JP2021167352A - 免疫グロブリンFcフラグメント結合を用いたタンパク質及びペプチドの溶解度を改善する方法 - Google Patents
免疫グロブリンFcフラグメント結合を用いたタンパク質及びペプチドの溶解度を改善する方法 Download PDFInfo
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Abstract
【解決手段】本発明は、生理活性タンパク質又はペプチドを免疫グロブリンFcフラグメントに結合させるステップを含む、免疫グロブリンFcフラグメントが結合されていない生理活性タンパク質又はペプチドに比べて生理活性タンパク質又はペプチドの溶解度を改善する方法、及び免疫グロブリンFcフラグメントを含む、免疫グロブリンFcフラグメントを含まない組成物に比べて改善された溶解度を示すことを特徴とする、生理活性タンパク質又はペプチドの溶解度改善用組成物に関する。
Description
アラニン Ala又はA
アルギニン Arg又はR
アスパラギン Asn又はN
アスパラギン酸 Asp又はD
システイン Cys又はC
グルタミン酸 Glu又はE
グルタミン Gln又はQ
グリシン Gly又はG
ヒスチジン His又はH
イソロイシン Ile又はI
ロイシン Leu又はL
リシン Lys又はK
メチオニン Met又はM
フェニルアラニン Phe又はF
プロリン Pro又はP
セリン Ser又はS
トレオニン Thr又はT
トリプトファン Trp又はW
チロシン Tyr又はY
バリン Val又はV
A鎖:Gly−Ile−Val−Glu−Gln−Cys−Cys−Thr−Ser−Ile−Cys−Ser−Leu−Tyr−Gln−Leu−Glu−Asn−Tyr−Cys−Asn(配列番号1)
B鎖:Phe−Val−Asn−Gln−His−Leu−Cys−Gly−Ser−His−Leu−Val−Glu−Ala−Leu−Tyr−Leu−Val−Cys−Gly−Glu−Arg−Gly−Phe−Phe−Tyr−Thr−Pro−Lys−Thr(配列番号2)
His−Ser−Gln−Gly−Thr−Phe−Thr−Ser−Asp−Tyr−Ser−Lys−Tyr−Leu−Asp−Ser−Arg−Arg−Ala−Gln−Asp−Phe−Val−Gln−Trp−Leu−Met−Asn−Thr(配列番号52)
インスリン及び持続型インスリン結合体の溶解度評価
(1)持続型インスリン結合体の作製
インスリン粉末を10mM HClに溶解し、その後3.4K propion−ALD2 PEG(プロピオンアルデヒド基を2つ有するPEG,NOF社,日本)をインスリンB鎖のN末端にペグ化(PEGylation)させるために、インスリン:PEGのモル比を1:2とし、インスリン濃度を5mg/mlとして、4℃で約2時間反応させた。ここで、反応は50mMクエン酸ナトリウム(pH5.0)、45%イソプロパノールにおいて行われ、2〜20mMの濃度のシアノ水素化ホウ素酸ナトリウム還元剤を添加して反応させた。反応液はクエン酸ナトリウム(pH3.0)バッファとKCl濃度勾配を用いたSP−HP(GE Healthcare)カラムにかけて精製した。インスリン−PEG−免疫グロブリンFcフラグメント結合体を作製するために、モノペグ化(mono-PEGylated)インスリンと免疫グロブリンFcフラグメントのモル比を1:1.2とし、総タンパク質濃度を20mg/mlとして、常温で13時間反応させた。ここで、反応液は100mM HEPES、22mMリン酸カリウム、pH8.2であり、還元剤として20mMシアノ水素化ホウ素酸ナトリウムを添加した。
インスリン及び持続型インスリン結合体の溶解度を確認するために、表1の組成でそれぞれインスリン及び持続型インスリン結合体の標準品及び試験物質を作製した。
オキシントモジュリン及び持続型オキシントモジュリン結合体の溶解度評価
(1)持続型オキシントモジュリン誘導体結合体の作製
MAL−10K−ALD PEG(NOF,日本)を配列番号27のオキシントモジュリン誘導体のアミノ酸配列の30番目のシステイン残基にペグ化させるために、前記オキシントモジュリン誘導体とMAL−10K−ALD PEGのモル比を1:1とし、オキシントモジュリン誘導体の濃度を3mg/mLとして、4℃で1時間反応させた。ここで、反応は50mMトリス(Tris)(pH7.5)に60%イソプロパノールが添加された環境下で行われた。反応終了後に、前記反応液をクエン酸ナトリウム(pH3.0)バッファとKCl濃度勾配を用いたSP HP(GE healthcare, Sweden)にかけてシステインにモノペグ化されたオキシントモジュリン誘導体を精製した。
配列番号27のオキシントモジュリン誘導体及び持続型オキシントモジュリン誘導体結合体の溶解度を確認するために、表4の組成でそれぞれオキシントモジュリン誘導体及び持続型オキシントモジュリン誘導体結合体の標準品及び試験物質を作製した。
次に、本発明の好ましい態様を示す。
1. 生理活性タンパク質又はペプチドを免疫グロブリンFcフラグメントに結合させるステップを含む、免疫グロブリンFcフラグメントが結合されていない生理活性タンパク質又はペプチドに比べて生理活性タンパク質又はペプチドの溶解度を改善する方法。
2. 前記免疫グロブリンFcフラグメントは、IgG、IgA、IgD、IgE又はIgMに由来するFcフラグメントである上記1に記載の方法。
3. 前記免疫グロブリンFcフラグメントは、それぞれのドメインがIgG、IgA、IgD、IgE及びIgMからなる群から選択される免疫グロブリンに由来する異なる起源を有するドメインのハイブリッドである上記2に記載の方法。
4. 前記免疫グロブリンFcフラグメントは、同一起源のドメインからなる単鎖免疫グロブリンで構成された二量体又は多量体である上記2に記載の方法。
5. 前記免疫グロブリンFcフラグメントは、ヒト非グリコシル化IgG4 Fcフラグメントである上記4に記載の方法。
6. 前記結合させるステップは、生理活性タンパク質又はペプチドと免疫グロブリンFcフラグメントを非ペプチド性重合体を介して結合させるものである上記1に記載の方法。
7. 前記方法により製造した、生理活性タンパク質又はペプチドと免疫グロブリンFcフラグメントが結合された物質は、融合タンパク質の形態である上記1に記載の方法。
8. 前記非ペプチド性重合体は、ポリエチレングリコールである上記6に記載の方法。
9. 前記非ペプチド性重合体は、ポリプロピレングリコール、エチレングリコールとプロピレングリコールの共重合体、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、PLA(ポリ乳酸,polylactic acid)やPLGA(ポリ乳酸−グリコール酸,polylactic-glycolic acid)などの生分解性高分子、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6に記載の方法。
10. 前記方法は、水溶液において生理活性タンパク質又はペプチドの溶解度を改善する上記1に記載の方法。
11. 前記水溶液は、クエン酸又は酢酸緩衝液、非イオン性界面活性剤としてのポリソルベート、糖アルコールとしてのマンニトール、及び等張化剤としての塩化ナトリウム又はメチオニンを含む上記10に記載の方法。
12. 前記水溶液は、pH5.0〜7.0である上記10に記載の方法。
13. 前記生理活性タンパク質又はペプチドは、エキセンジン−4、グルカゴン、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)、副甲状腺ホルモン(PTH)、カルシトニン、インスリン又はオキシントモジュリンである上記1に記載の方法。
14. 免疫グロブリンFcフラグメントを含む、免疫グロブリンFcフラグメントを含まない組成物に比べて改善された溶解度を示すことを特徴とする、生理活性タンパク質又はペプチドの溶解度改善用組成物。
15. 前記組成物は、生理活性タンパク質又はペプチドが免疫グロブリンFcフラグメントにペプチド性リンカー又は非ペプチド性リンカーを介して連結された、生理活性タンパク質又はペプチドと免疫グロブリンFcフラグメントの結合体を有効成分として含む上記14に記載の組成物。
Claims (15)
- 生理活性タンパク質又はペプチドを免疫グロブリンFcフラグメントに結合させるステップを含む、免疫グロブリンFcフラグメントが結合されていない生理活性タンパク質又はペプチドに比べて生理活性タンパク質又はペプチドの溶解度を改善する方法。
- 前記免疫グロブリンFcフラグメントは、IgG、IgA、IgD、IgE又はIgMに由来するFcフラグメントである請求項1に記載の方法。
- 前記免疫グロブリンFcフラグメントは、それぞれのドメインがIgG、IgA、IgD、IgE及びIgMからなる群から選択される免疫グロブリンに由来する異なる起源を有するドメインのハイブリッドである請求項2に記載の方法。
- 前記免疫グロブリンFcフラグメントは、同一起源のドメインからなる単鎖免疫グロブリンで構成された二量体又は多量体である請求項2に記載の方法。
- 前記免疫グロブリンFcフラグメントは、ヒト非グリコシル化IgG4 Fcフラグメントである請求項4に記載の方法。
- 前記結合させるステップは、生理活性タンパク質又はペプチドと免疫グロブリンFcフラグメントを非ペプチド性重合体を介して結合させるものである請求項1に記載の方法。
- 前記方法により製造した、生理活性タンパク質又はペプチドと免疫グロブリンFcフラグメントが結合された物質は、融合タンパク質の形態である請求項1に記載の方法。
- 前記非ペプチド性重合体は、ポリエチレングリコールである請求項6に記載の方法。
- 前記非ペプチド性重合体は、ポリプロピレングリコール、エチレングリコールとプロピレングリコールの共重合体、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、PLA(ポリ乳酸,polylactic acid)やPLGA(ポリ乳酸−グリコール酸,polylactic-glycolic acid)などの生分解性高分子、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6に記載の方法。
- 前記方法は、水溶液において生理活性タンパク質又はペプチドの溶解度を改善する請求項1に記載の方法。
- 前記水溶液は、クエン酸又は酢酸緩衝液、非イオン性界面活性剤としてのポリソルベート、糖アルコールとしてのマンニトール、及び等張化剤としての塩化ナトリウム又はメチオニンを含む請求項10に記載の方法。
- 前記水溶液は、pH5.0〜7.0である請求項10に記載の方法。
- 前記生理活性タンパク質又はペプチドは、エキセンジン−4、グルカゴン、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)、副甲状腺ホルモン(PTH)、カルシトニン、インスリン又はオキシントモジュリンである請求項1に記載の方法。
- 免疫グロブリンFcフラグメントを含む、免疫グロブリンFcフラグメントを含まない組成物に比べて改善された溶解度を示すことを特徴とする、生理活性タンパク質又はペプチドの溶解度改善用組成物。
- 前記組成物は、生理活性タンパク質又はペプチドが免疫グロブリンFcフラグメントにペプチド性リンカー又は非ペプチド性リンカーを介して連結された、生理活性タンパク質又はペプチドと免疫グロブリンFcフラグメントの結合体を有効成分として含む請求項14に記載の組成物。
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