JP2005531509A - アミロイドβペプチドに対する特異性抗体、医薬組成物、及びその使用方法 - Google Patents
アミロイドβペプチドに対する特異性抗体、医薬組成物、及びその使用方法 Download PDFInfo
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Abstract
Description
本発明は、アルツハイマー病、又はアミロイドβ沈着を特徴とする他の病気又は障害を有する患者の治療方法に関し、アミロイドβペプチド又はその断片をターゲットとする抗体分子を投与するステップを含んでいる。他の実施形態では、本発明は、アミロイドβペプチドのN末端又はC末端に対する遊離端に対して特異的な抗体分子、及びその抗体分子を含んでいる医薬組成物に関する。他の実施形態では、本発明は、N末端及び/又はC末端が切断されたアミロイドβペプチド断片の遊離C末端又はN末端をターゲットとする抗体分子、及びその抗体分子を含んでいる医薬組成物に関する。
(i)生物学的活性モノマーの周りで、機能性モノマーを重合する。これは、アミロイドβペプチド又はその断片に対する抗体(テンプレート)となる。(ii)テンプレート分子を除去する。そして、(iii)テンプレートを除去した空間で、モノマーのセカンドクラスの重合を行い、前記テンプレートと似ている1つ以上の望ましい性質を示す新しい有機分子を作製する。したがって、ある実施形態では、本発明は、アミロイドβペプチド及びその断片を選択的に認識し、抗体として働き、アルツハイマー病及び他のアミロイドβ沈着を特徴とする病気又は障害の治療に使用される分子認識ポリマー(molecularly imprinted polymers:MIP)である人工抗体に関する。
アミロイドβペプチドの遊離端に対して特異的な抗体を検出する“スパンニング・ペプチド”ELISA検出方法の実証
ペプチドH2N-Asp-Ala-Glu-Phe-Arg-アミノヘキサン酸-Cys-アミドは、SMCCリンカーを介して、BSAと共役する。スイスウェブスターマウスは、完全フロインドアジュバント内の100μgの共役により免疫される。そして、その後、さらなる不完全フロインドアジュバント内の100μgの共役により、2回追加免疫する。抗血清は、“スパンニング・ペプチドELISA検出方法”を使用してスクリーンされる。簡単に説明すると、Aβ1−40は、96ウエルプレート上にコーティングされる。96ウエルプレートは、その後、競合するペプチドA(免疫原)、C(節約ペプチド)、又はAβ1−40自身の存在下で培養される。共通の結果を図5に示す。予想どおりに、これらの動物から作られた抗体は、免疫付与に使用されたペプチドであるAβ(ペプチドA)の残基1−5、及び完全長Aβ1−40ペプチドと結合する。また、無傷のアミロイド前駆体タンパク質APPの場合と同様に、そのN末端(ペプチドC)において両側をさらなる配列に挟まれた場合は、これらの抗体はAβ1−5エピトープとも反応する。そのような抗体は、エピトープに対して特異的であると言われる(AβのN末端の配列1−5に対して)。
アミロイドβペプチドの遊離端に対して特異的なハイブリドーマを選択する“スパンニング・ペプチド”ELISA検出方法の実証
ペプチドH2N-Asp-Ala-Glu-Phe-Arg-アミノヘキサン酸-Cys-アミドは、MBSリンカーを介して、KLHと共役する。BaLb/c×C57BL/6 F1マウスは、完全フロインドアジュバント内の50μgの共役により免疫される。そして、その後、さらなる不完全フロインドアジュバント内の50μgの共役により、4回追加免疫する。標準方法を使用して、抗血清は検査され、融合が行われる。本明細書にて前述したように、ハイブリドーマは、“スパンニング・ペプチドELISA検出方法”を使用してスクリーンされる。簡単に説明すると、陽性ペプチド(BSAと共役したH2N-Asp-Ala-Glu-Phe-Arg-His)、又は陰性対照である“スパンニング”・ペプチド(アセチル-Glu-Val-Lys-Met-Asp-Ala-Glu-Phe-Arg-His)は、96ウエルプレート上にコーティングされる。96ウエルプレートは、その後、ハイブリドーマの上清と共に培養される。図7及び図8に示すように、いくつかのハイブリドーマは両方のペプチドを同じように認識する(例えば、クローン5E2、2A8、及び2F8)、又は微々たる差異を認識する(例えば、クローン4H9、1C12、及び3H3)。また、いくつかのクローンは、陰性対照スパンニング・ペプチド(免疫付与に使用されたのと同じ配列を含んでいる)よりも、免疫付与に使用された陽性ペプチドをより強く認識することにより、遊離端特異性を実証する。この例は、クローン4D12及び2A10に見られる。
仮説実験(Prophetic Experiments)
Aβ端部特異性抗体が、Aβ微小繊維形成、及びAβが引き起こす細胞毒性を阻止する効果を検査するためのインビトロ生物検定法
《Aβ端部が引き起こす神経毒性》
後期糖化反応生成物用の受容体(receptor for advanced glycation end-products:RAGE)は、神経細胞及び小膠細胞(microglia)におけるAβの神経毒性作用を仲介する(Yanら, 1996)。
血管細胞由来のヘパラン硫酸プロテオグリカン、ペルレカン(perlecan)は、全てのアミノ沈着物内で識別される。また、Aβとの高親和性結合による炎症性アミロイドの初期段階に関与している(Snowら, 1989; 1995)。ペルレカンのAβへの結合は、相互作用を妨げる分子がアミロイド生成を防止する又は阻止するという、第2及び第3アミロイド構造の特徴を授ける。
動力学的に溶性のペプチド(例えばAβ1−40)によるアミロイド微小繊維形成は、例えばAβ1−42のようなペプチド(境界C末端残基41(Ile)及び42(Ala)を含む)により核となる、又はシード(seed)される。C末端又はN末端特異性Aβ抗体の、Aβ1−42によるシーディングを阻止、又はアミロイドペプチドの会合を防止する能力は、標準的な会合分析法を使用して検査される(Woodら, 1996)。Aβ1−40ペプチドは、1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール内に5mg/ml可溶化される。前記ペプチドは、蒸発濃縮され、最終的な濃度が230μmとなるまで、pH7.4のリン酸緩衝生理食塩水(PBS)内に再可溶化される。Aβ1−40(20μm)の溶液は、3日間攪拌される。そして、Aβ微小繊維を生成すべく、30分間超音波切断される。2nM濃度の会合前Aβ1−42は、Aβ1−40の会合をシードするために、pH7.4の過飽和状態の培養に添加される。各Aβ端部特異性抗体の存在下又は非存在下での会合形成は、405nmでマイクロタイター・プレートリーダを使用して、マイクロタイター細胞上に作製された資料の濁度をモニターすることにより測定される。また、反応は、Woodら(1996)により説明された、チオフラビンT蛍光によりモニターされる。遊離端特異性抗体のアミロイドペプチド微小繊維の解離を促進する能力は、VI標識アミロイド会合ペプチドのコラーゲン・マトリクス(96ウエル・マイクロタイター・プラスチック・コーティング・プレート上にコーティングされた非会合ペプチドを含んでいる)からの変位を調べることにより検査される。さらに、遊離端特異性抗体のAβにより引き起こされるダメージから神経細胞を保護する能力は、トリパンブルー法、細胞内カルシウム測定、走査型及び透過電子顕微鏡法、及び共焦点顕微鏡法により評価される。
動物モデルは、脳のADのような病状の進行を遅らせる又は防止するために投与される抗体の潜在能力を実証するために必要である。また、ADはヒト固有の病気なので、ヒトAPPとPS1を過剰に発現する遺伝子導入マウスが数多く作成された。遺伝子導入マウスにおけるアルツハイマー病を連想する、相関関係にある行動、生化学、及び病理学の異常性は、Aβにより引き起こされる病態生理を遅らせる又は防止するための物質の有用性を調査する機会を与えた。
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Claims (23)
- アルツハイマー病患者を治療する薬剤を製造するための、アミロイドβペプチド又はその断片をターゲットとする抗体の使用。
- アミロイドβ沈着を特徴とする病気又は障害を有する患者を治療する薬剤を製造するための、アミロイドβペプチド又はその断片をターゲットとする抗体の使用。
- アミロイドβペプチド又はその断片が脳内に蓄積するのを遅らせる又は抑制する又は阻止する薬剤を製造するための、アミロイドβペプチド又はその断片をターゲットとする抗体の使用。
- 脳内にアミロイドβペプチド又はその断片による神経毒性を遅らせる又は抑制する又は阻止する薬剤を製造するための、アミロイドβペプチド又はその断片をターゲットとする抗体の使用。
- 前記抗体は、前記アミロイドβペプチド又はその断片と直接的に反応することを特徴とする請求項1から請求項4のいずれか一項に記載の抗体の使用。
- 前記抗体は、N末端が切断されたアミロイドβペプチド断片と直接的に反応することを特徴とする請求項1から請求項4のいずれか一項に記載の抗体の使用。
- 前記抗体は、C末端が切断されたアミロイドβペプチド断片と直接的に反応することを特徴とする請求項1から請求項4のいずれか一項に記載の抗体の使用。
- 前記抗体は、アミロイド前駆体タンパク質又はその断片と直接的に反応することを特徴とする請求項1から請求項4のいずれか一項に記載の抗体の使用。
- 前記抗体は、モノクローナル抗体、ヒト化抗体、キメラ抗体、二重特異性抗体、人工抗体、scFv抗体、F(ab)、又はそれらの断片であることを特徴とする請求項1から請求項4のいずれか一項に記載の抗体の使用。
- 前記アミロイドβ沈着を特徴とする病気又は障害は、軽度認識障害(MCI)、脳アミロイド・アンギオパチー又はコンジオフィリック・アンギオパチー(congiophylic angiopathy)、ダウン症と関連するアルツハイマー病、又は封入体筋炎であることを特徴とする請求項2に記載の抗体の使用。
- 遊離端に対して特異的であり、アミロイドβペプチドの遊離N末端をターゲットとする抗体。
- 遊離端に対して特異的であり、第1アミノ酸がアスパラギン酸塩であるアミロイドβペプチドの遊離N末端をターゲットとする抗体。
- 遊離端に対して特異的であり、N末端及び/又はC末端が切断されたアミロイドβペプチド断片の遊離N末端をターゲットとする抗体。
- 遊離端に対して特異的であり、アミロイドβペプチド:Aβ1−39、Aβ1−40、Aβ1−41、又はAβ1−43の遊離C末端をターゲットとする抗体。
- 遊離端に対して特異的であり、N末端及び/又はC末端が切断されたアミロイドβペプチド断片の遊離C末端をターゲットとする抗体。
- 遊離端に対して特異的であり、アミロイドβペプチド:Aβ1−42の遊離C末端をターゲットとする一本鎖又は人工抗体。
- 前記抗体は、モノクローナル抗体、ヒト化抗体、キメラ抗体、二重特異性抗体、人工抗体、scFv抗体、F(ab)、又はそれらの断片であることを特徴とする請求項11から請求項15のいずれか一項に記載の抗体。
- 請求項11から請求項16のいずれか一項に記載の抗体と、薬学的に許容されるキャリヤを含んでいることを特徴とする医薬組成物。
- 前記組成物は、皮下に、静脈内に、皮内に、筋肉内に、腹腔内に、脳内に、鼻腔内に、経口で、経皮で、頬側に、動脈内に、頭蓋内に、又は頭部に投与されることを特徴とする請求項18に記載の医薬組成物。
- アルツハイマー病患者を治療する薬剤を製造するための、請求項11から請求項16のいずれか一項に記載の抗体の使用。
- アミロイドβ沈着を特徴とする病気又は障害を有する患者を治療する薬剤を製造するための、請求項11から請求項16のいずれか一項に記載の抗体の使用。
- 脳内にアミロイドβペプチド又はその断片が蓄積するのを遅らせる又は抑制する又は阻止する薬剤を製造するための、請求項11から請求項16のいずれか一項に記載の抗体の使用。
- アミロイドβペプチド又はその断片による神経毒性を遅らせる又は抑制する又は阻止する薬剤を製造するための、請求項11から請求項16のいずれか一項に記載の抗体の使用。
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JP2009173680A (ja) * | 1997-04-09 | 2009-08-06 | Intellect Neurosciences Inc | β−アミロイド末端に特異的な組換え抗体、それをコードするDNA及びその使用法 |
WO2014136443A1 (ja) * | 2013-03-08 | 2014-09-12 | パナソニックヘルスケア株式会社 | 抗Aβ42モノクローナル抗体 |
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US8173127B2 (en) | 2012-05-08 |
EP1487488A1 (en) | 2004-12-22 |
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AU2002367734A1 (en) | 2003-09-16 |
US20120244159A1 (en) | 2012-09-27 |
ZA200409186B (en) | 2005-10-26 |
CN1649623A (zh) | 2005-08-03 |
US20030073655A1 (en) | 2003-04-17 |
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