JP2021059585A - 受容体媒介クリアランスが減少した、生理活性ポリペプチド単量体と免疫グロブリンFc断片との結合体及びその製造方法 - Google Patents
受容体媒介クリアランスが減少した、生理活性ポリペプチド単量体と免疫グロブリンFc断片との結合体及びその製造方法 Download PDFInfo
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Abstract
Description
3.4kDaのプロピオン(propion)−ALD2 PEG(IDB. 韓国)をGLP−1アゴニストのリシン(Lysine)と位置特異的に反応させ、その後PEGとGLP−1アゴニストが1:1で結合された連結体を得るために、前記反応混合物を陽イオン交換カラムを用いてモノペグ化された(mono-PEGylated)GLP−1アゴニストを精製した。免疫グロブリンFcのN末端と特異的にモノペグ化されたGLP−1アゴニストが連結されたGLP−1アゴニスト−免疫グロブリンFc断片結合体を製造するために、pH5.0〜8.2の条件で反応させた。カップリング反応後に疎水性カラムと陰イオン交換カラムを用いた2段階の精製方法を行うことにより、最終的に位置特異的に結合されたGLP−1アゴニスト−免疫グロブリンFc断片結合体を精製した。
GLP−1アゴニストと免疫グロブリンFc断片部位が連結されたDNA配列を動物細胞発現ベクターにクローニングした。この組換えタンパク質をコードするDNAをトランスフェクション溶液(FreeStyle MAX ReagentTM, Invitrogen)により動物細胞株である293−F(Freestyle 293-F cell, invtrogen)にトランスフェクションし、その後48時間培養して培養液を得た。発現したGLP−1アゴニスト二量体−免疫グロブリンFc断片結合体は親和性カラムを用いて培養液から精製した。
受容体インターナリゼーション(receptor internalization)を評価するために、PathHunter(登録商標) eXpress Activated GPCR Internalization Assayを用いた。ヒトGLP−1受容体を発現するU2OS細胞を白色96ウェルプレートに接種して24〜48時間培養した。実施例のGLP1アゴニスト結合体は3μMから、比較例のインフレームGLP1アゴニスト結合体は15μMから1/4ずつ段階希釈(serial dilution)して添加し、37℃のCO2培養器で3時間かけて受容体インターナリゼーションを誘導した。次に、エンドサイトーシスが起こった受容体を検出する基質を添加して室温で60分間反応させ、ルミネッセンスプレートリーダー(luminescence plate reader)で発光度を測定した。その結果を図2に示す。
実施例のGLP1アゴニスト結合体と比較例のGLP1アゴニスト結合体のインビボ薬物動態を比較するために、正常SDラットを用いて血中濃度の変化を確認した。
次に、本発明の好ましい態様を示す。
1. 生理活性ポリペプチドが免疫グロブリンFc断片に連結された結合体を含有する組成物であって、前記組成物は、1つの免疫グロブリンFc断片に対して1分子の生理活性ポリペプチドが連結された単量体結合体を含有し、任意的に1つの免疫グロブリンFc断片に対して同じ生理活性ポリペプチドが2分子以上連結された多量体結合体を含有し、前記組成物内の多量体結合体に対する単量体結合体のモル比は19以上である持続性薬剤組成物。
2. 前記結合体は、生理活性ポリペプチドと免疫グロブリンFc断片間に介在する非ペプチド性リンカーで連結されている、上記1に記載の持続性薬剤組成物。
3. 前記単量体結合体は、1つの免疫グロブリンFc断片に対して生理活性ポリペプチド2分子が非ペプチド性重合体により連結された二量体結合体、又は生理活性ポリペプチド二量体と免疫グロブリンFc断片のインフレーム結合体に比べて低い受容体媒介インターナリゼーション(receptor-mediated internalization)又は受容体媒介クリアランス(receptor-mediated clearance)を示すことを特徴とする、上記1に記載の持続性薬剤組成物。
4. 前記生理活性ポリペプチドは、グルカゴン様ペプチド−1(GLP−1)、好中球増加因子(G−CSF)、ヒト成長ホルモン(hGH)、エリスロポエチン(EPO)、グルカゴン、オキシントモジュリン、インスリン、成長ホルモン放出ホルモン、成長ホルモン放出ペプチド、インターフェロン、インターフェロン受容体、Gタンパク質共役受容体(G protein-coupled receptor)、インターロイキン、インターロイキン受容体、酵素類、インターロイキン結合タンパク質、サイトカイン結合タンパク質、マクロファージ活性因子、マクロファージペプチド、B細胞因子、T細胞因子、タンパク質A、アレルギー抑制因子、細胞壊死糖タンパク質、免疫毒素、リンホトキシン、腫瘍壊死因子、腫瘍抑制因子、転移成長因子、α1−アンチトリプシン、アルブミン、α−ラクトアルブミン、アポリポタンパク質E、高グリコシル化赤血球生成因子、アンジオポエチン類、ヘモグロビン、トロンビン、トロンビン受容体活性ペプチド、トロンボモジュリン、血液凝固第VII因子、第VIIa因子 、第VIII因子、第IX因子、及び第XIII因子、プラスミノーゲン活性因子、フィブリン結合ペプチド、ウロキナーゼ、ストレプトキナーゼ、ヒルジン、タンパク質C、C反応性タンパク質、レニンインヒビター、コラゲナーゼインヒビター、スーパーオキシドディスムターゼ、レプチン、血小板由来成長因子、上皮細胞成長因子、表皮細胞成長因子、アンジオスタチン、アンジオテンシン、骨形成成長因子、骨形成促進タンパク質、カルシトニン、アトリオペプチン、軟骨誘導因子、エルカトニン、結合組織活性因子、組織因子経路インヒビター、卵胞刺激ホルモン、黄体形成ホルモン、黄体形成ホルモン放出ホルモン、神経成長因子、副甲状腺ホルモン、リラキシン、セクレチン、ソマトメジン、インスリン様成長因子、副腎皮質ホルモン、コレシストキニン、膵臓ポリペプチド、ガストリン放出ペプチド、コルチコトロピン放出因子、甲状腺刺激ホルモン、オートタキシン、ラクトフェリン、ミオスタチン、細胞表面抗原、ウイルス由来ワクチン抗原、モノクローナル抗体、ポリクローナル抗体及び抗体断片からなる群から選択される、上記1に記載の持続性薬剤組成物。
5. 前記生理活性ポリペプチドは、グルカゴン様ペプチド−1(GLP−1)、好中球増加因子(G−CSF)、ヒト成長ホルモン(hGH)、エリスロポエチン(EPO)、グルカゴン、オキシントモジュリン、インスリン及びそれらの誘導体からなる群から選択される、上記1に記載の持続性薬剤組成物。
6. 前記非ペプチド性リンカーは、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール−プロピレングリコール共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、ポリサッカライド、デキストラン、ポリビニルエチルエーテル、生分解性高分子、脂質重合体、キチン、ヒアルロン酸及びそれらの組み合わせからなる群から選択される、上記2に記載の持続性薬剤組成物。
7. 前記非ペプチド性リンカーは、分子量が1〜100kDaの範囲である、上記2に記載の持続性薬剤組成物。
8. 前記免疫グロブリンFc断片は、CH1、CH2、CH3及びCH4ドメインからなる群から選択される1つ〜4つのドメインからなる、上記1に記載の持続性薬剤組成物。
9. 前記免疫グロブリンFc断片はヒンジ(hinge)領域をさらに含む、上記1に記載の持続性薬剤組成物。
10. 前記免疫グロブリンFc断片は、IgG、IgA、IgD、IgE、IgM、それらの組み合わせ(combination)及びそれらのハイブリッド(hybrid)からなる群から選択される、上記1に記載の持続性薬剤組成物。
11. 前記免疫グロブリンFc断片はIgG4 Fc断片である、上記1に記載の持続性薬剤組成物。
12. 前記免疫グロブリンFc断片は非グリコシル化されたものである、上記1に記載の持続性薬剤組成物。
13. 生理活性ポリペプチド単量体と免疫グロブリンFc断片が非ペプチド性リンカーで連結された、生理活性ポリペプチド単量体−免疫グロブリンFc断片結合体であって、
前記生理活性ポリペプチドが単量体形態で1つの免疫グロブリンFc断片に非ペプチド性リンカーで連結された前記結合体は、生理活性ポリペプチド2分子が1つの免疫グロブリンFc断片に非ペプチド性重合体により連結された二量体結合体、又は生理活性ポリペプチド二量体と免疫グロブリンFc断片のインフレーム結合体に比べて低い受容体媒介インターナリゼーション又は受容体媒介クリアランスを示すことを特徴とする結合体。
14. (a)生理活性ポリペプチドと免疫グロブリンFc断片を互いに連結させ、生理活性ポリペプチド−免疫グロブリンFc断片結合体の混合物を製造するステップと、
(b)前記混合物から、生理活性ポリペプチド単量体と免疫グロブリンFc断片が互いに連結された、1分子の生理活性ポリペプチドが1つの免疫グロブリンFc断片に連結された結合体を分離するステップとを含む、
上記1の持続性薬剤組成物の製造方法。
15. 前記生理活性ポリペプチドと免疫グロブリンFc断片が非ペプチド性リンカーにより互いに連結されている、上記14に記載の方法。
16. 前記持続性薬剤組成物の1分子の生理活性ポリペプチドが1つの免疫グロブリンFc断片に連結された結合体は、2分子の生理活性ポリペプチドが1つの免疫グロブリンFc断片に非ペプチド性重合体により連結された二量体結合体、又は生理活性ポリペプチド二量体と免疫グロブリンFc断片のインフレーム結合体に比べて低い受容体媒介インターナリゼーション又は受容体媒介クリアランス(receptor-mediated clearance)を示すことを特徴とする、上記14に記載の方法。
Claims (16)
- 生理活性ポリペプチドが免疫グロブリンFc断片に連結された結合体を含有する組成物であって、前記組成物は、1つの免疫グロブリンFc断片に対して1分子の生理活性ポリペプチドが連結された単量体結合体を含有し、任意的に1つの免疫グロブリンFc断片に対して同じ生理活性ポリペプチドが2分子以上連結された多量体結合体を含有し、前記組成物内の多量体結合体に対する単量体結合体のモル比は19以上である持続性薬剤組成物。
- 前記結合体は、生理活性ポリペプチドと免疫グロブリンFc断片間に介在する非ペプチド性リンカーで連結されている、請求項1に記載の持続性薬剤組成物。
- 前記単量体結合体は、1つの免疫グロブリンFc断片に対して生理活性ポリペプチド2分子が非ペプチド性重合体により連結された二量体結合体、又は生理活性ポリペプチド二量体と免疫グロブリンFc断片のインフレーム結合体に比べて低い受容体媒介インターナリゼーション(receptor-mediated internalization)又は受容体媒介クリアランス(receptor-mediated clearance)を示すことを特徴とする、請求項1に記載の持続性薬剤組成物。
- 前記生理活性ポリペプチドは、グルカゴン様ペプチド−1(GLP−1)、好中球増加因子(G−CSF)、ヒト成長ホルモン(hGH)、エリスロポエチン(EPO)、グルカゴン、オキシントモジュリン、インスリン、成長ホルモン放出ホルモン、成長ホルモン放出ペプチド、インターフェロン、インターフェロン受容体、Gタンパク質共役受容体(G protein-coupled receptor)、インターロイキン、インターロイキン受容体、酵素類、インターロイキン結合タンパク質、サイトカイン結合タンパク質、マクロファージ活性因子、マクロファージペプチド、B細胞因子、T細胞因子、タンパク質A、アレルギー抑制因子、細胞壊死糖タンパク質、免疫毒素、リンホトキシン、腫瘍壊死因子、腫瘍抑制因子、転移成長因子、α1−アンチトリプシン、アルブミン、α−ラクトアルブミン、アポリポタンパク質E、高グリコシル化赤血球生成因子、アンジオポエチン類、ヘモグロビン、トロンビン、トロンビン受容体活性ペプチド、トロンボモジュリン、血液凝固第VII因子、第VIIa因子 、第VIII因子、第IX因子、及び第XIII因子、プラスミノーゲン活性因子、フィブリン結合ペプチド、ウロキナーゼ、ストレプトキナーゼ、ヒルジン、タンパク質C、C反応性タンパク質、レニンインヒビター、コラゲナーゼインヒビター、スーパーオキシドディスムターゼ、レプチン、血小板由来成長因子、上皮細胞成長因子、表皮細胞成長因子、アンジオスタチン、アンジオテンシン、骨形成成長因子、骨形成促進タンパク質、カルシトニン、アトリオペプチン、軟骨誘導因子、エルカトニン、結合組織活性因子、組織因子経路インヒビター、卵胞刺激ホルモン、黄体形成ホルモン、黄体形成ホルモン放出ホルモン、神経成長因子、副甲状腺ホルモン、リラキシン、セクレチン、ソマトメジン、インスリン様成長因子、副腎皮質ホルモン、コレシストキニン、膵臓ポリペプチド、ガストリン放出ペプチド、コルチコトロピン放出因子、甲状腺刺激ホルモン、オートタキシン、ラクトフェリン、ミオスタチン、細胞表面抗原、ウイルス由来ワクチン抗原、モノクローナル抗体、ポリクローナル抗体及び抗体断片からなる群から選択される、請求項1に記載の持続性薬剤組成物。
- 前記生理活性ポリペプチドは、グルカゴン様ペプチド−1(GLP−1)、好中球増加因子(G−CSF)、ヒト成長ホルモン(hGH)、エリスロポエチン(EPO)、グルカゴン、オキシントモジュリン、インスリン及びそれらの誘導体からなる群から選択される、請求項1に記載の持続性薬剤組成物。
- 前記非ペプチド性リンカーは、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール−プロピレングリコール共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、ポリサッカライド、デキストラン、ポリビニルエチルエーテル、生分解性高分子、脂質重合体、キチン、ヒアルロン酸及びそれらの組み合わせからなる群から選択される、請求項2に記載の持続性薬剤組成物。
- 前記非ペプチド性リンカーは、分子量が1〜100kDaの範囲である、請求項2に記載の持続性薬剤組成物。
- 前記免疫グロブリンFc断片は、CH1、CH2、CH3及びCH4ドメインからなる群から選択される1つ〜4つのドメインからなる、請求項1に記載の持続性薬剤組成物。
- 前記免疫グロブリンFc断片はヒンジ(hinge)領域をさらに含む、請求項1に記載の持続性薬剤組成物。
- 前記免疫グロブリンFc断片は、IgG、IgA、IgD、IgE、IgM、それらの組み合わせ(combination)及びそれらのハイブリッド(hybrid)からなる群から選択される、請求項1に記載の持続性薬剤組成物。
- 前記免疫グロブリンFc断片はIgG4 Fc断片である、請求項1に記載の持続性薬剤組成物。
- 前記免疫グロブリンFc断片は非グリコシル化されたものである、請求項1に記載の持続性薬剤組成物。
- 生理活性ポリペプチド単量体と免疫グロブリンFc断片が非ペプチド性リンカーで連結された、生理活性ポリペプチド単量体−免疫グロブリンFc断片結合体であって、
前記生理活性ポリペプチドが単量体形態で1つの免疫グロブリンFc断片に非ペプチド性リンカーで連結された前記結合体は、生理活性ポリペプチド2分子が1つの免疫グロブリンFc断片に非ペプチド性重合体により連結された二量体結合体、又は生理活性ポリペプチド二量体と免疫グロブリンFc断片のインフレーム結合体に比べて低い受容体媒介インターナリゼーション又は受容体媒介クリアランスを示すことを特徴とする結合体。 - (a)生理活性ポリペプチドと免疫グロブリンFc断片を互いに連結させ、生理活性ポリペプチド−免疫グロブリンFc断片結合体の混合物を製造するステップと、
(b)前記混合物から、生理活性ポリペプチド単量体と免疫グロブリンFc断片が互いに連結された、1分子の生理活性ポリペプチドが1つの免疫グロブリンFc断片に連結された結合体を分離するステップとを含む、
請求項1の持続性薬剤組成物の製造方法。 - 前記生理活性ポリペプチドと免疫グロブリンFc断片が非ペプチド性リンカーにより互いに連結されている、請求項14に記載の方法。
- 前記持続性薬剤組成物の1分子の生理活性ポリペプチドが1つの免疫グロブリンFc断片に連結された結合体は、2分子の生理活性ポリペプチドが1つの免疫グロブリンFc断片に非ペプチド性重合体により連結された二量体結合体、又は生理活性ポリペプチド二量体と免疫グロブリンFc断片のインフレーム結合体に比べて低い受容体媒介インターナリゼーション又は受容体媒介クリアランス(receptor-mediated clearance)を示すことを特徴とする、請求項14に記載の方法。
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