JP2015503554A - 免疫グロブリンフラグメントを用いた部位特異的glp−2薬物結合体 - Google Patents
免疫グロブリンフラグメントを用いた部位特異的glp−2薬物結合体 Download PDFInfo
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- JP2015503554A JP2015503554A JP2014550024A JP2014550024A JP2015503554A JP 2015503554 A JP2015503554 A JP 2015503554A JP 2014550024 A JP2014550024 A JP 2014550024A JP 2014550024 A JP2014550024 A JP 2014550024A JP 2015503554 A JP2015503554 A JP 2015503554A
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Abstract
Description
1) 両末端にアルデヒド、マレイミド及びスクシンイミド誘導体から選択される反応基を有する非ペプチド重合体をGLP-2またはその誘導体のアミン基またはチオール基に共有的に連結する工程であって、GLP-2またはその誘導体はそのC末端に導入されたチオール基を有するものである工程と、
2) 工程1)の反応混合物から非ペプチド重合体がGLP-2またはその誘導体のアミン基またはチオール基に共有的に連結された複合体(complex)を分離する工程と、
3) 複合体の非ペプチド重合体の他方の末端に免疫グロブリンFcフラグメントを共有的に連結する工程、及び
4) 工程3)の反応混合物から非ペプチド重合体の両末端がそれぞれ免疫グロブリンFcフラグメント及びGLP-2またはその誘導体に連結されたGLP-2結合体を分離する工程とを含む、本発明によるGLP-2結合体の製造方法を提供する。
HADGSFSDEMNTILDNLAARDFINWLIQTKITD(配列番号:1)
1) 両末端に反応基を有する非ペプチド重合体をGLP-2またはその誘導体のアミン基もしくはチオール基に共有的に連結する工程であって、反応基がアルデヒド、マレイミド及びスクシンイミド誘導体からなる群から選択され、チオール基がGLP-2またはその誘導体のC末端に導入される工程と、
2) 工程1)の反応混合物から非ペプチド重合体及びGLP-2またはその誘導体を含む複合体(complex)を分離する工程であって、複合体は、非ペプチド重合体がGLP-2またはその誘導体のN末端アミン基以外の他のアミノ酸残基に共有的に連結される工程、及び
3) 工程2)から分離された複合体の非ペプチド重合体の他方の末端に免疫グロブリンFcフラグメントを共有的に連結して免疫グロブリンFc領域、非ペプチド重合体及びGLP-2またはその誘導体を含むGLP-2結合体を生産する工程であって、前記結合体は、非ペプチド重合体の一方の末端が免疫グロブリンFcフラグメントに共有的に連結され、その他方の末端がGLP-2またはその誘導体に連結される工程とを含む本発明によるGLP-2結合体を製造する方法を提供する。
1) 一方の末端にマレイミド反応基を、他方の末端にアルデヒド反応基を有する非ペプチド重合体をGLP-2またはその誘導体のチオール基に共有的に連結する工程であって、チオール基がGLP-2またはその誘導体のC末端に導入される工程と、
2)前記工程1)の反応混合物から非ペプチド重合体及びGLP-2またはその誘導体を含む複合体を分離する工程であって、複合体は非ペプチド重合体がGLP-2またはその誘導体のチオール基に共有的に連結される工程、及び
3) 工程2)から分離された複合体の非ペプチド重合体の他方の末端に免疫グロブリンFcフラグメントを共有的に連結して免疫グロブリンFcフラグメント、非ペプチド重合体及びGLP-2またはその誘導体を含むGLP-2結合体を生産する工程であって、GLP-2結合体は非ペプチド重合体の一方の末端が免疫グロブリンFcフラグメントに、その他方の末端がGLP-2またはその誘導体に共有的に連結される工程を含む。
イミダゾアセチル-GLP-2(CA-GLP-2, A2G, 34C, American peptide,米国)の34番目のシステイン残基をペグ化するために、CA-GLP-2を10K MAL-PEG-ALD(各末端にマレイミドとアルデヒド基を有するヘテロ二作用性(heterobifunctional)PEG, NOF,日本)と反応させた。この時、CA-GLP-2対PEGのモル比は1:3であり、3.5 mg/mlのペプチド濃度で室温にて3時間反応を行った。また、還元剤として20 mMナトリウムシアノボロヒドリド(sodium cyanoborohydride, SCB)の存在下で50 mM濃度のTris-HCl緩衝液内で反応を行った。反応が終結した後、結果生成物、モノペグ化された(monopegylated)CA-GLP-2-PEG複合体を下記条件でSOURCE Sカラム(LRC25, Pall Corporation)を用いたクロマトグラフィーで精製した。
流速:4.0 ml/分
勾配:溶離液B 0%→40%240分間(A:20 mMクエン酸、pH 2.0+45%エタノール、B:A+1 M KCl)
前記で精製されたモノペグ化されたCA GLP-2(A2G,34C)を免疫グロブリンFcフラグメント(特許文献10)と1:6のモル比で混合し、20 mg/mlのペプチド濃度において4℃で16時間これらを反応させた。この時、還元剤として20 mM SCBの存在下で100 mMポタシウムホスフェート(Potassium phosphate)緩衝液(pH 6.0)内で反応を行った。反応が終結した後、反応混合物を下記条件下でSource Pheカラム(XK 16, GE Healthcare)、Source 15Qカラム(LRC25, Pall Corporation)及びSource ISOカラム(HR16, GE Healthcare)を用いた3段階クロマトグラフィーに適用した。
流速:2.0 ml/分
勾配:溶離液B 100→0%(A:20mM Tris-HCl, pH 8.0, B:A+2.6 M NaCl)
流速:5.0 ml/分
勾配:溶離液B 0→30%120分間(A:20 mM Tris-HCl, pH 8.0, B:A+1 M NaCl)
流速:2.0 ml/分
勾配:溶離液B 100→0%100分間(A:20 mM Tris-HCl, pH 8.0, B:A+1.1 Mアンモニウムサルフェート)
実施例2で製造されたCA GLP-2(A2G, 34C)-10K PEG-Fc結合体(以下、「GLP-2結合体」)の効能を測定するために、下記のように試験管内細胞活性を測定する方法を用いた。この方法では、ヒトGLP-2受容体をコードする遺伝子を発現するように形質転換された中国ハムスターの卵巣(chinese hamster ovary, CHO)細胞株、CHO/hGLP-2Rを用いた。
Claims (23)
- 非ペプチド重合体を介して共有的に連結された、グルカゴン様ペプチド-2(GLP-2)またはその誘導体と免疫グロブリンFcフラグメントとを含むGLP-2結合体であって、天然型GLP-2またはその誘導体がそのC末端に導入されたチオール基を有し、非ペプチド重合体の一方の末端がGLP-2のN末端アミノ基以外のアミノ酸残基に連結されることを特徴とする、GLP-2結合体。
- 前記GLP-2またはその誘導体のチオール基が、それらのC末端にシステインを結合させることによって導入される、請求項1に記載のGLP-2結合体。
- 前記GLP-2の誘導体が、天然型GLP-2のN末端アミン基の置換、除去または修飾により製造され、GLP-2受容体に結合する機能を有する、請求項1に記載のGLP-2結合体。
- 前記GLP-2の誘導体が、天然型GLP-2のN末端で最初のアミノ酸であるヒスチジンのα炭素及びそれに結合したN末端アミン基を削除して製造されたGLP-2誘導体、天然型GLP-2のN末端アミン基を削除して製造されたGLP-2誘導体、天然型GLP-2のN末端アミン基をヒドロキシル基に置換して製造されたGLP-2誘導体、天然型GLP-2のN末端アミン基をジメチル基で修飾して製造されたGLP-2誘導体、及び天然型GLP-2のN末端アミン基をカルボキシル基に置換して製造されたGLP-2誘導体からなる群から選択される、請求項3に記載のGLP-2結合体。
- 前記非ペプチド重合体の一方の末端が、前記免疫グロブリンFcフラグメントに共有的に連結し、その他方の末端が前記GLP-2またはその誘導体のアミン基またはチオール基に共有的に連結される、請求項1に記載のGLP-2結合体。
- 前記非ペプチド重合体が、前記GLP-2またはその誘導体のチオール基に共有的に連結される、請求項5に記載のGLP-2結合体。
- 前記非ペプチド重合体が、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合わせからなる群から選択される、請求項1に記載のGLP-2結合体。
- 前記非ペプチド重合体が、その両末端にアルデヒド基、プロピオンアルデヒド基、ブチルアルデヒド基、マレイミド基、及びスクシンイミド誘導体からなる群から選択される反応基を有する、請求項1に記載のGLP-2結合体。
- 前記スクシンイミド誘導体が、スクシンイミジルプロピオネート、スクシンイミジルカルボキシメチル、ヒドロキシスクシンイミジル及びスクシンイミジルカーボネートからなる群から選択される、請求項8に記載のGLP-2結合体。
- 前記非ペプチド重合体が、一方の末端にマレイミド基を有し、他方の末端にアルデヒド基を有する、請求項8に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、非グリコシル化される、請求項1に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、CH1、CH2、CH3及びCH4ドメインからなる群から選択される1〜4個のドメインからなる、請求項1に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、ヒンジ領域をさらに含む、請求項12に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、IgG、IgA、IgD、IgEまたはIgMに由来する、請求項1に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントの各ドメインが、IgG、IgA、IgD、IgE及びIgMからなる群から選択される異なる免疫グロブリンに由来したドメインのハイブリッドである、請求項14に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、同一の免疫グロブリンに由来したドメインを含む糖鎖化された免疫グロブリンからなる二量体または多量体である、請求項14に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、IgG4 Fcフラグメントである、請求項14に記載のGLP-2結合体。
- 前記免疫グロブリンFcフラグメントが、ヒト非グリコシル化IgG4 Fcフラグメントである、請求項17に記載のGLP-2結合体。
- 請求項1〜18のいずれか一項に記載のGLP-2結合体を製造する方法であって、
1) 両末端にアルデヒド、マレイミド及びスクシンイミド誘導体からなる群から選択される反応基を有する非ペプチド重合体を、GLP-2またはその誘導体のアミン基またはチオール基に共有的に連結する工程であって、前記GLP-2またはその誘導体がそのC末端に導入されたチオール基を有する工程と、
2) 工程1)の反応混合物から、前記非ペプチド重合体が前記GLP-2またはその誘導体のアミン基またはチオール基に共有的に連結されている複合体を分離する工程と、
3) 前記複合体内の非ペプチド重合体の他方の末端を、免疫グロブリンFcフラグメントに共有的に連結する工程と、
4) 工程3)の反応混合物から、前記非ペプチド重合体の両末端がそれぞれ前記免疫グロブリンFcフラグメント及びGLP-2またはその誘導体に共有的に連結されているGLP-2結合体を分離する工程とを含むことを特徴とする、方法。 - 工程1)における非ペプチド重合体が、前記GLP-2またはその誘導体のC末端チオール基に共有的に連結される、請求項19に記載の方法。
- 工程1)における前記GLP-2またはその誘導体と前記非ペプチド重合体とを、1:2〜1:10のモル比でpH 2〜4の条件で反応させる、請求項19に記載の方法。
- 請求項1〜18のいずれか一項に記載のGLP-2結合体を有効成分として含む、腸疾患、腸損傷及び胃腸疾患から選択される1種以上の疾患を予防または治療するための医薬組成物。
- 腸疾患、腸損傷及び胃疾患から選択される1種以上の疾患の予防または治療を必要とする患者に、請求項1〜18のいずれか一項に記載のGLP-2結合体を投与することを含む、腸疾患、腸損傷及び胃疾患から選択される1種以上の疾患を予防または治療する方法。
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