JP6583411B2 - 薬物複合体 - Google Patents
薬物複合体 Download PDFInfo
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- JP6583411B2 JP6583411B2 JP2017525472A JP2017525472A JP6583411B2 JP 6583411 B2 JP6583411 B2 JP 6583411B2 JP 2017525472 A JP2017525472 A JP 2017525472A JP 2017525472 A JP2017525472 A JP 2017525472A JP 6583411 B2 JP6583411 B2 JP 6583411B2
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- Prior art keywords
- vegf
- peptide
- amino acid
- block
- binding
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Classifications
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61P35/00—Antineoplastic agents
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Description
ジスルフィド結合により安定化された環状VEGF標的ペプチド(M49)に対して、薬物結合用のリンカーを導入するとともに、ペプチドの安定化を図るためにペプチドの主鎖部分を環状化したVEGF結合性ペプチド誘導体(M49K)を合成した(図1)。表2にペプチドM49及びペプチドM49Kのアミノ酸配列を示した。ペプチドM49の配列は、配列番号7に示すアミノ酸配列を有するAブロックと、配列番号6に示すアミノ酸配列を有するBブロックと、配列番号13に示すアミノ酸配列を有するCブロックを有する。なお、図1にはN末端のアミノ酸であるシステインとC末端のアミノ酸であるシステインがSS結合により環化されており、C末端のカルボキシル基がアミノ化されたものを示している。ペプチドM49Kは、Aブロックから1つのアミノ酸(アラニン)が欠落し、CブロックのC末端のシステインを欠き、4つのグリシンをリンカーとして結合させて環状化したものである。
ペプチド誘導体M49KはVEGFとVEGF受容体との相互作用を阻害しない。そこで次に、M49KがVEGFと共にVEGF受容体を介したエンドサイトーシスでHUVEC(ヒト臍帯静脈内皮細胞:Human Umbilical Vein Endothelial Cells )内に取り込まれるか調べた。ガラスベースディッシュにHUVECを播種、培養した。そこへ、Alexa-488で蛍光標識したVEGFと、Cy5で蛍光標識したM49KをHUVECに添加し、6時間後にレーザー共焦点顕微鏡観察を行った。その結果、図4に示すようにAlexa-488の蛍光とCy5の蛍光が細胞内で観察できた。また、これらの蛍光が共局在していたことから、M49KはVEGFとともに細胞内へ取り込まれていることが判明した。
次にペプチド誘導体M49Kに薬物を結合し、薬物複合体を合成した。薬物には、チューブリン重合阻害剤であるセマドチン(Cemadotin)の類縁体であるCemCH2-SHを用いて、M49Kのシステイン残基とジスルフィド結合を介して結合させた。CemCH2-SHは公知の化合物である(Bernardes, G. J. L. et al. Angew. Chem. Int. Ed. 124, 965-968 (2012))。細胞内は、存在する多量のグルタチオンのために還元条件下であると考えられるため、M49K-薬物複合体が取り込まれると、このジスルフィド結合は切断され、薬物が毒性を発揮すると想像される。
M49K-Cemを用いてHUVECの増殖阻害試験を実施した。96穴平底プレートにEBM-2培地で懸濁したHUVEC(3000cells/100μL/well)を添加し、37℃、5%C02 で一晩培養した。次に、培地を抜き取り、そこへ25ng/mLのVEGFと各濃度のサンプルを含むDMEM培地(0.2%FCS)を添加した。37℃、5%C02で24時間培養後、WST-1アッセイ(Ishiyama, M.et al., Biol. Pharm. Bull. 19, 1518-1520 (1996))により細胞増埴度を調べた。その結果、図8に示すように、M49K-Cemは濃度依存的に細胞増殖を阻害し、HUVECに対するIC50値は45nMであった。一方、対照であるM49KとYT1-Cemは細胞増殖を阻害しなかった。YT1-CemはVEGFに結合しない配列番号18に示すアミノ酸配列を有するヘリックス−ループ−ヘリックスペプチドであって、YT1-Cys(CAELAALEAELAALEGGGGGGGKLAALKAKLAALKA-NH2)とCemCH2-S-TNBをPBS中で反応させることで得られる。
Claims (10)
- α−ヘリックス構造を形成するペプチドからなりN末端側に位置するAブロックと、α−ヘリックス構造を形成するペプチドからなりC末端側に位置するCブロックと、前記Aブロックと前記Cブロックを共有結合で結ぶペプチドからなるBブロックとからなるヘリックス−ループ−ヘリックス構造を有するVEGF結合性ペプチドと薬物が結合したVEGF結合性ペプチド−薬物複合体であって、
前記薬物が、前記VEGF結合性ペプチドのN末端のアミノ酸及び/又はC末端のアミノ酸に直接又は間接に結合し、
VEGF受容体のエンドサイトースによりVEGF受容体発現細胞内に取り込まれるVEGF結合性ペプチド−薬物複合体。 - 前記薬物は、細胞内酵素により切断されうる結合様式にて前記VEGF結合性ペプチドのN末端アミノ酸又はC末端アミノ酸に結合した請求項1項に記載のVEGF結合性ペプチド−薬物複合体。
- 前記薬物は、前記VEGF結合性ペプチドのN末端のアミノ酸又はC末端のアミノ酸が有する縮合性官能基に直接結合した請求項1又は2に記載のVEGF結合性ペプチド−薬物複合体。
- 前記縮合性官能基は、チオール基、アミノ基、水酸基、カルボキシル基、アルデヒド基の何れかである請求項3に記載のVEGF結合性ペプチド−薬物複合体。
- 前記VEGF結合性ペプチドのN末端のアミノ酸と当該VEGF結合性ペプチドのC末端のアミノ酸が、直接又は間接に結合した請求項1〜4の何れか1項に記載のVEGF結合性ペプチド−薬物複合体。
- 前記AブロックのN末端アミノ酸と前記BブロックのC末端アミノ酸が、1〜数個のアミノ酸からなるリンカーで結合した請求項5に記載のVEGF結合性ペプチド−薬物複合体。
- 前記Bブロックは、配列番号3〜6の何れかで表されるアミノ酸配列からなるペプチドである請求項1〜6の何れか1項に記載のVEGF結合性ペプチド−薬物複合体。
- 前記Aブロックは配列番号7で表されるアミノ酸配列からなるペプチドであり、前記Cブロックは配列番号8で表されるアミノ酸配列からなるペプチドであることを特徴とする請求項7に記載のVEGF結合性ペプチド−薬物複合体。
- 前記Aブロックは配列番号7で表されるアミノ酸配列からなるペプチドであり、前記Cブロックは配列番号9で表されるアミノ酸配列(KLXXLKXKLXXLKXAC:但し、Xはスレオニン、アラニン及びプロリン以外のアミノ酸)からなるペプチドである請求項7に記載のVEGF結合性ペプチド−薬物複合体。
- 前記Aブロックは配列番号7で表されるアミノ酸配列からなるペプチドであり、前記Cブロックは配列番号10〜13の何れかで表されるアミノ酸配列からなるペプチドである請求項7に記載のVEGF結合性ペプチド−薬物複合体。
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