JP2010505875A - グリセロール連結のpeg化された糖および糖ペプチド - Google Patents
グリセロール連結のpeg化された糖および糖ペプチド Download PDFInfo
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- JP2010505875A JP2010505875A JP2009531613A JP2009531613A JP2010505875A JP 2010505875 A JP2010505875 A JP 2010505875A JP 2009531613 A JP2009531613 A JP 2009531613A JP 2009531613 A JP2009531613 A JP 2009531613A JP 2010505875 A JP2010505875 A JP 2010505875A
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Abstract
Description
本出願は、あらゆる目的のためにその全体を本明細書中に参照により組み込まれる、2006年10月4日出願の米国仮特許出願第60/828,208号の優先権を主張するものである。
PEG、ポリ(エチレングリコール);PPG、ポリ(プロピレングリコール);Ara、アラビノシル;Fru、フルクトシル;Fuc、フコシル;Gal、ガラクトシル;GalNAc、N−アセチルガラクトサミニル;Glc、グルコシル;GlcNAc、N−アセチルグルコサミニル;Man、マンノシル;ManAc、酢酸マンノサミニル;Xyl、キシロシル;NeuAc、シアリルまたはN−アセチルノイラミニル;Sia、シアリルまたはN−アセチルノイラミニル;ならびにその誘導体および類似体。
別段に定義しない限りは、本明細書中で使用するすべての専門用語および科学用語は、一般に、本発明が属する分野の技術者によって一般的に理解されるものと同じ意味を有する。一般に、本明細書中で使用する学名、ならびに細胞培養、分子遺伝学、有機化学、核酸化学およびハイブリダイゼーションにおける実験室の手順は、当分野で周知かつ一般的に用いられるものである。核酸およびペプチド合成には標準技術を用いる。技術および手順は、一般に、当分野の慣用方法および本明細書全体にわたって提供する様々な一般参考文献(一般に、本明細書中に参照により組み込れられるSambrook他、分子クローニング:実験室の手引き(MOLECULAR CLONING: A LABORATORY MANUAL)、第2版(1989)Cold Spring Harbor Laboratory Press、ニューヨーク州Cold Spring Harbor参照)に従って行う。本明細書中で使用する学名および分析化学における実験室の手順および以下に記載する有機合成は、当分野で周知かつ一般的に用いられているものである。標準技術またはその変形を、化学合成および化学分析に用いる。
治療目的で使用する組換えペプチドの有効性を改善するために、本発明は、グリコシル化および非グリコシル化ペプチドと修飾基とのコンジュゲートを提供する。修飾基は、高分子修飾基、たとえば、PEG(m−PEG)、PPG(m−PPG)など、治療用部分、診断用部分、標的化部分などから選択し得る。たとえば水溶性高分子修飾基を用いたペプチドの修飾は、患者の循環中の組換えペプチドの安定性および保持時間を改善する、および/または組換えペプチドの抗原性を低下させることができる。
第1の態様では、本発明は、修飾糖とペプチドとの間のコンジュゲートを提供する。また、本発明は、修飾基とペプチドとの間のコンジュゲートも提供する。ペプチドコンジュゲートは、いくつかの形態のうちの1つを有することができる。例示的な実施形態では、ペプチドコンジュゲートは、ペプチドおよびグリコシル連結基を介してペプチドのアミノ酸と連結している修飾基を含むことができる。別の例示的な実施形態では、ペプチドコンジュゲートは、ペプチドおよびグリコシル連結基を介してペプチドのグリコシル残基と連結している修飾基を含むことができる。別の例示的な実施形態では、ペプチドコンジュゲートは、ペプチド、ならびに糖ペプチド炭水化物に結合しており、かつペプチド主鎖のアミノ酸残基に直接結合しているグリコシル連結基を含むことができる。さらに別の例示的な実施形態では、ペプチドコンジュゲートは、ペプチドおよびペプチドのアミノ酸残基に直接連結した修飾基を含むことができる。本実施形態では、ペプチドコンジュゲートはグリコシル基を含んでいなくてもよい。これらの実施形態の任意のものにおいて、ペプチドは、グリコシル化されていても、されていなくてもよい。
ペプチドコンジュゲート中のペプチドは、図7のペプチドから選択されるメンバーである。このような場合には、ペプチドコンジュゲート中のペプチドは、骨形態発生タンパク質(たとえば、BMP−1、BMP−2、BMP−3、BMP−4、BMP−5、BMP−6、BMP−7、BMP−8、BMP−9、BMP−10、BMP−11、BMP−12、BMP−13、BMP−14、BMP−15)、ニューロトロフィン(たとえば、NT−3、NT−4、NT−5)、成長分化因子(たとえばGDF−5)、グリア細胞系由来神経栄養因子(GDNF)、脳由来神経栄養因子(BDNF)、神経成長因子(NGF)、フォンウィルブランド因子(vWF)プロテアーゼ、第VII因子、第VIIa因子、第VIII因子、第IX因子、第X因子、第XI因子、B−ドメイン欠失第VIII因子、完全長第VIII因子を有するvWF−第VIII因子融合タンパク質、B−ドメイン欠失第VIII因子を有するvWF−第VIII因子融合タンパク質、エリスロポエチン(EPO)、顆粒球コロニー刺激因子(G−CSF)、顆粒球−マクロファージコロニー刺激因子(GM−CSF)、インターフェロンα、インターフェロンβ、インターフェロンγ、α1−抗トリプシン(ATT、すなわちα−1プロテアーゼ阻害剤、グルコセレブロシダーゼ、組織型プラスミノーゲン活性化剤(TPA)、インターロイキン−2(IL−2)、ウロキナーゼ、ヒトDNase、インスリン、B型肝炎表面タンパク質(HbsAg)、ヒト成長ホルモン、TNF受容体−IgG Fc領域融合タンパク質(Enbrel(商標))、抗HER2モノクローナル抗体(Herceptin(商標))、呼吸器合胞体ウイルスのタンパク質Fに対するモノクローナル抗体(Synagis(商標))、TNF−αに対するモノクローナル抗体(Remicade(商標))、糖タンパク質IIb/IIIaに対するモノクローナル抗体(Reopro(商標))、CD20に対するモノクローナル抗体(Rituxan(商標))、抗トロンビンIII(AT III)、ヒト絨毛性ゴナドトロピン(hCG)、α−ガラクトシダーゼ(Fabrazyme(商標))、α−イズロニダーゼ(Aldurazyme(商標))、卵胞刺激ホルモン、β−グルコシダーゼ、抗TNF−αモノクローナル抗体、グルカゴン様ペプチド−1(GLP−1)、グルカゴン様ペプチド−2(GLP−2)、β−グルコシダーゼ、α−ガラクトシダーゼAおよび線維芽細胞成長因子から選択されるメンバーである。特定の実施形態では、ペプチドコンジュゲート中のペプチドは、第VIII因子である。他の実施形態では、ペプチドコンジュゲート中のペプチドは、インターフェロンαである。
例示的な実施形態では、第VIII因子、インターフェロンα、および図7に記載のペプチドなどの本発明のペプチドを、修飾糖と反応させて、ペプチドコンジュゲートを形成させる。修飾糖は、「糖ドナー部分」ならびに「糖転移部分」を含む。糖ドナー部分とは、グリコシル部分またはアミノ酸部分のどちらかを介して、本発明のコンジュゲートとしてペプチドと結合する、修飾糖の任意の部分である。糖ドナー部分には、修飾糖からペプチドコンジュゲートのグリコシル連結基へそれを変換する間に化学的に変更される原子が含まれる。糖転移部分とは、本発明のコンジュゲートとしてペプチドと結合しない、修飾糖の任意の部分である。たとえば、本発明の修飾糖は、PEG化された糖ヌクレオチド、PEG−シアル酸CMPである。PEG−シアル酸CMPでは、糖ドナー部分、またはPEG−シアリルドナー部分はPEG−シアル酸を含み、一方で、糖転移部分、またはシアリル転移部分はCMPを含む。
例示的な実施形態では、本発明は、本発明の修飾糖とペプチドとの間で形成されたペプチドコンジュゲートを提供する。別の例示的な実施形態では、修飾糖上の修飾基が
Mは、H、塩対イオンおよび単一の負電荷から選択されるメンバーであり;Lは、結合、置換または非置換アルキルおよび置換または非置換ヘテロアルキルから選択されるメンバーであるリンカーである。例示的な実施形態では、DがOHである場合、GはR1−L−である。別の例示的な実施形態では、Gは−C(O)(C1〜C6)アルキルである場合、DはR1−L−NH−である。
本発明のペプチドコンジュゲートは、修飾基を含む。この基は、アミノ酸またはグリコシル連結基を介してペプチドと共有結合していることができる。別の例示的な実施形態では、修飾基が、
修飾基のリンカーは、修飾基(すなわち、高分子修飾基、標的化部分、治療用部分および生体分子)をペプチドに結合させる役割を果たす。例示的な実施形態では、高分子修飾基は、以下に示すように、一般に核上のヘテロ原子、たとえば窒素を介して、リンカーLを介して、グリコシル連結基と結合している。
多くの水溶性ポリマーが当業者に知られており、本発明の実施において有用である。用語、水溶性ポリマーには、サッカライド(たとえば、デキストラン、アミロース、ヒアロウロン酸、ポリ(シアル酸)、ヘパラン、ヘパリンなど);ポリ(アミノ酸)、たとえば、ポリ(アスパラギン酸)およびポリ(グルタミン酸);核酸;合成ポリマー(たとえば、ポリ(アクリル酸)、ポリ(エーテル)、たとえばポリ(エチレングリコール);ペプチド、タンパク質などの種が包含される。本発明は、任意の水溶性ポリマーを用いて実施し得るが、唯一の制限は、ポリマーにはコンジュゲートの残りの部分が結合できる点が含まれていなければならないことである。
別の実施形態では、高分子修飾部分は、複数の直鎖状または分枝鎖状PEG部分が結合した分枝鎖状PEG構造である。分枝鎖状PEGの例は、米国特許第5,932,462号;米国特許第5,342,940号;米国特許第5,643,575号;米国特許第5,919,455号;米国特許第6,113,906号;米国特許第5,183,660号;国際公開公報WO02/09766号;Kodera Y.、Bioconjugate Chemistry 5:283〜288(1994);およびYamasaki他、Agric.Biol.Chem.、52:2125〜2127、1998に記載されている。
Mは、H、塩対イオンおよび単一の負電荷から選択されるメンバーであり;Lは、結合、置換または非置換アルキルおよび置換または非置換ヘテロアルキルから選択されるメンバーであるリンカーである。例示的な実施形態では、DがOHである場合、GはR1−L−である。別の例示的な実施形態では、Gは−C(O)(C1〜C6)アルキルである場合、DはR1−L−NH−である。
別の実施形態では、上述のものに類似して、修飾糖には、水溶性ポリマーではなく非水溶性ポリマーが含まれる。また、本発明のコンジュゲートには、1つまたは複数の水溶性ポリマーが含まれ得る。本発明の本実施形態は、コンジュゲートを、調節された様式で治療ペプチドを送達するために用いるビヒクルとして使用することによって、例示されている。高分子薬物の送達系は当分野で知られている。たとえば、Dunn他編、高分子薬物および薬物送達系(POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS)、ACS Symposium Series第469巻、American Chemical Society、ワシントンD.C.1991を参照されたい。当業者は、実質的に任意の既知の薬物送達系が本発明のコンジュゲートに適用可能であることを、理解されよう。
高分子修飾基は、グリコシルもしくは糖部分またはアミノ酸部分と反応させるために活性化させることができる。活性種(たとえば、カーボネートおよび活性エステル)の例示的な構造には、以下が含まれる。
化学的または酵素的に付加したグリコシル連結基を介して形成されたペプチドコンジュゲートを提供することに加えて、本発明は、その置換パターンが高度に均質なペプチドコンジュゲートを含む組成物を提供する。本発明の方法を使用して、ペプチドコンジュゲートの集団にわたって相当な割合のグリコシル連結基およびグリコシル部分が構造的に同一のアミノ酸またはグリコシル残基と結合しているペプチドコンジュゲートを形成することが可能である。したがって、第2の態様では、本発明は、グリコシル連結基、たとえば完全なグリコシル連結基を介してペプチドと共有結合している、水溶性ポリマー部分の集団を有するペプチドコンジュゲートを提供する。本発明の例示的なペプチドコンジュゲートでは、水溶性ポリマー集団の本質的にそれぞれのメンバーが、グリコシル連結基を介してペプチドのグリコシル残基と結合しており、グリコシル連結基が結合しているペプチドのそれぞれのグリコシル残基は、同じ構造を有する。
本発明の別の態様では、本発明は、糖ヌクレオチドも提供する。例示的な本実施形態による種には、以下が含まれる。
上述のコンジュゲートに加えて、本発明は、これらおよび他のコンジュゲートを調製する方法を提供する。さらに、本発明は、本発明のコンジュゲートを、疾患を発生する危険性にある対象または疾患に罹患している対象に投与することによって、病状を予防、治癒または寛解させる方法を提供する。
(a)それだけには限定されないが、N−ヒドロキシスクシンイミドエステル、N−ヒドロキシベンズトリアゾールエステル、酸ハロゲン化物、アシルイミダゾール、チオエステル、p−ニトロフェニルエステル、アルキル、アルケニル、アルキニルおよび芳香族エステルを含めた、カルボキシル基およびその様々な誘導体;
(b)たとえば、エステル、エーテル、アルデヒド、などに変換することができるヒドロキシル基
(c)ハロゲン化物を、後にたとえばアミン、カルボン酸陰イオン、チオール陰イオン、カルボアニオン、またはアルコキシドイオンなどの求核基で置き換えて、ハロゲン原子の官能基で新しい基の共有結合をもたらすことができる、ハロアルキル基;
(d)たとえばマレイミド基など、ディールズ−アルダー反応に参加することができるジエノフィル基;
(e)たとえばイミン、ヒドラゾン、セミカルバゾンもしくはオキシムなどのカルボニル誘導体の形成を介して、または、グリニャール付加もしくはアルキルリチウム付加などの機構を介して、続いて誘導化が可能な、アルデヒドまたはケトン基;
(f)続いてアミンと反応させて、たとえば、スルホンアミドを形成する、ハロゲン化スルホニル基;
(g)たとえばジスルフィドに変換させるまたはハロゲン化アシルと反応させることができるチオール基;
(h)たとえば、アシル化、アルキル化または酸化することができる、アミンまたはスルフヒドリル基;
(i)たとえば、シクロ付加、アシル化、ミカエル付加などを受けることができるアルケン;ならびに
(j)たとえば、アミンおよびヒドロキシル化合物と反応することができるエポキシド。
PEG修飾糖は、コンジュゲーションを媒介するために適切な酵素を用いて、グリコシル化または非グリコシル化ペプチドとコンジュゲートされている。好ましくは、修飾されたドナー糖、酵素および受容体ペプチドの濃度は、グリコシル化が、受容体が消費されるまで進行するように選択する。以下に記述の検討事項は、シアリルトランスフェラーゼのコンテクストで記載しているが、一般に他のグリコシルトランスフェラーゼ反応に適用可能である。本発明で使用するための好ましいシアリルトランスフェラーゼリストを図6に提供する。
本発明は、グリコpeg化の「ワンポット」方法を提供する。ワンポット方法は、ペプチドコンジュゲートを作製する他の例示的なプロセスとは明確に異なり、シアリダーゼを用いた逐次的な脱シアリル化、続いて陰イオン交換カラム上でのアシアロペプチドの精製、その後、CMP−シアル酸−PEGおよびグリコシルトランスフェラーゼ(ST3Gal3など)、エキソグリコシダーゼまたはエンドグリコシダーゼを使用したグリコPEG化を用いる。その後、ペプチドコンジュゲートを陰イオン交換、次いでサイズ排除クロマトグラフィーによって精製して、精製したペプチドコンジュゲートを生成する。
別の例示的な実施形態では、本発明は、ペプチドを脱シアリル化する方法を提供する。本方法は、好ましくは、少なくとも約40%、好ましくは45%、好ましくは約50%、好ましくは約55%、好ましくは約60%、好ましくは約65%、好ましくは約70%、好ましくは約75%、好ましくは約80%、好ましくは少なくとも85%、より好ましくは少なくとも90%、さらにより好ましくは、少なくとも92%、好ましくは少なくとも94%、さらにより好ましくは少なくとも96%、さらにより好ましくは少なくとも98%、さらにより好ましくは100%ジシアリル化されたペプチドを提供する。
本明細書中に記載のペプチドコンジュゲートを合成する例示的な実施形態では、選択した時間の後、反応構成要素/試薬の1つまたは複数の追加のアリコートを反応混合物に加える。例示的な実施形態では、ペプチドコンジュゲートはペプチドコンジュゲートである。別の例示的な実施形態では、加える反応構成要素/試薬は修飾糖ヌクレオチドである。修飾糖ヌクレオチドを反応内に導入することにより、グリコPEG化反応が完了まで駆動される可能性が高まる。例示的な実施形態では、ヌクレオチド糖は、本明細書中に記載のCMP−SA−PEGである。例示的な実施形態では、加える反応構成要素/試薬はシアリダーゼである。例示的な実施形態では、加える反応構成要素/試薬はグリコシルトランスフェラーゼである。例示的な実施形態では、加える反応構成要素/試薬はマグネシウムである。例示的な実施形態では、加える追加のアリコートは、反応の開始時に加えた最初の量の約10%、または20%、または30%、または40%、または50%、または60%、または70%、または80%または90%を表す。例示的な実施形態では、反応構成要素/試薬は、反応開始の約3時間、または6時間、または8時間、または10時間、または12時間、または18時間、または24時間、または30時間、または36時間後に反応に加える。
上記プロセスによって生成した生成物は、精製せずに使用することができる。しかし、通常は、生成物ならびに中間体の1つまたは複数の、たとえば、ヌクレオチド糖、分枝鎖状および直鎖状PEG種、修飾糖および修飾ヌクレオチド糖を回収することが好ましい。薄層もしくは厚層クロマトグラフィー、カラムクロマトグラフィー、イオン交換クロマトグラフィー、または膜濾過などの、グリコシル化されたペプチドを回収するための標準の周知の技術を使用することができる。膜濾過、より好ましくは逆浸透膜を利用すること、または、本明細書以下および本明細書中で言及した文献に記載されている、回収のための1つもしくは複数のカラムクロマトグラフィー技術を使用することが好ましい。たとえば、膜が約3000〜約10,000の分子量カットオフを有する膜濾過を使用して、グリコシルトランスフェラーゼなどのタンパク質を除去することができる。特定の事例では、生成物の精製を確実にするために、不純物と生成物との間の分子量カットオフの差異を利用する。たとえば、生成物ペプチド−SA−PEG−40kDを未反応のCMP−SA−PEG−40kDから精製するためには、たとえば、ペプチド−SA−PEG−40kDが濃縮水中に留まることを可能にする一方で、CMP−SA−PEG−40kDが濾液中に流れることを可能にするフィルターを選択しなければならない。その後、ナノ濾過または逆浸透を使用して、塩を除去するおよび/または生成物サッカライドを精製することができる(たとえば国際公開公報WO98/15581号参照)。ナノフィルター膜は、一価の塩を通すが、使用する膜に応じて約100〜約2,000ダルトンより大きい多価の塩および非帯電の溶質を保持する、逆浸透膜のクラスである。したがって、典型的な応用では、本発明の方法によって調製したサッカライドは膜中に保持され、汚染塩は通過する。
別の態様では、本発明は薬剤組成物を提供する。薬剤組成物には、薬学的に許容される希釈剤、および天然に存在しない、PEG部分、治療用部分または生体分子とグリコシル化または非グリコシル化ペプチドとの間の共有コンジュゲートが含まれる。ポリマー、治療用部分または生体分子は、ペプチドとポリマー、治療用部分または生体分子との間に差し込まれており、その両方に共有結合している、完全なグリコシル連結基を介して、ペプチドとコンジュゲートしている。
実施例
無血清培地中で発現させた第VIIa因子、血清含有培地中で産生させた第VIIa因子、ならびに3つの第VIIa因子の突然変異体N145Q、N322Q、および類似体DVQ(V158D/E296V/M298Q)。
アシアロ−第VIIa因子(1mg/mL)のシアリル−PEG化(「グリコPEG化」)を、100U/LのST3Gal−IIIならびに200μMのCMP−シアル酸−PEG(40kD、20kD、10kD、5kD、および2kD)を用いて、32℃、脱シアリル化緩衝液中で2〜6時間行った。適切な反応時間が終了した後、さらなるグリコPEG化を最小限にするためにPEG化された試料を直ちに精製した。
第VIIa因子のグリコPEG化された試料を、変性陰イオン交換方法で精製した。試料は5℃で取り扱った。カラムにロードする直前に、10mLの第VIIa因子の溶液あたり1gのChelex 100(BioRad)を、再構築した試料に加えた。10分間撹拌した後、懸濁液を、真空系を用いて酢酸セルロース膜(0.2μm)上で濾過した。フィルター上の保持されたキレート剤樹脂を、10mLのバルクあたり1〜2mLの水で1回洗浄した。濾液の伝導率を5℃で10mS/cmに調節し、必要な場合はpH8.6に調節した。
PEG化された第VIIa因子を、逆相カラム(Zorbax 300SB-C3、5μmの粒子径、2.1×150mm)上のHPLCで分析した。溶出液は、A)水中の0.1のTFAおよびB)アセトニトリル中の0.09%のTFAであった。検出は214nmであった。勾配、流速、およびカラム温度は、PEGの長さに依存した(40kD、20kD、および10kDのPEG:35〜65%のB、30分、0.5mL/分、45℃;10kDのPEG:35〜60%のB、30分、0.5mL/分、45℃;5kD:40〜50%のB、40分、0.5mL/分、45℃;2kD:38〜43%のB、67分、0.6mL/分、55℃)。それぞれのピークのアイデンティティーは、4つの異なる証拠、すなわち、ネイティブ第VIIa因子の既知の保持時間、単離したピークのSDS−PAGE遊走、単離したピークのMALDI−TOF質量スペクトル、および結合しているPEG数の増加に伴うそれぞれのピークの保持時間の規則的な進行のうちの、2つ以上に基づいて割り当てた。
試料(1mg/mLの濃度で10μL)を還元緩衝液(40μL、50mMのNaCl、10mMのグリシルグリシン、15mMのEDTA、8Mの尿素、20mMのDTT、pH8.6)と、15分間、室温で混合することによって、第VIIa因子およびPEG化された第VIIa因子の変異体を還元した。水(50μL)を加え、HPLCに注入するまで(12時間未満)試料を4℃まで冷却した。HPLCカラム、溶出液、および検出は、非還元試料について上述したとおりである。流速は0.5mL/分であり、勾配は30〜55%のB、90分間であり、次いで、90%のBまでの手短な洗浄サイクルであった。それぞれのピークのアイデンティティーは、実施例4に記載のように割り当てた。
PEG化された試料および標準物質を2つ組で試験し、100mMのNaCl、5mMのCaCl2、0.1%のBSA(重量/体積)、50mMのトリス、pH7.4で希釈した。標準物質および試料は、0.1〜10ng/mLの範囲にわたってアッセイした。等体積の希釈した標準物質および試料を、第VIIa因子欠乏血漿(Diagnostica Stago)と混合し、アッセイするまで、氷上で4時間以内までだけ保存した。
本実施例では、BHK細胞中で作製された組換え第VIIa因子のPEG化を記載する。
第VIIa因子(5mgを生成物調製緩衝液で最終濃度1mg/mLまで希釈)、CMP−SA−PEG−10kD(10mM、60μL)ならびにクロカビ酵素ST3Gal3(33U/L)および10mMのヒスチジン、50mMのNaCl、20mMのCaCl2を、10U/L、1U/L、0.5U/Lまたは0.1U/Lのシアリダーゼ(CalBiochem)と共に反応器内で合わせた。成分を混合し、32℃でインキュベーションした。アリコートを30分間隔で最初の4時間分析することによって、反応の進行を測定した。その後、アリコートを20時間時点で取り出し、SDS−PAGEに供した。PEG化の程度は、1mLを1.5、2.5および3.5時間時点で取り出し、試料をPoros 50HQカラムで精製することによって決定した。
a.化合物1の合成
水酸化カリウム(84.2mg、1.5mmol、粉末として)を、無水メタノール(20L)中のL−システイン(93.7mg、0.75mmol)の溶液に、アルゴン下で加えた。混合物を室温で30分間撹拌し、その後、分子質量20キロダルトンのmPEG−O−トシレート(Ts;1.0g、0.05mmol)をいくつかの部分に分けて、2時間かけて加えた。混合物を室温で5日間撹拌し、ロータリーエバポレーターで濃縮した。残渣を水(30mL)で希釈し、室温で2時間撹拌して、任意の過剰の20キロダルトンのmPEG−O−トシレートをすべて破壊した。その後、溶液を酢酸で中和し、pHをpH5.0に調節し、逆相クロマトグラフィー(C−18シリカ)カラムにロードした。カラムをメタノール/水の勾配で溶出させ(生成物は約70%のメタノールで溶出する)、生成物の溶出は蒸発光散乱によって監視し、適切な画分を採取し、水(500mL)で希釈した。この溶液のクロマトグラフィーを行い(イオン交換、XK 50 Q、大きなビーズ、300mL、水酸化物の形態;水から水/酢酸−0.75Nの勾配)、適切な画分のpHを酢酸で6.0まで下げた。その後、この溶液を逆相カラム(C−18シリカ)で捕捉し、上述のメタノール/水の勾配で溶出させた。生成物の画分をプールし、濃縮し、水に再度溶かし、凍結乾燥して、453mg(44%)の白色固体(1)が得られた。
トリエチルアミン(約0.5mL)を、無水CH2Cl2(30mL)中の化合物1(440mg、22μmol)の溶液に、溶液が塩基性になるまで滴下した。CH2Cl2(20mL)中の20キロダルトンのmPEG−O−p−ニトロフェニルカーボネート(660mg、33μmol)およびN−ヒドロキシスクシンイミド(3.6mg、30.8μmol)の溶液をいくつかの部分に分けて、1時間かけて室温で加えた。反応混合物を室温で24時間撹拌した。その後、溶媒をロータリーエバポレーターによって除去し、残渣を水(100mL)に溶かし、1.0NのNaOHでpHを9.5に調節した。塩基性の溶液を室温で2時間撹拌し、その後、酢酸でpH7.0まで中和した。その後、溶液を逆相クロマトグラフィー(C−18シリカ)カラムにロードした。カラムをメタノール/水の勾配で溶出させ(生成物は約70%のメタノールで溶出する)、生成物の溶出は蒸発光散乱によって監視し、適切な画分を採取し、水(500mL)で希釈した。この溶液のクロマトグラフィーを行い(イオン交換、XK 50 Q、大きなビーズ、300mL、水酸化物の形態;水から水/酢酸−0.75Nの勾配)、適切な画分のpHを酢酸で6.0まで下げた。その後、この溶液を逆相カラム(C−18シリカ)で捕捉し、上述のメタノール/水の勾配で溶出させた。生成物の画分をプールし、濃縮し、水に再度溶かし、凍結乾燥して、575mg(70%)の白色固体(2)が得られた。
第VIIa因子のグリコPEG化(キャッピングを用いたワンポット)。第VIIa因子のグリコPEG化をワンポット反応で達成し、ここでは、脱シアリル化およびPEG化が同時に起こり、次いでシアル酸でのキャッピングが起こる。反応は、再循環水浴によって32℃に調節したジャケット付きガラス容器内で行った。最初に、濃縮した0.2μmで濾過した第VIIa因子を容器内に導入し、撹拌子と共に20分間撹拌することによって32℃まで加熱した。10mMのヒスチジン/50mMのNaCl/20mMのCaCl2、pH6.0中に4,000U/Lの濃度の乾燥粉末からシアリダーゼの溶液を作製した。第VIIa因子が32℃に達した後、シアリダーゼを第VIIa因子に加え、均一な溶液を確実にするために反応を約5分間撹拌し、その後、撹拌を停止した。脱シアリル化を1.0時間32℃で進行させた。脱シアリル化反応中、CMP−SA−PEG−40kDを10mMのヒスチジン/50mMのNaCl/20mMのCaCl2、pH6.0の緩衝液に溶かし、濃度は271nmでのUV吸光度によって決定した。CMP−SA−PEG−40kDが溶けた後、CMP−SA−PEG−40kDおよびST3Gal3を反応に加え、均一な溶液を確実にするために反応を約15分間、撹拌子と共に混合した。さらなる85mLの体積の緩衝液を加えて、反応を1.0Lにした。反応を撹拌子なしで24時間進行させた後、CMP−SAを4.3mMの濃度まで加えて、反応を停止させて残りの末端ガラクトース残基をシアル酸でキャッピングした。30分間、32℃で混合しながら反応停止を進行させた。反応の合計体積は、反応停止前に1.0Lであった。時点の試料(1mL)を0、4.5、7.5、および24時間で採取し、CMP−SAで反応停止させ、RP−HPLCおよびSDS−PAGEで分析した。
Claims (4)
- a)以下から選択されるメンバーである部分と共有結合したペプチドを含むペプチドコンジュゲート
R7は、H、置換または非置換アルキルおよび置換または非置換ヘテロアルキルから選択されるメンバーであり;
R3、R4、R5およびR6は、H、置換または非置換アルキル、OR8およびNHC(O)R9から独立して選択されるメンバーであり;
R8およびR9は、H、置換または非置換アルキル、置換または非置換ヘテロアルキル、シアル酸およびポリシアル酸から独立して選択され;
R3、R4、R5、R6のうちの少なくとも1つは、以下から選択されるメンバーである部分を含み:
A1、A2、A3、A4、A5、A6、A7、A8、A9、A10およびA11は、H、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、置換または非置換ヘテロアリール、−NA12A13、−OA12および−SiA12A13から独立して選択されるメンバーであり;
A12およびA13は、置換または非置換アルキル、置換または非置換ヘテロアルキル、置換または非置換シクロアルキル、置換または非置換ヘテロシクロアルキル、置換または非置換アリール、および置換または非置換ヘテロアリールから独立して選択されるメンバーである]。 - ペプチドコンジュゲート中の前記ペプチドが、骨形態発生タンパク質2(BMP−2)、骨形態発生タンパク質7(BMP−7)、骨形態発生タンパク質15(BMP−15)、ニューロトロフィン−3(NT−3)、フォンウィルブランド因子(vWF)プロテアーゼ、第VII因子、第VIIa因子、第VIII因子、第IX因子、第X因子、第XI因子、B−ドメイン欠失第VIII因子、完全長第VIII因子を有するvWF−第VIII因子融合タンパク質、B−ドメイン欠失第VIII因子を有するvWF−第VIII因子融合タンパク質、エリスロポエチン(EPO)、顆粒球コロニー刺激因子(G−CSF)、顆粒球−マクロファージコロニー刺激因子(GM−CSF)、インターフェロンα、インターフェロンβ、インターフェロンγ、α1−抗トリプシン(ATT、すなわちα−1プロテアーゼ阻害剤)、グルコセレブロシダーゼ、組織型プラスミノーゲン活性化剤(TPA)、インターロイキン−2(IL−2)、ウロキナーゼ、ヒトDNase、インスリン、B型肝炎表面タンパク質(HbsAg)、ヒト成長ホルモン、TNF受容体−IgG Fc領域融合タンパク質(Enbrel(商標))、抗HER2モノクローナル抗体(Herceptin(商標))、呼吸器合胞体ウイルスのタンパク質Fに対するモノクローナル抗体(Synagis(商標))、TNF−αに対するモノクローナル抗体(Remicade(商標))、糖タンパク質IIb/IIIaに対するモノクローナル抗体(Reopro(商標))、CD20に対するモノクローナル抗体(Rituxan(商標))、抗トロンビンIII(AT III)、ヒト絨毛性ゴナドトロピン(hCG)、α−ガラクトシダーゼ(Fabrazyme(商標))、α−イズロニダーゼ(Aldurazyme(商標))、卵胞刺激ホルモン、β−グルコシダーゼ、抗TNF−αモノクローナル抗体、グルカゴン様ペプチド−1(GLP−1)、グルカゴン様ペプチド−2(GLP−2)、β−グルコシダーゼ、α−ガラクトシダーゼAおよび線維芽細胞成長因子から選択されるメンバーである、請求項1に記載のペプチドコンジュゲート。
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