JP2013520205A - ピチア・パストリスにおいて産生される治療用糖タンパク質上のn−グリコシル化部位占拠を増加させるための方法 - Google Patents
ピチア・パストリスにおいて産生される治療用糖タンパク質上のn−グリコシル化部位占拠を増加させるための方法 Download PDFInfo
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Abstract
Description
本発明は、異種糖タンパク質を発現するように遺伝的に操作され本発明により修飾された組換え宿主細胞において産生される該異種糖タンパク質のN−グリコシル化部位占拠を、本発明により修飾されていない組換え宿主細胞において産生される治療用糖タンパク質のN−グリコシル化部位占拠と比べて増加させるための方法に関する。特に、本発明は、異種単一サブユニットオリゴサッカリルトランスフェラーゼ[これは、特定の実施形態においては、酵母オリゴサッカリルトランスフェラーゼ(OTase)複合体の少なくとも1つの必須タンパク質の突然変異の致死表現型を、宿主細胞の内在性OTase複合体の存在下、機能的に抑制しうる]を過剰発現する組換え宿主細胞、および異種糖タンパク質を製造するためのこれらの宿主細胞の使用方法を提供する。
組換えヒトタンパク質の製造は、それが可能となったことにより、ヒトに対する医療に大きな進歩をもたらしており、依然として、薬物発見の、活発な領域である。多数の治療用タンパク質は、適切な構造−機能活性およびその後のヒト血清中での安定性を確保するためには、該タンパク質の特定のアスパラギン残基へのグリカンの翻訳後付加(N−グリコシル化)を要する。ヒトにおける治療用途の場合、糖タンパク質はヒト様N−グリコシル化を要する。ヒト様糖タンパク質プロセシングを模擬しうる哺乳類細胞系(例えば、チャイニーズハムスター卵巣(CHO)細胞、ヒト網膜細胞)は、低いタンパク質力価、長い発酵時間、不均一な産物および継続的なウイルス混入を含む幾つかの欠点を有する。したがって、短い発酵時間で高いタンパク質力価を与えるだけでなくヒト様糖タンパク質をも産生しうる発現系を使用することが望ましい。
本発明は、本明細書に開示されているとおりに修飾された宿主細胞において産生される糖タンパク質のN−グリコシル化部位占拠が、本明細書に開示されているとおりには修飾されていない宿主細胞において産生される同じ糖タンパク質のN−グリコシル化部位占拠と比べて増加している治療用糖タンパク質の、本明細書に開示されているとおりに修飾された組換え宿主細胞における製造方法を提供する。例えば、本明細書に開示されているとおりに修飾された酵母宿主細胞においては、それにおいて産生される糖タンパク質のN−グリコシル化部位占拠は、組換え哺乳類またはヒト細胞において産生される同じ糖タンパク質のN−グリコシル化部位占拠と同じか又はより類似しているであろう。
本明細書中で用いる「N−グリカン」および「グリコフォーム(glycoform)」なる語は互換的に用いられ、N−結合オリゴ糖を意味し、例えば、ポリペプチドのアスパラギン残基にアスパラギン−N−アセチルグルコサミン結合により結合しているN−結合オリゴ糖を意味する。N−結合糖タンパク質は、タンパク質中のアスパラギン残基のアミド窒素に結合したN−アセチルグルコサミン残基を含有する。糖タンパク質上で見出される主な糖としては、グルコース、ガラクトース、マンノース、フコース、N−アセチルガラクトサミン(GalNAc)、N−アセチルグルコサミン(GlcNAc)およびシアル酸(例えば、N−アセチル−ノイラミン酸(NANA))が挙げられる。N−結合糖タンパク質の場合、糖基のプロセシングは翻訳と共に小胞体の内腔(ERルーメン)で生じ、翻訳後にゴルジ装置内で継続する。
本発明は、糖タンパク質のN−グリコシル化部位占拠が、本明細書に開示されているとおりには修飾されていない宿主細胞において産生された同じ糖タンパク質のN−グリコシル化部位占拠と比べて増加している治療用糖タンパク質の、宿主細胞における製造方法を提供する。下等真核宿主細胞、例えば酵母宿主細胞または糸状菌宿主細胞において本発明を実施する場合、該宿主細胞において産生された組換え糖タンパク質のN−グリコシル化部位占拠は、哺乳類またはヒト宿主細胞において産生された同じ組換え糖タンパク質のN−グリコシル化部位占拠と同じであるか又はより類似している。
(グリコシル化タンパク質のモル)/(グリコシル化タンパク質のモル+非グリコシル化タンパク質のモル)×100=Nグリコシル化部位占拠率(%)
を用いて、N−グリコシル化部位占拠を決定するというものである。
(GHCのモル)/(GHCのモル+NGHCのモル)×100=Nグリコシル化部位HC占拠率(%)
を用いて決定される。
(Nグリカンの合計モル)/(糖タンパク質の合計モル×部位の数)×100=Nグリコシル化部位占拠率(%)
前記の式は、占拠されている合計N−グリコシル化部位の割合(%)を与えるであろう。
用いた高速液体クロマトグラフィー(HPLC)系は、自動注入装置、カラム加熱区画ならびに210および280nmで検出するUV検出装置を備えたAgilent 1200からなるものであった。この系で行った全てのLC−MS実験は1mL/分で行った。該流速はMS検出で分かれ(split)なかった。質量分析は、Accurate−Mass Q−TOF LC/MS 6520(Agilent technology)で正イオンモードで行った。二重ESI源の温度は350℃に設定された。窒素気流速度はコーンに関しては13L/時間および350L/時間に設定され、ネブライザーは45psigに設定され、キャピラリーに4500ボルトが加えられた。質量校正およびタンパク質質量測定のために、API−TOF参照質量対処キットにより、922.009の参照質量をHP−0921から調製した。300〜3000m/zのイオンスペクトル範囲のデータを得、Agilent Masshunterを使用して処理した。
この研究において用いた高速液体クロマトグラフィー(HPLC)系は、自動注入装置、カラム加熱区画ならびに210および280nmで検出するUV検出装置を備えたAgilent 1200からなるものであった。この系で行った全てのLC−MS実験は1mL/分で行った。該流速はMS検出で分かれ(split)なかった。質量分析は、Accurate−Mass Q−TOF LC/MS 6520(Agilent technology)で正イオンモードで行った。二重ESI源の温度は350℃に設定された。窒素気流速度はコーンに関しては13L/時間および350L/時間に設定され、ネブライザーは45psigに設定され、キャピラリーに4500ボルトが加えられた。質量校正およびタンパク質質量測定のために、API−TOF参照質量対処キットにより、922.009の参照質量をHP−0921から調製した。300〜3000m/zのイオンスペクトル範囲のデータを得、Agilent Masshunterを使用して処理した。
完全抗体サンプル(50μg)を、50μLの25mM NH4HCO3(pH7.8)を使用して調製した。脱グリコシル化抗体に関しては、50μLのアリコートの完全抗体サンプルをPNGアーゼF(10単位)で37℃で18時間処理した。還元抗体を、完全抗体または脱グリコシル化抗体のアリコートに1M DTTを10mMの最終濃度まで加えることにより調製し、37℃で30分間インキュベートした。
実施例1〜4に開示されている株の幾つかを製造するために使用した配列を表12に示す。
Claims (26)
- 異種糖タンパク質の製造方法であって、
(a)異種単一サブユニットオリゴサッカリルトランスフェラーゼをコードする少なくとも1つの核酸分子と、該異種糖タンパク質をコードする核酸分子とを含む宿主細胞[ここにおいて、内在性OTase複合体を含むタンパク質をコードする内在性宿主細胞遺伝子が発現される]を準備し、
(b)該異種糖タンパク質を発現させるための条件下、該宿主細胞を培養して、該異種糖タンパク質を産生させることを含む製造方法。 - 該単一サブユニットオリゴサッカリルトランスフェラーゼがリーシュマニア属種(Leishmania sp.)STT3Aタンパク質、STT3Bタンパク質、STT3Cタンパク質、STT3Dタンパク質またはそれらの組合せである、請求項1記載の製造方法。
- 該単一サブユニットオリゴサッカリルトランスフェラーゼがリーシュマニア・メジャー(Leishmania major)STT3Dタンパク質である、請求項1記載の製造方法。
- 該宿主細胞により産生された該異種糖タンパク質の少なくとも70%が完全占拠N−グリコシル化部位を有する、請求項1記載の製造方法。
- 該宿主細胞が、1以上の哺乳類またはヒト様N−グリカンを含む糖タンパク質を産生するように遺伝的に操作されている、請求項1記載の製造方法。
- 該異種糖タンパク質が、エリスロポエチン(EPO);サイトカイン、例えばインターフェロンα、インターフェロンβ、インターフェロンγおよびインターフェロンω;ならびに顆粒球−コロニー刺激因子(GCSF);顆粒球マクロファージ−コロニー刺激因子(GM−CSF);凝固因子、例えば因子VIII、因子IXおよびヒトプロテインC;アンチトロンビンIII;トロンビン;可溶性IgE受容体α鎖;免疫グロブリン、例えばIgG、IgGフラグメント、IgG融合体およびIgM;免疫接着物質および他のFc融合タンパク質、例えば可溶性TNF受容体−Fc融合タンパク質;RAGE−Fc融合タンパク質;インターロイキン;ウロキナーゼ;キマーゼ;尿素トリプシンインヒビター;IGF結合性タンパク質;上皮増殖因子;成長ホルモン放出因子;アネキシンV融合タンパク質;アンジオスタチン;血管内皮増殖因子−2;骨髄前駆体抑制因子−1;オステオプロテジェリン;α−1−アンチトリプシン;α−フェトプロテイン;DNアーゼII;ヒトプラスミノーゲンのクリングル3;グルコセレブロシダーゼ;TNF結合タンパク質1;濾胞刺激ホルモン;細胞傷害性Tリンパ球関連抗原4−Ig;膜貫通アクチベーターおよびカルシウムモジュレーターおよびシクロフィリンリガンド;グルカゴン様タンパク質1;またはIL−2受容体アゴニストである、請求項1記載の製造方法。
- 該異種タンパク質が抗Her2抗体、抗RSV(呼吸器性シンシチウムウイルス)抗体、抗TNFα抗体、抗VEGF抗体、抗CD3受容体抗体、抗CD41 7E3抗体、抗CD25抗体、抗CD52抗体、抗CD33抗体、抗IgE抗体、抗CD11a抗体、抗EGF受容体抗体または抗CD20抗体である、請求項1記載の製造方法。
- 該宿主細胞が、ピチア・パストリス(Pichia pastoris)、ピチア・フィンランディカ(Pichia finlandica)、ピチア・トレハロフィラ(Pichia trehalophila)、ピチア・コクラメ(Pichia koclamae)、ピチア・メンブラネファシエンス(Pichia membranaefaciens)、ピチア・オプンチエ(Pichia opuntiae)、ピチア・テルモトレランス(Pichia thermotolerans)、ピチア・サリクタリア(Pichia salictaria)、ピチア・グエルクウム(Pichia guercuum)、ピチア・ピエペリ(Pichia pijperi)、ピチア・スチプティス(Pichia stiptis)、ピチア・メタノリカ(Pichia methanolica)、ピチア・ミヌタ(Pichia minuta)(オガタエア・ミヌタ(Ogataea minuta)、ピチア・リンドネリ(Pichia lindneri))、ピチア属種(Pichia sp.)、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)、サッカロミセス属種(Saccharomyces sp.)、ハンゼヌラ・ポリモルファ(Hansenula polymorpha)、クライベロミセス属種(Kluyveromyces sp.)、クライベロミセス・ラクチス(Kluyveromyces lactis)、カンジダ・アルビカンス(Candida albicans)、アスペルギルス・ニデュランス(Aspergillus nidulans)、アスペルギルス・ニガー(Aspergillus niger)、アスペルギルス・オリゼ(Aspergillus oryzae)、トリコデルマ・レーゼイ(Trichoderma reesei)、クリソスポリウム・ルックノウエンス(Chrysosporium lucknowense)、フザリウム属種(Fusarium sp.)、フザリウム・グラミネウム(Fusarium gramineum)、フザリウム・ベネナツム(Fusarium venenatum)、ニューロスポラ・クラッサ(Neurospora crassa)、植物細胞、昆虫細胞および哺乳類細胞からなる群から選択される、請求項1記載の製造方法。
- 該宿主細胞がピチア・パストリス(P.pastoris)のoch1突然変異体である、請求項1記載の製造方法。
- 糖タンパク質組成物における糖タンパク質上のN−グリコシル化部位の少なくとも70%がN−グリカンで占拠されている、該糖タンパク質組成物の製造方法であって、
(a)異種単一サブユニットオリゴサッカリルトランスフェラーゼをコードする少なくとも1つの核酸分子と、該糖タンパク質をコードする核酸分子とを含む組換え宿主細胞[ここにおいて、内在性OTase複合体をコードする宿主細胞遺伝子が発現される]を準備し、
(b)該糖タンパク質を発現させるための条件下、該組換え宿主細胞を培養して、該組成物における糖タンパク質上のN−グリコシル化部位の少なくとも70%がN−グリカンで占拠されている該組成物を産生させることを含む製造方法。 - 該単一サブユニットオリゴサッカリルトランスフェラーゼがリーシュマニア属種(Leishmania sp.)STT3Aタンパク質、STT3Bタンパク質、STT3Cタンパク質、STT3Dタンパク質またはそれらの組合せである、請求項10記載の製造方法。
- 該単一サブユニットオリゴサッカリルトランスフェラーゼがリーシュマニア・メジャー(Leishmania major)STT3Dタンパク質である、請求項10記載の製造方法。
- 該異種糖タンパク質が、エリスロポエチン(EPO);サイトカイン、例えばインターフェロンα、インターフェロンβ、インターフェロンγおよびインターフェロンω;ならびに顆粒球−コロニー刺激因子(GCSF);顆粒球マクロファージ−コロニー刺激因子(GM−CSF);凝固因子、例えば因子VIII、因子IXおよびヒトプロテインC;アンチトロンビンIII;トロンビン;可溶性IgE受容体α鎖;免疫グロブリン、例えばIgG、IgGフラグメント、IgG融合体およびIgM;免疫接着物質および他のFc融合タンパク質、例えば可溶性TNF受容体−Fc融合タンパク質;RAGE−Fc融合タンパク質;インターロイキン;ウロキナーゼ;キマーゼ;尿素トリプシンインヒビター;IGF結合性タンパク質;上皮増殖因子;成長ホルモン放出因子;アネキシンV融合タンパク質;アンジオスタチン;血管内皮増殖因子−2;骨髄前駆体抑制因子−1;オステオプロテジェリン;α−1−アンチトリプシン;α−フェトプロテイン;DNアーゼII;ヒトプラスミノーゲンのクリングル3;グルコセレブロシダーゼ;TNF結合タンパク質1;濾胞刺激ホルモン;細胞傷害性Tリンパ球関連抗原4−Ig;膜貫通アクチベーターおよびカルシウムモジュレーターおよびシクロフィリンリガンド;グルカゴン様タンパク質1;またはIL−2受容体アゴニストである、請求項10記載の製造方法。
- 該異種タンパク質が抗Her2抗体、抗RSV(呼吸器性シンシチウムウイルス)抗体、抗TNFα抗体、抗VEGF抗体、抗CD3受容体抗体、抗CD41 7E3抗体、抗CD25抗体、抗CD52抗体、抗CD33抗体、抗IgE抗体、抗CD11a抗体、抗EGF受容体抗体または抗CD20抗体である、請求項10記載の製造方法。
- 該組換え宿主細胞が酵母または糸状菌宿主細胞である、請求項10記載の製造方法。
- (a)少なくとも1つの異種単一サブユニットオリゴサッカリルトランスフェラーゼをコードする第1核酸分子と、
(b)異種糖タンパク質をコードする第2核酸分子とを含む宿主細胞であって、
該宿主細胞が、内在性オリゴサッカリルトランスフェラーゼ(OTase)複合体を含むタンパク質をコードする遺伝子を発現する、宿主細胞。 - 該単一サブユニットオリゴサッカリルトランスフェラーゼがリーシュマニア属種(Leishmania sp.)STT3Aタンパク質、STT3Bタンパク質、STT3Cタンパク質またはSTT3Dタンパク質である、請求項16記載の製造方法。
- 該単一サブユニットオリゴサッカリルトランスフェラーゼがリーシュマニア・メジャー(Leishmania major)STT3Dタンパク質である、請求項16記載の製造方法。
- 該宿主細胞が、1以上の哺乳類またはヒト様N−グリカンを含む糖タンパク質を産生するように遺伝的に操作されている、請求項16記載の宿主細胞。
- 該異種糖タンパク質が、エリスロポエチン(EPO);サイトカイン、例えばインターフェロンα、インターフェロンβ、インターフェロンγおよびインターフェロンω;ならびに顆粒球−コロニー刺激因子(GCSF);顆粒球マクロファージ−コロニー刺激因子(GM−CSF);凝固因子、例えば因子VIII、因子IXおよびヒトプロテインC;アンチトロンビンIII;トロンビン;可溶性IgE受容体α鎖;免疫グロブリン、例えばIgG、IgGフラグメント、IgG融合体およびIgM;免疫接着物質および他のFc融合タンパク質、例えば可溶性TNF受容体−Fc融合タンパク質;RAGE−Fc融合タンパク質;インターロイキン;ウロキナーゼ;キマーゼ;尿素トリプシンインヒビター;IGF結合性タンパク質;上皮増殖因子;成長ホルモン放出因子;アネキシンV融合タンパク質;アンジオスタチン;血管内皮増殖因子−2;骨髄前駆体抑制因子−1;オステオプロテジェリン;α−1−アンチトリプシン;α−フェトプロテイン;DNアーゼII;ヒトプラスミノーゲンのクリングル3;グルコセレブロシダーゼ;TNF結合タンパク質1;濾胞刺激ホルモン;細胞傷害性Tリンパ球関連抗原4−Ig;膜貫通アクチベーターおよびカルシウムモジュレーターおよびシクロフィリンリガンド;グルカゴン様タンパク質1;またはIL−2受容体アゴニストである、請求項16記載の宿主細胞。
- 該異種糖タンパク質が抗Her2抗体、抗RSV(呼吸器性シンシチウムウイルス)抗体、抗TNFα抗体、抗VEGF抗体、抗CD3受容体抗体、抗CD41 7E3抗体、抗CD25抗体、抗CD52抗体、抗CD33抗体、抗IgE抗体、抗CD11a抗体、抗EGF受容体抗体または抗CD20抗体である、請求項16記載の宿主細胞。
- 該宿主細胞が、ピチア・パストリス(Pichia pastoris)、ピチア・フィンランディカ(Pichia finlandica)、ピチア・トレハロフィラ(Pichia trehalophila)、ピチア・コクラメ(Pichia koclamae)、ピチア・メンブラネファシエンス(Pichia membranaefaciens)、ピチア・オプンチエ(Pichia opuntiae)、ピチア・テルモトレランス(Pichia thermotolerans)、ピチア・サリクタリア(Pichia salictaria)、ピチア・グエルクウム(Pichia guercuum)、ピチア・ピエペリ(Pichia pijperi)、ピチア・スチプティス(Pichia stiptis)、ピチア・メタノリカ(Pichia methanolica)、ピチア・ミヌタ(Pichia minuta)(オガタエア・ミヌタ(Ogataea minuta)、ピチア・リンドネリ(Pichia lindneri))、ピチア属種(Pichia sp.)、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)、サッカロミセス属種(Saccharomyces sp.)、ハンゼヌラ・ポリモルファ(Hansenula polymorpha)、クライベロミセス属種(Kluyveromyces sp.)、クライベロミセス・ラクチス(Kluyveromyces lactis)、カンジダ・アルビカンス(Candida albicans)、アスペルギルス・ニデュランス(Aspergillus nidulans)、アスペルギルス・ニガー(Aspergillus niger)、アスペルギルス・オリゼ(Aspergillus oryzae)、トリコデルマ・レーゼイ(Trichoderma reesei)、クリソスポリウム・ルックノウエンス(Chrysosporium lucknowense)、フザリウム属種(Fusarium sp.)、フザリウム・グラミネウム(Fusarium gramineum)、フザリウム・ベネナツム(Fusarium venenatum)、ニューロスポラ・クラッサ(Neurospora crassa)、植物細胞、昆虫細胞および哺乳類細胞からなる群から選択される、請求項16記載の宿主細胞。
- 複数の抗体と医薬上許容される担体とを含む糖タンパク質組成物であって、該組成物中の抗体分子の少なくとも70%が、占拠された両方のN−グリコシル化部位を有し、該N−グリカンの約50〜70モル%がG0であり、該N−グリカンの15〜25モル%がG1であり、該N−グリカンの約5〜15モル%がMan5GlcNAc2コア構造を含む、糖タンパク質組成物。
- 該抗体が、抗Her2抗体、抗RSV(呼吸器性シンシチウムウイルス)抗体、抗TNFα抗体、抗VEGF抗体、抗CD3受容体抗体、抗CD41 7E3抗体、抗CD25抗体、抗CD52抗体、抗CD33抗体、抗IgE抗体、抗CD11a抗体、抗EGF受容体抗体および抗CD20抗体からなる群から選択される抗体を含む、請求項23記載の組成物。
- 組換えピチア・パストリス(Pichia pastoris)株YGLY14401の遺伝子型と同じ遺伝子型を有する組換えピチア・パストリス(Pichia pastoris)宿主細胞。
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KR20120134116A (ko) | 2012-12-11 |
CA2788992A1 (en) | 2011-09-01 |
US8715963B2 (en) | 2014-05-06 |
BR112012020882A2 (pt) | 2015-11-03 |
WO2011106389A1 (en) | 2011-09-01 |
EP2539430A4 (en) | 2014-02-12 |
CN102858949A (zh) | 2013-01-02 |
EP2539430A1 (en) | 2013-01-02 |
JP5976549B2 (ja) | 2016-08-24 |
US20120328626A1 (en) | 2012-12-27 |
EP2539430B1 (en) | 2016-09-14 |
US20140227290A1 (en) | 2014-08-14 |
MX2012009802A (es) | 2012-09-12 |
KR101930961B1 (ko) | 2018-12-19 |
RU2012140429A (ru) | 2014-03-27 |
CN102858949B (zh) | 2016-07-06 |
AU2011220878A1 (en) | 2012-08-23 |
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