JP6964519B2 - ゴナドトロピンの製造方法 - Google Patents
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- JP6964519B2 JP6964519B2 JP2017555503A JP2017555503A JP6964519B2 JP 6964519 B2 JP6964519 B2 JP 6964519B2 JP 2017555503 A JP2017555503 A JP 2017555503A JP 2017555503 A JP2017555503 A JP 2017555503A JP 6964519 B2 JP6964519 B2 JP 6964519B2
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Description
細胞株開発プロセスの概要
別個のCMVieプロモーターからそれぞれ制御されるhCGアルファ鎖およびベータ鎖を保持する単一のプラスミドを、エレクトロポレーションによってPER.C6(登録商標)細胞にトランスフェクトした。
hCGアルファポリペプチドの遺伝子のコード領域を図1に示す。hCGアルファポリペプチド配列の遺伝子のコード領域は、本明細書において配列番号1として参照される。
phCGは、hCGの合成アルファ鎖であり、哺乳類細胞におけるコドン使用のために最適化されており、天然のhCGアルファシグナルペプチドを含む。それは当技術分野において周知の方法によって改変されうる。
ST3GAL4遺伝子はpST3において発現される。β−ガラクトシドα−2,3−シアリルトランスフェラーゼ4(ST3、L23767、配列番号3、図3)のコード配列を、2,3STfwおよび2,3STrevのプライマーの組み合わせを用いたPCRによって増幅した。
2,3STrev 5’−TTTTTTTCTTAAGTCAGAAGGACGTGAGGTTCTTG−3’
原核生物β−ラクタマーゼ遺伝子中に位置する単一のPvuI部位を有するプラスミドphCG(図4)をPvuI(New England Biolabsカタログ番号R0150)を用いて線状化した。線状化したプラスミドDNAを以下のようにしてPER.C6(登録商標)細胞にトランスフェクトした。
実施例3において先に記載したようにして、安定なクローンを生成した。
電気泳動は、電場による溶媒を介した荷電分子の輸送として定義される。電場による生体分子の移動度は、電界強度、分子上の正味の電荷、分子のサイズおよび形状、イオン強度および分子が移動する媒体の性質に依存することになる。
無血清培地中で懸濁培養したPER.C6細胞中で組換えhCGを製造するための手順が開発された。この手順は以下に記載され、いくつかのhCG産生PER.C6細胞株に適用された。
シアル酸は、単糖とみなされるタンパク質結合炭水化物であり、ガラクトース、マンノース、グルコサミン、ガラクトサミンおよびフコースのような他の単糖との組み合わせで生じる。本発明に従う精製rhCG上の全シアル酸は、Stantonらの方法(J.Biochem.Biophys.Methods.30(1995),37−48)に基づく方法を用いて測定した。
以下の表1のサンプルの各々について、hCG比活性を決定するためにhCGバイオアッセイを実施した。活性は、標準としてOvitrelleを用いて、USP(USP Monographs:Chorionic Gonadotropin,USPC Official 8/1/09−11/30/09)に従って測定した。Ovitrelleは26,000IU/mgの生物学的活性を有する(Curr Med Res Opin.2005 Dec;21(12):1969−76)。許容限度は>21,000IU hCG/mgであった。α2,3−シアリルトランスフェラーゼにより改変されたヒト細胞株由来hCG組換えhCGのサンプルに関する生物学的活性を表1に示す。
Claims (10)
- 配列番号1に記載の核酸配列を含むポリヌクレオチド。
- 配列番号4に記載の核酸配列を含むポリヌクレオチド。
- 配列番号1の核酸と少なくとも97%の配列同一性を有し、hCGのα鎖をコードする核酸配列を含むポリヌクレオチド。
- 配列番号4の核酸と少なくとも97%の配列同一性を有し、hCGのα鎖をコードする核酸配列を含むポリヌクレオチド。
- そのゲノム中に組み込まれた、配列番号1に記載の配列;配列番号1の配列と少なくとも97%の相同性を有する配列;配列番号4に記載の配列;および配列番号4の配列と少なくとも97%の相同性を有する配列から選択されるhCGのα鎖をコードする配列を含むポリヌクレオチドを含むことを特徴とする細胞。
- PER.C6(登録商標)細胞である、請求項5に記載の細胞。
- そのゲノム中に組み込まれた、α2,3−シアリルトランスフェラーゼをコードするcDNAをさらに含むことを特徴とする、請求項5または6に記載の細胞。
- そのゲノム中に組み込まれた、hCGのβ鎖をコードする核酸配列をさらに含むことを特徴とする、請求項5から7のいずれかに記載の細胞。
- 組換えタンパク質を細胞中で製造する方法であって、請求項5から8のいずれかに記載の細胞を適切な培地中で培養すること、ならびに前記細胞および/または前記培地から組換えタンパク質を回収することを含む方法。
- 組換えhCGを細胞中で製造する方法であって、適切な培地中で細胞を培養すること、ならびに前記細胞および/または前記培地から組換えタンパク質(hCG)を回収することを含み、細胞が、そのゲノム中に組み込まれた、配列番号1に記載の配列;配列番号1の配列と少なくとも97%の相同性を有する配列;配列番号4に記載の配列;および配列番号4の配列と少なくとも97%の相同性を有する配列から選択されるhCGのα鎖をコードする配列を含むポリヌクレオチドを含むPER.C6(登録商標)細胞である、方法。
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