JP2022512843A - スフィンゴシンキナーゼ1とその融合タンパク質およびその使用 - Google Patents
スフィンゴシンキナーゼ1とその融合タンパク質およびその使用 Download PDFInfo
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Abstract
Description
[実施例1 融合タンパク質SPHK1-Fcの調製]
IL-2シグナルペプチドによってarmSP-F(上流プライマー)(SEQ ID NO:6 :CTCCATAGAAGATTCTAGAGCTAGGGATCCGCCACCATGTACAGGATGCAACTCCTG)とarmSP-R(下流プライマー) (SEQ ID NO:7 :GGGCCGCCCGCTGGGTCCATCGAATTCGTGACAAGTGCAAG)を含むプライマーを設計した。プラスミドpFUSE-hIgG4-Fc2(Dakwei Biotechnology Co., Ltd.から購入)をテンプレートとして、PCRによりフラグメントSPを増幅させた(116bp)。SEQ ID NO:5などのSPHK1のヌクレオチド配列によってSPHK1-F(上流プライマー)(SEQ ID NO:8:ATGGACCCAGCGGGCGGCC)とSPHK1-R (下流プライマー)(SEQ ID NO:9: GCCACCGCCGCTTCCTCCGCCTCCGCTTCCGCCTCCGCCTAAGGGCTCTTCTGGCGGTG)を含むプライマーを設計した。プラスミドpcDNA3.1-WSPK1c(Military Medical Academy)をテンプレートとしてPCRによりフラグメントSPHK1を増幅させた(1191bp)。
該PCR産物フラグメントの3’セグメントには、リンカー配列Lの一部が含まれる(5’-GGCGGAGGCGGAAGCGGAGGCGGAGGAAGCGGCGGTGGC-3’)。SEQ ID NO:などのFcタンパク質のヌクレオチド配列によってFc-F(SEQ ID NO:10:GCGGAGGAAGCGGCGGTGGCGGCAGCGAGTCCAAATATGGTCCCCCATGCCCATCATGC)とFc-R (SEQ ID NO:11 GTAATCCAGAGGTTGATTGTCGACTCATTTACCCGGAGACAGGG)を含むプライマーを設計した。プラスミドpFUSE-hIgG4-Fc2(Dakwei Biotechnology Co., Ltd.から購入)をテンプレートとして、PCRによりフラグメントFcを増幅させた(740bp)。該PCR産物フラグメント5’セグメントはリンカー配列Lの一部が含まれる(配列5’- GCGGAGGAAGCGGCGGTGGCGGCAGC-3’)。全てのプライマーは、Beijing Kinco Xinye Biotechnology Co., Ltd.によって合成された。PCR反応系と反応条件は表1と表2に示す通りである。
[実施例2 プラスミドpCDH-SPHK1-L-Fcを持つレンチウイルス粒子の調製]
[実施例3 レンチウイルス感染したCHO-S細胞及び陽性モノクローナルのスクリーニング和検証]
[実施例5 SPHK1-Fcタンパク質のin vivoでの有効性に関する研究。]
以上は、具体的な実施の形態と例示的な例を参照して本発明に詳細に説明したが、これらの説明は本発明の限定として理解することはできない。当業者は、本発明の精神および範囲から逸脱することなく、本発明およびその実施の形態の技術的解決策に対して様々な同等の置換、修正または改善を行うことができ、これらはすべて本発明に含まれる。
Claims (10)
- 肥満、高血中性脂肪症又は糖尿病を予防及び/又は治療するためのタンパク質薬物への調製におけるスフィンゴシンキナーゼ1又はその活性を有するアミノ酸配列の使用。
好ましくは、前記スフィンゴシンキナーゼ1又はその活性を有するアミノ酸配列は、SEQ ID NO:1に示されるアミノ酸配列を含む。 - スフィンゴシンキナーゼ1又はその活性を有するアミノ酸配列を含むタンパク質薬物。
好ましくは、前記タンパク質薬物は、スフィンゴシンキナーゼ1又はその活性を有するアミノ酸配列を含有する融合タンパク質である。 - 前記融合タンパク質は、スフィンゴシンキナーゼ1(SPHK1)又はその活性を有するアミノ酸配列、FC配列、及びリンカー配列を含む請求項2に記載のタンパク質薬物。
前記FC配列は、ヒト又は動物の免疫グロブリンおよびそのサブタイプと改変体のアミノ酸配列、或いはヒト又は動物アルブミンおよびその改変体のアミノ酸配列から選択される。
前記リンカー配列の一般式は(GGGGS)nであり、nが0~5の整数である。
好ましくは、前記ヒト又は動物の免疫グロブリンは、IgG4FCフラグメントから選択される。
より好ましくは、前記ヒト又は動物の免疫グロブリンは、SEQ ID NO:12に示されるアミノ酸配列から選択される。
前記融合タンパク質は、SEQ ID NO:2に示されるアミノ酸配列を含む。 - 前記融合タンパク質はポリエチレングリコールで修飾され、好ましくは、前記ポリエチレングリコールの平均分子量が5~50KDである請求項2に記載のタンパク質薬物。
- 請求項2~4のいずれか一項に記載のタンパク質薬物のコーディングヌクレオチド配列を含有し、好ましくは、前記コーディングヌクレオチド配列はSEQ ID NO:3に示されているコーディング遺伝子。
- 請求項2~4のいずれか一項に記載のタンパク質薬物のコーディングヌクレオチド配列を含有し、好ましくは、前記コーディングヌクレオチド配列はSEQ ID NO:3に示されている発現コンストラクト。
前記発現コンストラクトは、原核発現コンストラクト又は真核発現コンストラクトである。 - 前記原核発現コンストラクトは、pETベクターシリーズである請求項6に記載の発現コンストラクト。
前記真核発現コンストラクトは、プラスミドDNAベクターであり、好ましくはpVAX1ベクター及びpSV1.0ベクターである。
組換えウイルスベクターは好もしくは組換えワクシニアウイルスベクター、組換えアデノウイルススベクター又は組換えアデノ関連ウイルスベクターであり、
又は逆転写ウイルスベクター、好ましくはHIVウイルスベクター、又はレンチウイルスベクターである。 - 請求項6又は7に記載の発現コンストラクトを含む宿主細胞。
前記発現コンストラクトは原核発現コンストラクトである場合に、前記宿主細胞は原核生物細胞であり、好ましくは細菌細胞である。
前記発現コンストラクトは真核発現コンストラクトである場合に、前記宿主細胞は真核生物細胞であり、好ましくは哺乳動物細胞であり、より好ましくはCHO細胞である。 - 請求項2~4のいずれか一項に記載のタンパク質薬物のヌクレオチド配列を発現ベクターにクローニングするステップを含むタンパク質薬物の調製方法。
具体的には、前記調製方法は:
1)上記タンパク質薬物の核酸配列を構築すること、
2)ステップ1)の核酸配列を含む発現ベクターを構築すること、
3)ステップ2)の発現ベクターを宿主細胞のトランスフェクト又は形質転換に用いて、前記核酸配列を宿主細胞で発現させること、を含む
好ましくは、ステップ3)において、前記宿主細胞はCHO-S細胞である。 - 肥満、高血中性脂肪症又は糖尿病を予防及び/又は治療するための医薬品組成物への調製における請求項2~4のいずれか一項に記載のタンパク質薬物、請求項5に記載のコーディング遺伝子、請求項6又は7に記載の発現コンストラクト、請求項8に記載の宿主細胞の使用。
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