JP5335785B2 - 目的物質の送達用ペプチドベクターの製造のためのvhh抗体の使用及びその適用 - Google Patents
目的物質の送達用ペプチドベクターの製造のためのvhh抗体の使用及びその適用 Download PDFInfo
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- JP5335785B2 JP5335785B2 JP2010514188A JP2010514188A JP5335785B2 JP 5335785 B2 JP5335785 B2 JP 5335785B2 JP 2010514188 A JP2010514188 A JP 2010514188A JP 2010514188 A JP2010514188 A JP 2010514188A JP 5335785 B2 JP5335785 B2 JP 5335785B2
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Description
本発明のVHH抗体は、少なくとも8.5、好ましくは少なくとも9、より好ましくは少なくとも9.5、更により好ましくは9.6〜9.9の等電点を有する。
本発明のより好ましい実施形態では、VHH抗体は、配列番号:1及び配列番号:2からなる群より選択されるアミノ酸配列を含んでなるか、又は該アミノ酸配列からなる(それぞれ、VHH V31-1及びVHH 61-3とも呼ぶ)。これらVHHは国際出願第WO 2004/044204号に記載されている。
VHH 61-3を発現する宿主細胞もまた、CNCM(28 rue du Dr Roux,75724 Paris Cedex 15,France)から、番号I-2933で入手可能である;これは2002年9月20に寄託された。
− 酵素、例えば、西洋ワサビペルオキシダーゼ、アルカリホスファターゼ、グルコース-6-ホスファターゼ、β-ガラクトシダーゼ;
− 蛍光体、例えば、緑色蛍光タンパク質(GFP)、紫外(UV)部のスペクトル中の波長で励起される青色蛍光染料(例えば、AMCA(7-アミノ-4-メチルクマリン-3-酢酸);Alexa Fluor 350)、青色光により励起される緑色蛍光染料(例えば、FITC、Cy2、Alexa Fluor 488)、緑色光により励起される赤色蛍光染料(例えば、ローダミン、Texas Red、Cy3、Alexa Fluor 546、564及び594)、又は近赤外光で励起され、電子検出器(CCDカメラ、光電子倍増管)で可視化される染料(例えばCy5);
− 放射性同位体、例えば、[18F]フルオロデオキシグルコース、11C-、125I-、131I-、3H-、14C-、35S-又は99Tc-標識化合物。
材料
EBM-2培地はClonetics(Cambrex BioScience,Wokingham,UK)製を用い、製造業者が推奨するようにVEGF、IGF-1、EGF、塩基性FGF、ヒドロコルチゾン、アスコルベート、ゲンタマイシン及び2.5%胎仔ウシ血清(FBS)を補充した:この十分に補充された培地は、微小血管内皮細胞培地-2(EGM-2 MV、本明細書ではEGM-2培地と呼ぶ)と名付けられている。I型コラーゲンはBD Biosciences PharMingen(Le Pont de Claix,France)から入手した。
VHH V31-1(配列番号:1)
VHH 61-3(配列番号:2)
VHH L1-3(配列番号:3)
これらVHH抗体のpI算出は、EMBOSS iepソフトウェアを用いて行った。VHH V31-1及びVHH 61-3は塩基性のpI(それぞれ、9.69及び9.83)を有する一方、VHH L1-3は7.67のpIを有する。
不死化ヒト脳内皮細胞hCMEC/D3は、以前にWekslerら(2005)に詳細に記載されている。VHH抗体の存在下での細胞生存能を、Wekslerら(2005)に記載されるMTTアッセイにより評価した。
標準ELISAの変法を使用して培養上清中のVHH抗体の存在について試験した。マイクロタイタープレート(Nunc,Denmark)を、PBS中に希釈した1μg/mlの抗原で、4℃にて一晩のインキュベーションによりコーティングした。プレートを緩衝剤A(PBS中0.1% Tween 20)で4回洗浄し、VHH抗体を緩衝剤B(緩衝剤A中0.5%ゼラチン)に希釈した。プレートを37℃にて2時間インキュベートし、再度洗浄した後、ウサギ抗-Hisタグ抗体(Santa Cruz,Ca,USA)を添加した。次いで、プレートを緩衝剤Aで洗浄し、ペルオキシダーゼ(ICN,aurora,OH)又はβ-ガラクトシダーゼ(Biosys,les Ullis,France)で標識したヤギ抗-ウサギIgG抗体を37℃にて1時間加えた。
VHH抗体の免疫ブロット検出のために、標準ウェスタンブロットの変法を使用した。アリコートに、等量のゲルローディング緩衝剤を添加し、次いで100℃にて5分間処理した。NuPAGE Novex 4-12% Bis-trisゲル(Invitrogen)を用いるポリアクリルアミドゲル電気泳動(PAGE)による分離後、半乾燥のままでHybond-C(Amersham)に移し、Xcell II blot module(Invitrogen)を使用してウェスタンブロッティングを行った。免疫化学反応の前に、メンブレンを4%脱脂乳溶液中でブロックし、ペルオキシダーゼ-標識ウサギ抗-Hisタグ(Santa Cruz,Ca,USA)とその後のペルオキシダーゼ標識ヤギ抗-ウサギ免疫グロブリンにより顕現した。最後に、化学発光キット(Amersham)を用いてペルオキシダーゼ活性を可視化した。
Wekslerら(2005)に記載のインビトロBBBモデルでトランスサイトーシスアッセイを行った。上方チャンバにVHH抗体を加え、細胞単層の管腔側からアブルミナル(abluminal)側へのVHH抗体の通過速度を測定した。図1は、hCMEC/D3を横切る機能的なVHH V31-1及びVHH 61-3のトランスサイトーシスが存在する一方で、hCMEC/D3を横切るVHH L1-3の通過がないことを示す。この通過は時間依存性であり、30分で最大に達した。60分で、VHH抗体の約1%が下方チャンバに存在した。
− Abulrob A.ら,J. Neurochem., 2005, 95, 1201-14.
− Bickel U.ら,Adv. Drug Deliv. Rev., 2001, 46(1-3), 247-279.
− Girod J.ら,J. Neurochem., 1999, 73: 2002-2008.
− Hussain R.ら,J. Immunol. Methods, 1993, 160: 89-96.
− Miller DW., J. Neurovirol., 1999, 5, 570-578.
− Muyldermans S., J. Biotechnol., 2001, 74, 277-302.
− Nguyen VK.ら,Adv. Immunol., 2001, 79, 261-96
− Triguero D.ら,Proc. Natl. Acad. Sci USA., 1989, 86, 4761-4765.
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Claims (19)
- 少なくとも8.5の等電点を有するラクダ科動物単鎖抗体の可変フラグメント(VHH抗体)(このVHH抗体の脳経内皮移動はインビトロでアミロライドの存在下で阻害される)について、哺乳動物血液脳関門を横切る目的物質の送達用ペプチドベクターの製造のための使用。
- 前記VHH抗体が少なくとも9の等電点を有することを特徴とする請求項1に記載の使用。
- 前記VHH抗体が配列番号:1及び配列番号:2からなる群より選択されるアミノ酸配列を含んでなるか又は該アミノ酸配列からなることを特徴とする請求項1又は2に記載の使用。
- 前記目的物質が哺乳動物血液脳関門を透過しないことを特徴とする請求項1〜3のいずれか1項に記載の使用。
- 前記目的物質が治療用又は診断用化合物であることを特徴とする請求項1〜4のいずれか1項に記載の使用。
- 前記治療用又は診断用化合物が、ペプチド、酵素、核酸、ウイルス、蛍光体、重金属キレート、化学物質及び放射性同位体からなる群より選択されることを特徴とする請求項1〜5のいずれか1項に記載の使用。
- 前記目的物質が、請求項6に規定の治療用又は診断用化合物を含んでなるリポソーム又はポリマー物質であることを特徴とする請求項1〜4のいずれか1項に記載の使用。
- 前記治療用化合物が、抗ガン化合物、鎮痛化合物、抗-炎症化合物、抗鬱化合物、抗痙攣化合物又は抗-神経変性化合物からなる群より選択されることを特徴とする請求項1〜7
のいずれか1項に記載の使用。 - 前記診断用化合物が、酵素、蛍光体、重金属キレート及び放射性同位体からなる群より選択されることを特徴とする請求項1〜5のいずれか1項に記載の使用。
- 前記VHH抗体が、前記目的物質に直接又は間接に、共有結合的又は非共有結合的に連結されていることを特徴とする請求項1〜9のいずれか1項に記載の使用。
- 前記目的物質に直接又は間接に、共有結合的又は非共有結合的に連結されている請求項1〜3のいずれか1項に規定のVHH抗体を含んでなる治療用又は診断用薬剤。
- 請求項11に記載の治療用薬剤と医薬的に許容され得るキャリアとを含んでなる医薬組成物。
- 脳ガン、疼痛、精神疾患又は神経変性疾患の治療に使用するための請求項11に記載の治療用薬剤又は請求項12に記載の医薬組成物。
- 脳イメージング又は脳疾患の診断に使用するための請求項11に記載の診断用薬剤。
- 少なくとも請求項1〜3のいずれか1項に規定のVHH抗体と診断用化合物とを含んでなることを特徴とする脳疾患の診断用キット。
- 前記診断用化合物が、ペプチド、酵素、核酸、ウイルス、蛍光体、重金属キレート、化学物質及び放射性同位体からなる群より選択されることを特徴とする請求項15に記載の脳疾患の診断用キット。
- 前記ペプチドベクターがヒト血液脳関門を横切って目的物質を送達するために使用されることを特徴とする請求項1〜10のいずれか1項に記載の使用。
- 前記VHH抗体が少なくとも9.5の等電点を有することを特徴とする請求項2〜10及び17のいずれか1項に記載の使用。
- 前記目的物質がヒト血液脳関門を透過しないことを特徴とする請求項4〜10、17及び18のいずれか1つに記載の使用。
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EP2008666A1 (en) * | 2007-06-29 | 2008-12-31 | Institut Pasteur | Use of VHH antibodies for the preparation of peptide vectors for delivering a substance of interest and their applications |
EP2009445A1 (en) * | 2007-06-29 | 2008-12-31 | Institut Pasteur | Use of a camelid single-domain antibody for detecting an oligomeric form of an amyloid beta peptide and its applications |
US20110200525A1 (en) * | 2008-10-09 | 2011-08-18 | Patz Jr Edward F | Vhh antibody fragments for use in the detection and treatment of cancer |
-
2007
- 2007-06-29 EP EP07290811A patent/EP2008666A1/en not_active Withdrawn
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2008
- 2008-06-26 WO PCT/IB2008/002691 patent/WO2009004495A2/en active Application Filing
- 2008-06-26 AU AU2008272541A patent/AU2008272541B2/en active Active
- 2008-06-26 JP JP2010514188A patent/JP5335785B2/ja active Active
- 2008-06-26 CA CA2691750A patent/CA2691750C/en active Active
- 2008-06-26 EP EP08807221.0A patent/EP2173386B1/en active Active
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EP2008666A1 (en) | 2008-12-31 |
WO2009004495A3 (en) | 2009-03-12 |
JP2010533130A (ja) | 2010-10-21 |
US20100021384A1 (en) | 2010-01-28 |
AU2008272541A1 (en) | 2009-01-08 |
US9387260B2 (en) | 2016-07-12 |
AU2008272541B2 (en) | 2013-09-12 |
EP2173386A2 (en) | 2010-04-14 |
CA2691750C (en) | 2015-09-08 |
EP2173386B1 (en) | 2018-08-08 |
US10174105B2 (en) | 2019-01-08 |
WO2009004495A2 (en) | 2009-01-08 |
US20170002065A1 (en) | 2017-01-05 |
CA2691750A1 (en) | 2009-01-08 |
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