合活性と比較し、アネキシン活性を有する修飾されたアネキシン蛋白質を同定する、上記方法。 - 請求項4記載の方法により同定された、修飾されたアネキシン蛋白質。
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Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7645739B2 (en) * | 2001-02-21 | 2010-01-12 | Alavita Pharmaceuticals, Inc. | Modified annexin compositions and methods of using same |
US20090291086A1 (en) * | 2001-02-21 | 2009-11-26 | Alavita Pharmaceuticals, Inc. | Compositions and Methods for Treating Cerebral Thrombosis and Global Cerebral Ischemia |
US7635676B2 (en) * | 2001-02-21 | 2009-12-22 | Alavita Pharmaccuticals, Inc. | Modified annexin proteins and methods for their use in organ transplantation |
US20050222030A1 (en) * | 2001-02-21 | 2005-10-06 | Anthony Allison | Modified annexin proteins and methods for preventing thrombosis |
DE10162434A1 (de) * | 2001-12-18 | 2003-09-25 | November Ag Molekulare Medizin | Expressionsvektor und Verfahren zur Herstellung eines Expressionsvektors |
WO2005023096A2 (en) * | 2003-09-09 | 2005-03-17 | Point Biomedical Corporation | Methods and compositions for ultrasound imaging of apoptosis |
CA2559167A1 (en) * | 2004-03-11 | 2005-09-22 | Alavita, Inc. | Modified annexin proteins and methods for preventing thrombosis |
DE602005018914D1 (de) * | 2004-04-15 | 2010-03-04 | Athera Biotechnologies Ab | Annexin zur prävention von der ruptur des plaques |
US7393833B2 (en) * | 2005-03-09 | 2008-07-01 | The Board Of Regents Of The University Of Oklahoma | Chimeric proteins with phosphatidylserine binding domains |
CA2656063C (en) | 2006-06-21 | 2016-10-18 | Musc Foundation For Research Development | Targeting complement factor h for treatment of diseases |
KR100835879B1 (ko) | 2006-10-10 | 2008-06-09 | 학교법인 한림대학교 | 아넥신 융합 단백질 |
CN101015686B (zh) * | 2007-02-06 | 2010-05-19 | 中国人民解放军军事医学科学院基础医学研究所 | 一种溶栓药物增效剂及其制备方法 |
WO2009105231A1 (en) | 2008-02-20 | 2009-08-27 | The General Hospital Corporation | Compositions and methods for treating vascular disorders |
DK3216457T3 (da) | 2008-02-22 | 2019-07-15 | Annexin Pharmaceuticals Ab | Forbindelser og fremgangsmåder til forebyggelsen eller behandlingen af restenose |
EP2123258A1 (en) * | 2008-05-23 | 2009-11-25 | Liplasome Pharma A/S | Liposomes for drug delivery |
US8431521B2 (en) | 2008-10-03 | 2013-04-30 | Advanced Proteome Therapeutics, Inc. | Site-specific chemical modification of proteins at their N-termini, enabling the formation of homogeneous adducts |
EP3805758A1 (en) | 2008-12-19 | 2021-04-14 | Medirista Biotechnologies AB | Oxidized cardiolipin as a novel pro-inflammatory factor |
CA2767105A1 (en) | 2009-07-02 | 2011-01-06 | Musc Foundation For Research Development | Methods of stimulating liver regeneration |
MX2012005151A (es) | 2009-11-05 | 2012-08-23 | Federico Ii University Of Naples | Tratamiento de hemoglobinuria nocturna paroxismica, anemias hemoliticas y estados de enfermedad que involucran hemolisis intravascular y extravascular. |
US9650447B2 (en) | 2010-05-14 | 2017-05-16 | The Regents Of The University Of Colorado, A Body Corporate | Complement receptor 2 (CR2) targeting groups |
SG186397A1 (en) | 2010-06-22 | 2013-01-30 | Univ Colorado Regents | Antibodies to the c3d fragment of complement component 3 |
JP5584026B2 (ja) * | 2010-07-02 | 2014-09-03 | 株式会社ダイヘン | 抵抗溶接制御方法 |
CN102690345B (zh) * | 2011-03-24 | 2014-03-19 | 江苏靶标生物医药研究所有限公司 | 人膜联蛋白v变体及其表达、制备和应用 |
DK2694538T3 (da) | 2011-04-05 | 2017-01-02 | Annexin Pharmaceuticals Ab | Terapeutiske og profylaktiske fremgangsmåder, anvendelser og sammensætninger omfattende anexin a5 |
WO2014028865A1 (en) | 2012-08-17 | 2014-02-20 | The Regents Of The University Of Colorado, A Body Corporate | Compositions and methods for detecting complement activation |
US10413620B2 (en) | 2012-08-17 | 2019-09-17 | The Regents Of The University Of Colorado, A Body Corporate | Light-emitting versions of the monoclonal antibody to C3D (MAB 3D29) for imaging |
WO2016205062A1 (en) * | 2015-06-15 | 2016-12-22 | Shifa Biomedical Corporation | Antithrombotic therapies |
GB2542391A (en) | 2015-09-17 | 2017-03-22 | Annexin Pharmaceuticals Ab | Process of manufacture |
CN105906800A (zh) * | 2016-05-06 | 2016-08-31 | 中国科学院长春应用化学研究所 | 一种基因传递系统及其制备方法 |
CA3034105A1 (en) | 2016-09-23 | 2018-03-29 | Csl Limited | Coagulation factor binding proteins and uses thereof |
GB201702144D0 (en) | 2017-02-09 | 2017-03-29 | Annexin Pharmaceuticals Ab | Therapeutic compositions |
CN114672483B (zh) * | 2022-05-31 | 2022-09-02 | 上海百力格生物技术有限公司 | 超声法核酸探针制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05508664A (ja) * | 1991-05-09 | 1993-12-02 | ボード・オブ・リージェンツ・オブ・ザ・ユニヴァーシティ・オブ・ワシントン | リン脂質標的血栓溶解剤 |
US5612460A (en) * | 1989-04-19 | 1997-03-18 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
WO1998031383A1 (en) * | 1997-01-15 | 1998-07-23 | Phoenix Pharmacologics, Inc. | Modified tumor necrosis factor |
JP2000504210A (ja) * | 1995-12-27 | 2000-04-11 | ジェネンテク・インコーポレイテッド | 半減期の長いobタンパク質誘導体 |
JP2001500116A (ja) * | 1996-07-26 | 2001-01-09 | ネオルクス コーポレイション | 放射線標識化アネキシン |
Family Cites Families (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
US4002531A (en) | 1976-01-22 | 1977-01-11 | Pierce Chemical Company | Modifying enzymes with polyethylene glycol and product produced thereby |
DE3315000A1 (de) | 1983-04-26 | 1984-10-31 | Behringwerke Ag, 3550 Marburg | Gewebeprotein pp(pfeil abwaerts)4(pfeil abwaerts), verfahren zu seiner gewinnung sowie seine verwendung |
US5066788A (en) | 1984-09-21 | 1991-11-19 | Boehringer Ingelheim International Gmbh | Blood coagulation inhibiting proteins, processes for preparing them and their uses |
DE3572179D1 (en) | 1984-09-21 | 1989-09-14 | Boehringer Ingelheim Int | Blood coagulation inhibiting proteins, process for preparing them and their use |
US4897355A (en) | 1985-01-07 | 1990-01-30 | Syntex (U.S.A.) Inc. | N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
CA1265446A (en) | 1985-09-30 | 1990-02-06 | Masahiro Maki | Anticoagulating substance, process for preparing same and anticoagulant comprising same as an effective component |
JPH08840B2 (ja) | 1986-11-14 | 1996-01-10 | 興和株式会社 | 抗pciモノクローナル抗体、これを用いた抗pciの精製法及び免疫学的測定法 |
DE3643182A1 (de) | 1986-12-18 | 1988-06-30 | Behringwerke Ag | Arzneimittel enthaltend das gewebeprotein pp4, verfahren zur herstellung von pp4 und zu seiner pasteurisierung sowie die verwendung von pp4 |
US4937324A (en) | 1987-02-06 | 1990-06-26 | Zymogenetics, Inc. | Chromatographic purification of human proteins having anticoagulant and anti-inflammatory activity |
JP2660514B2 (ja) | 1987-02-20 | 1997-10-08 | 興和株式会社 | 抗血液凝固作用を有するポリペプチド |
PT87083B (pt) * | 1987-03-28 | 1992-07-31 | Boehringer Ingelheim Int | Processo para a preparacao de uma proteina anticoagulante vascular, de adn que codifica para esta proteina e de composicoes farmaceuticas que a contem |
US4965251A (en) | 1987-04-03 | 1990-10-23 | The Board Of Regents Of The University Of Washington | Pulse treatment of hemoglobinopathies with erythropoietin |
DE3737239A1 (de) | 1987-11-03 | 1989-10-12 | Behringwerke Ag | Gentechnische herstellung von anticoagulatorischem protein pp4 |
ATE124087T1 (de) * | 1988-02-26 | 1995-07-15 | Biogen Inc | Dna-sequenzen, rekombinante dna-moleküle und verfahren zur herstellung von lipocortin iii, iv, v, und vi. |
ATE95189T1 (de) * | 1989-07-15 | 1993-10-15 | Boehringer Ingelheim Int | Verfahren zur reinigung von annexinen. |
DK0409052T3 (da) | 1989-07-15 | 1993-06-07 | Boehringer Ingelheim Int | Middel, der indeholder et antikoagulans |
DE3937607A1 (de) | 1989-11-11 | 1991-05-16 | Boehringer Ingelheim Int | Verwendung eines antikoagulanz zur behandlung von tumorerkrankungen |
DE3942081A1 (de) * | 1989-12-20 | 1991-06-27 | Behringwerke Ag | Mittel zur verbesserung der wiederfindung von annexinen |
US5627036A (en) * | 1989-12-27 | 1997-05-06 | Boehringer Ingelheim International Gmbh | Use of an anticoagulant as a diagnostic agent |
US5225537A (en) | 1989-12-29 | 1993-07-06 | Zymogenetics, Inc. | Methods for producing hybrid phospholipid-binding proteins |
WO1991016882A1 (en) | 1990-05-08 | 1991-11-14 | Liposome Technology, Inc. | Direct spray-dried drug/lipid powder composition |
EP0555328A1 (en) | 1990-11-02 | 1993-08-18 | Genentech, Inc. | Platelet aggregation inhibitors |
ES2143467T3 (es) * | 1990-11-20 | 2000-05-16 | Kowa Co | Agente terapeutico para el tratamiento de las heridas. |
JP2916947B2 (ja) * | 1990-11-28 | 1999-07-05 | 興和株式会社 | Cpb―iの安定化方法及び製剤組成物 |
US5229367A (en) * | 1991-01-21 | 1993-07-20 | Sclavo S.P.A. | Antiinflammatory peptide derived from human lipocortin V |
US5632986A (en) * | 1991-05-09 | 1997-05-27 | The University Of Washington | Phospholipid-targeted thrombolytic agents |
JPH051096A (ja) | 1991-06-26 | 1993-01-08 | Kowa Co | 抗血液凝固活性を持つオリゴペプチド |
EP1138334A3 (en) | 1992-06-09 | 2002-04-03 | Neorx Corporation | Pretargeting methods and compounds |
WO1994001554A1 (en) | 1992-07-08 | 1994-01-20 | N.V. Innogenetics S.A. | Polypeptides, derived from endonexin 2, having hepatitis b virus receptor activity and their use in diagnostic and pharmaceutical compositions |
JP3416912B2 (ja) | 1992-10-08 | 2003-06-16 | 興和株式会社 | 抗血液凝固活性を持つオリゴペプチド |
JPH0772149A (ja) | 1993-06-30 | 1995-03-17 | Nippon Shinyaku Co Ltd | 肝癌又は肝硬変の診断薬及び診断法 |
JPH0772147A (ja) | 1993-07-02 | 1995-03-17 | Noboru Kaneko | 抗アネキシンv抗体並びに該抗体の製法及び利用 |
US5849600A (en) * | 1993-11-10 | 1998-12-15 | The Mclean Hospital Corporation | Diagnostic assays for Alzheimer's disease |
US5747446A (en) * | 1994-03-22 | 1998-05-05 | Beth Israel Deaconess Medical Center | Modified polypeptides with increased biological activity |
EP0765166B1 (en) | 1994-06-16 | 2003-05-21 | Neorx Corporation | Radiolabeled annexin-galactose conjugates |
DE69513027T2 (de) | 1994-07-23 | 2000-03-16 | Roche Diagnostics Gmbh | Verfahren zur bestimmung des präthrombotischen status |
DE19541284C2 (de) | 1995-11-06 | 1998-09-24 | Kalden Joachim Robert Prof Dr | Verfahren zur Immunmodulation |
AU731924B2 (en) | 1996-07-05 | 2001-04-05 | Philip E. Branton | Adenovirus E4 proteins for inducing cell death |
AU736032B2 (en) | 1996-12-30 | 2001-07-26 | Innogenetics N.V. | Annexin V-binding polypeptides derived from HBsAg and their uses |
US6358508B1 (en) | 1997-06-11 | 2002-03-19 | Human Genome Sciences, Inc. | Antibodies to human tumor necrosis factor receptor TR9 |
US6242570B1 (en) | 1997-07-10 | 2001-06-05 | Beth Israel Deaconess Medical Center | Production and use of recombinant protein multimers with increased biological activity |
US6284475B1 (en) | 1997-07-11 | 2001-09-04 | Mount Sinai School Of Medicine Of The City Of New York | Assays for diagnosis of thrombophilic disease |
US6511829B1 (en) * | 1997-10-09 | 2003-01-28 | The Regents Of The University Of California | GFP-annexin fusion proteins |
EP1028742B1 (en) | 1997-11-06 | 2006-12-27 | Innogenetics N.V. | Apo b, annexin v and tubulin : medical, diagnostic and purification uses for hcv |
EP1064378A2 (en) | 1998-03-27 | 2001-01-03 | The Board Of Trustees Of The Leland Stanford Junior University | Hypoxia-inducible human genes, proteins, and uses thereof |
US6169078B1 (en) | 1998-05-12 | 2001-01-02 | University Of Florida | Materials and methods for the intracellular delivery of substances |
US20040002056A1 (en) * | 1998-05-12 | 2004-01-01 | Lorens James B. | Methods of screening for bioactive agents using cells transformed with self-inactivating viral vectors |
ATE230614T1 (de) * | 1998-07-13 | 2003-01-15 | Univ Texas | Krebsbehandlung mit aminophospholipide bindenden, therapeutischen konjugaten |
WO2000010673A1 (en) | 1998-08-24 | 2000-03-02 | Nst Neurosurvival Technologies Ltd. | Apparatus and method for capturing particles with surface exposure of anionic phospholipids from biological fluids |
IL125908A (en) | 1998-08-24 | 2005-05-17 | Nst Neurosurvival Technologies | Peptides and pharmaceutical compositions comprising same |
EP1107983A2 (en) | 1998-09-01 | 2001-06-20 | Innogenetics N.V. | Benzodiazepine and benzothiazepine derivatives and hbsag peptides binding to annexins, their compositions and use |
US6387366B1 (en) | 1998-12-31 | 2002-05-14 | Alg Company | Methods for reducing adverse side effects associated with cellular transplantation |
CN1125084C (zh) * | 1999-03-12 | 2003-10-22 | 中国科学院上海生物化学研究所 | 一种血栓靶向性溶栓融合蛋白 |
US6323313B1 (en) * | 1999-06-01 | 2001-11-27 | The University Of Washington | Annexin derivative with endogenous chelation sites |
US6645465B2 (en) | 1999-08-06 | 2003-11-11 | Michigan, University Of The Regents | Annexin proteins and autoantibodies as serum markers for cancer |
EP1610751A4 (en) * | 2001-04-26 | 2006-05-24 | Univ Texas | AGENTE / LIGAND CONJUGATED THERAPEUTIC COMPOSITIONS, METHODS OF SYNTHESIS AND USE THEREOF |
-
2002
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- 2002-02-21 WO PCT/US2002/005079 patent/WO2002067857A2/en active IP Right Grant
- 2002-02-21 JP JP2002567229A patent/JP2004528025A/ja not_active Withdrawn
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-
2005
- 2005-04-20 US US11/110,306 patent/US7407475B2/en not_active Expired - Fee Related
-
2008
- 2008-05-27 JP JP2008137728A patent/JP2008263991A/ja active Pending
-
2010
- 2010-04-01 JP JP2010084883A patent/JP2010189405A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5612460A (en) * | 1989-04-19 | 1997-03-18 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
JPH05508664A (ja) * | 1991-05-09 | 1993-12-02 | ボード・オブ・リージェンツ・オブ・ザ・ユニヴァーシティ・オブ・ワシントン | リン脂質標的血栓溶解剤 |
JP2000504210A (ja) * | 1995-12-27 | 2000-04-11 | ジェネンテク・インコーポレイテッド | 半減期の長いobタンパク質誘導体 |
JP2001500116A (ja) * | 1996-07-26 | 2001-01-09 | ネオルクス コーポレイション | 放射線標識化アネキシン |
WO1998031383A1 (en) * | 1997-01-15 | 1998-07-23 | Phoenix Pharmacologics, Inc. | Modified tumor necrosis factor |
Non-Patent Citations (2)
Title |
---|
THROMBOSIS RESEARCH, vol. 61, JPN6011009050, 1991, pages 93 - 104, ISSN: 0001852079 * |
THROMBOSIS RESEARCH, vol. 69, JPN6011009049, 1993, pages 289 - 296, ISSN: 0001852080 * |
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EP1379266B1 (en) | 2007-04-18 |
WO2002067857A2 (en) | 2002-09-06 |
ES2286247T3 (es) | 2007-12-01 |
US7407475B2 (en) | 2008-08-05 |
DE60219611T2 (de) | 2007-12-27 |
JP2010189405A (ja) | 2010-09-02 |
WO2002067857A3 (en) | 2002-11-07 |
US20050197295A1 (en) | 2005-09-08 |
EP1379266A4 (en) | 2004-05-06 |
JP2004528025A (ja) | 2004-09-16 |
ATE359807T1 (de) | 2007-05-15 |
DE60219611D1 (de) | 2007-05-31 |
EP1839670A2 (en) | 2007-10-03 |
US20030166532A1 (en) | 2003-09-04 |
EP1839670A3 (en) | 2009-11-11 |
US6962903B2 (en) | 2005-11-08 |
EP1379266A2 (en) | 2004-01-14 |
AU2002252035A1 (en) | 2002-09-12 |
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