JP2022172121A - タンパク質の半減期延長方法 - Google Patents
タンパク質の半減期延長方法 Download PDFInfo
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Abstract
Description
Claims (69)
- タンパク質又は(ポリ)ペプチドの半減期を延長する方法であって、タンパク質又は(ポリ)ペプチドの1つ以上のリジン残基をアルギニンで置換することを含み、
リジン残基は、ユビキチンのC末端グリシンに結合する方法。 - タンパク質は、β-トロフィンである請求項1に記載の方法。
- 前記β-トロフィンは、配列番号1のアミノ酸配列を有し、前記β-トロフィンのN末端から62、124、153、及び158に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項2に記載の方法。
- 前記タンパク質は、成長ホルモン(GH)である請求項1に記載の方法。
- 前記成長ホルモンは、配列番号10のアミノ酸配列を有し、前記成長ホルモンのN末端から64、67、96、141、166、171、184、194、及び198に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項4に記載の方法。
- 前記タンパク質は、インスリンである請求項1に記載の方法。
- 前記インスリンは、配列番号17のアミノ酸配列を有し、前記インスリンのN末端から53及び88に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項6に記載の方法。
- 前記タンパク質は、インターフェロン-αである請求項1に記載の方法。
- 前記インターフェロン-αは、配列番号22のアミノ酸配列を有し、前記インターフェロン-αのN末端から17、54、72、93、106、135、144、154、156、157、及び187に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項8に記載の方法。
- 前記タンパク質は、G-CSFである請求項1に記載の方法。
- 前記G-CSFは、配列番号31のアミノ酸配列を有し、前記G-CSFのN末端から11、46、53、64、及び73に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項10に記載の方法。
- 前記タンパク質は、インターフェロン-βである請求項1に記載の方法。
- 前記インターフェロン-βは、配列番号36のアミノ酸配列を有し、前記インターフェロン-βのN末端から4、40、54、66、73、120、126、129、136、144、155、及び157に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項12に記載の方法。
- 前記タンパク質は、エリスロポエチン(EPO)である請求項1に記載の方法。
- 前記エリスロポエチン(EPO)は、配列番号43のアミノ酸配列を有し、前記エリスロポエチン(EPO)のN末端から47、72、79、124、143、167、179、及び181に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項14に記載の方法。
- 前記タンパク質は、BMP2である請求項1に記載の方法。
- 前記BMP2は、配列番号51のアミノ酸配列を有し、前記BMP2のN末端から32、64、127、178、185、236、241、272、278、281、285、287、290、293、297、355、358、379、及び383に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項16に記載の方法。
- 前記タンパク質は、FGF-1である請求項1に記載の方法。
- 前記FGF-1は、配列番号59のアミノ酸配列を有し、前記FGF-1のN末端から15、24、25、27、72、115、116、120、127、128、133、及び143に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項18に記載の方法。
- 前記タンパク質は、レプチンである請求項1に記載の方法。
- 前記レプチンは、配列番号64のアミノ酸配列を有し、前記レプチンのN末端から26、32、36、54、56、74、及び115に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項20に記載の方法。
- 前記タンパク質は、VEGFAである請求項1に記載の方法。
- 前記VEGFAは、配列番号73のアミノ酸配列を有し、前記VEGFAのN末端から22、42、74、110、127、133、134、141、142、147、149、152、154、156、157、169、180、184、191、及び206に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項22に記載の方法。
- 前記タンパク質は、グレリン/オベスタチンプレプロホルモン(prepro-GHRL)である請求項1に記載の方法。
- 前記グレリン/オベスタチンプレプロホルモン(prepro-GHRL)は、配列番号78のアミノ酸配列を有し、前記G-CSFのN末端から39、42、43、47、85、100、111、及び117に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項24に記載の方法。
- 前記タンパク質は、食欲刺激ホルモン(グレリン)である請求項1に記載の方法。
- 前記食欲刺激ホルモン(グレリン)は、配列番号80のアミノ酸配列を有し、前記食欲刺激ホルモン(グレリン)のN末端から39、42、43、及び47に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項26に記載の方法。
- 前記タンパク質は、GLP-1である請求項1に記載の方法。
- 前記GLP-1は、配列番号89のアミノ酸配列を有し、前記GLP-1のN末端から117及び125に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項28に記載の方法。
- 前記タンパク質は、IgG重鎖(HC)である請求項1に記載の方法。
- 前記IgG重鎖(HC)は、配列番号94のアミノ酸配列を有し、前記IgG重鎖(HC)のN末端から49、62、84、95、143、155、169、227、232、235、236、240、244、268、270、296、310、312、339、342、344、348、356、360、362、382、392、414、431、436、及び461に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項30に記載の方法。
- 前記タンパク質は、IgG軽鎖(LC)である請求項1に記載の方法。
- 前記IgG軽鎖(LC)は、配列番号101のアミノ酸配列を有し、IgG軽鎖(LC)のN末端から61、64、67、125、129、148、167、171、191、205、210、212、及び229に対応する位置における1つ以上のリジン残基は、アルギニンで置換される請求項32に記載の方法。
- 半減期の延長されたタンパク質であって、
前記タンパク質のアミノ酸配列の1つ以上のリジン残基は、アルギニンで置換され、前記リジン残基は、ユビキチンのC末端グリシンに結合するタンパク質。 - 前記タンパク質は、β-トロフィン、GLP-1、IgG重鎖、IgG軽鎖、食欲刺激ホルモン(グレリン)、G-CSF、VEGFA、レプチン、FGF-1、BMP2、Gタンパク質結合受容体、ヒト成長ホルモン、成長ホルモン放出ホルモン(GHRH)、成長ホルモン放出ペプチド、食欲刺激ホルモン前駆体、インターフェロン-α、インターフェロン-β、インターフェロン受容体、コロニー刺激因子(CSF)、グルカゴン様ペプチド、Gタンパク質結合受容体、インターロイキン、インターロイキン受容体、酵素、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化因子、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、アレルギー阻害剤、細胞壊死糖タンパク質、免疫毒素、リンフォトキシン、腫瘍壊死因子、腫瘍抑制因子、転移成長因子、α-1抗トリプシン、アルブミン、α-ラクトアルブミン、アポリポタンパク質-E、エリスロポエチン、高度グリコシル化エリスロポエチン、アンギオポエチン、ヘモグロビン、トロンビン、トロンビン受容体活性化ペプチド、トロンボモジュリン、第VII因子、第VIIa因子、第VIII因子、第IX因子、第XIII因子、プラスミノゲン活性化因子、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、レニン阻害剤、コラゲナーゼ阻害剤、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、上皮成長因子、表皮成長因子、アンギオスタチン、アンギオテンシン、骨成長因子、骨刺激タンパク質、カルシトニン、インスリン、アトリオペプチン、軟骨誘導因子、エルカトニン、結合組織活性化因子、組織因子経路阻害剤、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、レラキシン、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、グルカゴン、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、副腎皮質刺激ホルモン放出因子、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、受容体、受容体拮抗薬、細胞表面抗原、ウィ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、又は抗体フラグメントである請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号1のアミノ酸配列を有するβ-トロフィンであり、前記β-トロフィンのN末端から62、124、153、及び158に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号10のアミノ酸配列を有する成長ホルモンであり、前記成長ホルモンのN末端から64、67、96、141、166、171、184、194、及び198に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号17のアミノ酸配列を有するインスリンであり、前記インスリンのN末端から53及び88に対応する位置における1つ以上のリジン残基は、アルギニン置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号22のアミノ酸配列を有するインターフェロン-αであり、前記インターフェロン-αのN末端から17、54、72、93、106、135、144、154、156、157、及び187に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号31のアミノ酸配列を有するG-CSFであり、前記G-CSFのN末端から11、46、53、64、及び73に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号36のアミノ酸配列を有するインターフェロン-βであり、前記インターフェロン-βのN末端から4、40、54、66、73、120、126、129、136、144、155、及び157に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号43のアミノ酸配列を有するエリスロポエチン(EPO)であり、前記エリスロポエチン(EPO)のN末端から47、72、79、124、143、167、179、及び181に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号51のアミノ酸配列を有するBMP2であり、前記BMP2のN末端から32、64、127、178、185、236、241、272、278、281、285、287、290、293、297、355、358、379、及び383に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号59のアミノ酸配列を有するFGF-1であり、前記FGF-1のN末端から15、24、25、27、72、115、116、120、127、128、133、及び143に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号64のアミノ酸配列を有するレプチンであり、前記レプチンのN末端から26、32、36、54、56、74、及び115に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号73のアミノ酸配列を有するVEGFAであり、前記VEGFAのN末端から22、42、74、110、127、133、134、141、142、147、149、152、154、156、157、169、180、184、191、及び206に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号78のアミノ酸配列を有するグレリン/オベスタチンプレプロホルモン(prepro-GHRL)であり、前記グレリン/オベスタチンプレプロホルモン(prepro-GHRL)のN末端から39、42、43、47、85、100、111、及び117に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記食欲刺激ホルモン(グレリン)は、配列番号80のアミノ酸配列を有し、前記食欲刺激ホルモン(グレリン)のN末端から39、42、43、及び47に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号89のアミノ酸配列を有するGLP-1であり、前記GLP-1のN末端から117及び125に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号94のアミノ酸配列を有するIgG重鎖(HC)であり、前記IgG重鎖(HC)のN末端から49、62、84、95、143、155、169、227、232、235、236、240、244、268、270、296、310、312、339、342、344、348、356、360、362、382、392、414、431、436、及び461に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 前記タンパク質は、配列番号101のアミノ酸配列を有するIgG軽鎖(LC)であり、前記IgG軽鎖(LC)のN末端から61、64、67、125、129、148、167、171、191、205、210、212、及び229に対応する位置における1つ以上のリジン残基は、アルギニンで置換されている請求項34に記載の半減期の延長されたタンパク質。
- 糖尿病及び/又は肥満を予防及び/又は治療するための医薬組成物であって、
請求項36に記載のβ-トロフィンと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 小人症、歌舞伎症候群、及び/又はカーンズ・セイヤー症候群(KSS)を予防及び/又は治療するための医薬組成物であって、
請求項37に記載の成長ホルモンと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 糖尿病を治療するための医薬組成物であって、
請求項38に記載のインスリンと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 多発性硬化症、自己免疫疾患、関節リウマチを含む免疫疾患、及び/又は、固形癌及び/又は血液癌を含む癌、及び/又は、ウィルス感染、HIV関連疾患、及びC型肝炎を含む感染症を予防及び/又は治療するための医薬組成物であって、
請求項39に記載のインターフェロン-αと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 好中球減少症を予防及び/又は治療する医薬組成物であって、
請求項40に記載のG-CSFと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 多発性硬化症、自己免疫疾患、関節リウマチを含む免疫疾患、及び/又は、固形癌及び/又は血液癌を含む癌、及び/又はウィルス感染、HIV関連疾患、及びC型肝炎を含む感染症を予防及び/又は治療するための医薬組成物であって、
請求項41に記載のインターフェロン-βと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 貧血を予防及び/又は治療するための医薬組成物であって、
請求項42に記載のエリスロポエチン(EPO)と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 貧血及び骨疾患を予防及び/又は治療するための医薬組成物であって、
請求項43に記載のBMP2と、
薬学的に許容される賦形剤とを含む医薬組成物。 - ニューロン疾患を予防及び/又は治療するための医薬組成物であって、
請求項44に記載のFGF-1と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 脳疾患、心臓疾患、及び/又は肥満を予防及び/又は治療するための医薬組成物であって、
請求項45に記載のレプチンと、
薬学的に許容される賦形剤とを含む医薬組成物。 - アンチエイジング、毛髪成長、傷痕、及び/又は血管形成に関連の疾患を予防及び/又は治療するための医薬組成物であって、
請求項46に記載のVEGFAと、
薬学的に許容される賦形剤とを含む医薬組成物。 - 肥満、栄養不良、及び/又は神経性無食欲症等の摂食障害を予防及び/又は治療するための医薬組成物であって、
請求項47に記載の食欲刺激ホルモン前駆体、グレリン/オベスタチンプレプロホルモン(prepro-GHRL)と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 肥満、栄養不良、及び/又は神経性無食欲症等の摂食障害を予防及び/又は治療するための医薬組成物であって、
請求項48に記載の食欲刺激ホルモン(グレリン)と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 糖尿病を予防及び/又は治療するための医薬組成物であって、
請求項49に記載のGLP-1と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 癌を予防及び治療するための医薬組成物であって、
請求項50に記載のIgG重鎖(HC)と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 癌を予防及び/又は治療するための医薬組成物であって、
請求項51に記載のIgG軽鎖(LC)と、
薬学的に許容される賦形剤とを含む医薬組成物。 - 発現ベクターであって、
(a)プロモータと、
(b)請求項34~51のいずれか一項に記載のタンパク質をコードする核酸配列と、
任意で、リンカーとを含み、
前記プロモータ及び前記核酸配列は、作動可能に連結される発現ベクター。 - 請求項68に記載の発現ベクターを含む宿主細胞。
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