JP5743898B2 - ニューレグリンペプチド及びその使用 - Google Patents
ニューレグリンペプチド及びその使用 Download PDFInfo
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- JP5743898B2 JP5743898B2 JP2011537817A JP2011537817A JP5743898B2 JP 5743898 B2 JP5743898 B2 JP 5743898B2 JP 2011537817 A JP2011537817 A JP 2011537817A JP 2011537817 A JP2011537817 A JP 2011537817A JP 5743898 B2 JP5743898 B2 JP 5743898B2
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- neuregulin
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Description
本発明は、全般に、様々な心臓病又は障害を治療するための、ErbB2受容体について増強された親和性を有するニューレグリンペプチド及びその使用に関する。
心(心室)肥大は、心仕事量に対するストレス又は需要の増加に応答しての重要な適応生理反応である。肥大のための刺激後に発生する初期の細胞変化の1つは、個々の細胞のサイズの比例増加を伴うミトコンドリアの合成及び筋原線維質量の増加(壁肥厚化)であるが、細胞数の増加はない(又は最小限である)。
本発明は、ErbB受容体に対し、増強された親和性を有するニューレグリンペプチドを提供する。いくつかの実施態様において、本発明のニューレグリンペプチドは、ニューレグリンのEGFドメインを含む。いくつかの実施態様において、本発明のニューレグリンペプチドは、ヒトニューレグリンβ2アイソフォームのEGFドメインを含む。いくつかの実施態様において、ErbB受容体に対し増強された親和性を有するニューレグリンペプチドは、配列番号5のアミノ酸配列を含む。
(5.1定義)
他に定義がない限り、本明細書において使用される全ての技術用語及び科学用語は、本発明が属している技術分野の当業者によって一般に理解されているのと同じ意味を有する。本明細書において参照される全ての特許、出願、公開された出願及び他の刊行物は、引用によりその全てが本明細書に組み込まれる。この節に記載される定義が、引用により本明細書に組み込まれる特許、出願、公開された出願及び他の刊行物に記載される定義と反対又はそうでなければ矛盾する場合、この節に記載される定義は、引用により本明細書に組み込まれる定義を超えて優先する。
本発明は、ErbB受容体を結合し得るニューレグリンペプチドを提供する。いくつかの実施態様において、本発明のニューレグリンペプチドは、ErbB受容体に対し増強された親和性を有する。いくつかの実施態様において、本発明のニューレグリンペプチドは、ニューレグリンのEGFドメインを含む。いくつかの実施態様において、本発明のニューレグリンペプチドは、ヒトニューレグリンβ2アイソフォームのEGFドメインを含む。いくつかの実施態様において、ニューレグリンペプチドは、配列番号3、5、7及び9から選択されるアミノ酸配列を含む。
本発明のニューレグリンペプチドは、当業者にとって明らかな任意の技術に従って調製できる。ニューレグリン調製の例示的技術は、例えば、米国特許第7,226,907号、米国特許第5,367,060号、WO 94/026298、WO 03/099300に記載され、当該内容は引用によりその全てが本明細書に組み込まれる。
本発明のニューレグリンペプチドは、当業者の判断に従って使用できる。例示的使用は、例えば米国特許第7,226,907号、米国特許第5,367,060号、WO 94/026298、WO 03/099300に記載され、それぞれの内容は引用によりその全てが本明細書に組み込まれる。
本発明において使用するニューレグリンペプチドの量は、当該性質及び疾患若しくは状態の重篤度、及び当該活性成分が投与される経路により、変更する。頻度及び投与量は、投与される具体的な療法(例えば、治療剤又は予防剤)、障害、疾患若しくは状態の重篤度、投与経路、並びに患者の年齢、身体、体重、応答性及び過去の医療履歴に応じて、各患者に特異的な因子に従っても変更する。有効用量は、インビトロ又は動物モデル試験系に由来する用量反応曲線から推定してもよい。
(6.1 実施例1:ニューレグリンペプチドの化学合成)
5つのニューレグリンペプチド、すなわちNRG53(配列番号3)、NRG55(配列番号4)、NRG57(配列番号5)、NRG59(配列番号6)、NRG61(配列番号1)は、GL Biochem(上海)社により合成された。
MCF-7細胞を回収し、計数し、ペレット化し、5×104細胞/mlでDMEM(10% 血清及び9μg/mlインスリン含有)に再懸濁した。100μlの細胞懸濁液を96穴プレートの各ウェルに加え、該プレートを37℃で終夜インキュベートした。該細胞をそれからPBSで3回洗浄し、無血清DMEMにおいてさらに24時間培養した。
心筋細胞内のErbB2及びErbB4シグナル伝達における合成ペプチドの効果を調査するために、新生仔マウスの左心室から抽出された心臓細胞を使用した。
Claims (4)
- 配列番号5のアミノ酸配列から構成されるニューレグリンペプチド。
- 配列番号5のアミノ酸配列から構成されるニューレグリンペプチド、及び医薬として許容し得る担体、賦形剤又は希釈剤を含む、医薬組成物。
- 配列番号5のアミノ酸配列から構成されるニューレグリンペプチドの有効量を含む、その必要のある対象における心不全を治療するための請求項2記載の医薬組成物。
- 静脈内投与用に製剤化されている、請求項2又は3記載の医薬組成物。
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