JP2018511325A - グルタミン酸オキサロ酢酸トランスアミナーゼ1(got1)、その調製物および製造方法およびその使用 - Google Patents
グルタミン酸オキサロ酢酸トランスアミナーゼ1(got1)、その調製物および製造方法およびその使用 Download PDFInfo
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Abstract
Description
本発明は、いくつかの実施形態において、精製されたグルタミン酸オキサロ酢酸トランスアミナーゼ1(GOT1)調製物およびその製造方法に関する。
本発明のいくつかの実施形態の態様によると、グルタミン酸オキサロ酢酸トランスアミナーゼ1(GOT1)ポリペプチド分子を含むタンパク質調製物が提供され、ここで、そのGOT1ポリペプチド分子の100%が、GOT1ポリペプチドの1位にアラニンを有し、そのGOT1ポリペプチド分子は、その調製物中のタンパク質の少なくとも95%を構成する。
(a)ポリペプチドおよびSUMOを含む融合タンパク質を宿主細胞において発現させる工程であって、そのポリペプチドのN末端は、SUMOのC末端に翻訳段階で融合され、その融合タンパク質は、異種親和性タグを欠く、工程;
(b)その融合タンパク質からSUMOを除去する工程;および
(c)宿主細胞からポリペプチドを単離することによって、ポリペプチドを精製する工程
を含む。
(a)熱処理によってGOT1を精製する工程;
(b)塩誘導沈殿によってGOT1を精製する工程;
(c)混合モードクロマトグラフィーによってGOT1を精製する工程;
(d)陽イオン交換クロマトグラフィーによってGOT1を精製する工程;および
(e)陰イオン交換クロマトグラフィーによってGOT1を精製する工程
によって実施され、ここで、工程(e)は、工程(d)の後に行われ、工程(d)は、工程(c)の後に行われ、工程(c)は、工程(b)の後に行われ、工程(b)は、工程(a)の後に行われる。
本発明のいくつかの実施形態は、添付の図面および像を参照しながら、ほんの一例として本明細書中に記載される。ここから図面を詳細に具体的に参照していくが、その詳細は、一例としておよび本発明の実施形態を例証的に考察する目的で示されることが強調される。この点において、図面とともに行われる説明によって、本発明の実施形態がどのように実施され得るかが当業者に明らかになる。
図面において:
本発明は、そのいくつかの実施形態において、精製されたグルタミン酸オキサロ酢酸トランスアミナーゼ1(GOT1)調製物およびそれを生成する方法に関する。
(a)ポリペプチドおよびSUMOを含む融合タンパク質を宿主細胞において発現させる工程であって、ここで、そのポリペプチドのN末端は、SUMOのC末端に翻訳段階で融合され、その融合タンパク質は、異種親和性タグを欠く、工程;
(b)その融合タンパク質からSUMOを除去する工程;および
(c)宿主細胞からそのポリペプチドを単離することによって、ポリペプチドを精製する工程
を含む。
高温ではタンパク質ごとに異なる安定性を有するので、標的タンパク質が、混入タンパク質よりも高い熱安定性を有する場合、数分から数時間までの様々な時間にわたる高温でのインキュベーションによって、望まれないタンパク質が沈殿することが多く、それらのタンパク質は、遠心分離によって除去することができる。高温での標的タンパク質の安定性は、場合によっては、基質またはその折り畳みを増強する他の特定のリガンドの存在によって高められ得る。アルファ−ケトグルタレート(例えば、10mM)およびピリドキサール5−リン酸(例えば、20μM)の存在下におけるGOT1は、70℃において熱安定性である。したがって、温度を約70℃に上昇させることによって、変性した混入タンパク質が沈殿し得る。
タンパク質の溶解度は、その溶液のイオン強度、ゆえに塩濃度に従って変動する。2つの異なる影響が認められる:低い塩濃度では、タンパク質の溶解度は、塩濃度の上昇(すなわちイオン強度の上昇)とともに上昇する(塩溶と呼ばれる作用)。塩濃度(イオン強度)がさらに上昇すると、タンパク質の溶解度は、下がり始める。十分に高いイオン強度では、タンパク質は、その溶液からほぼ完全に沈殿する(塩析)。タンパク質は、高イオン強度ではその溶解度が著しく異なるので、塩析(または塩誘導沈殿)が、所与のタンパク質の精製を助ける非常に有用な手順である。通常使用される塩は、非常に水溶性であることから硫酸アンモニウムであり、これは、ホフマイスター系列において高い2種のイオンを形成し、酵素活性に対して有害作用を及ぼさない。それは、通常、飽和水溶液として使用され、その飽和水溶液は、必要とされる濃度に希釈され、その濃度は、飽和溶液(100%溶液)に対するパーセント濃度として表現される。
用語「クロマトグラフィー樹脂」または「クロマトグラフィー媒体」は、本明細書中で交換可能に使用され、混合物中に存在する他の分子から目的の被検体(例えば、目的のポリペプチドまたは本発明の融合タンパク質)を分離する任意の種類の固相のことを指す。通常、目的の被検体は、その混合物の個々の分子が、移動相の影響下においてまたは結合および溶出プロセスにおいて固定固相を通って移動する速度の差の結果として、他の分子から分離される。非限定的な例としては、陽イオン交換樹脂、陰イオン交換樹脂および混合モード樹脂が挙げられる。使用される樹脂の体積、カラムの長さおよび直径、ならびに動的容量および流速は、いくつかのパラメータ、例えば、処理される流体の体積、本発明のプロセスに供される流体中のタンパク質の濃度などに依存する。各工程に対するこれらのパラメータの決定は、十分に当業者の平均的な技術の範囲内である。
混合モードクロマトグラフィーは、混合モードのクロマトグラフィーリガンドを利用するクロマトグラフィーである。ある特定の実施形態において、そのようなリガンドは、結合されるべき物質と相互作用する少なくとも2つの異なるが協同的な部位を提供することができるリガンドのことを指す。これらの部位の1つは、リガンドと目的の物質との間に引力型の電荷間相互作用を付与する。他方の部位は、典型的には、電子受容体−供与体相互作用ならびに/または疎水性および/もしくは親水性相互作用を付与する。電子供与体−受容体相互作用には、水素結合、π−π、陽イオン−π、電荷移動、双極子間、誘起双極子などのような相互作用が含まれる。
分離を行う際、種々の手法のいずれか、例えば、バッチ精製法またはクロマトグラフ法を用いることによって、タンパク質混合物を陽イオン交換材と接触させることができる。当該タンパク質のpIより低いpHを有する緩衝液中に存在するとき全体的に正電荷を有するタンパク質は、負に帯電した官能基を含む陽イオン交換材に良く結合する。溶出は、通常、イオン交換マトリックスの帯電した部位について溶質と競合するように緩衝液のイオン強度(すなわち、伝導率)を高めることによって達成される。pHを変更することおよびそれによって溶質の電荷を変化させることが、溶質を溶出させる別の方法である。伝導率またはpHの変更は、漸進的(勾配溶出)であってもよいし、段階的(段階溶出)であってもよい。クロマトグラフィーのための陽イオン担体を形成するために、マトリックスに陽イオン性置換基を付着させてもよい。陽イオン交換置換基(substitutents)の非限定的な例としては、カルボキシメチル(CM)、スルホエチル(SE)、スルホプロピル(SP)、ホスフェート(P)およびスルホネート(S)が挙げられる。
様々な陰イオン交換クロマトグラフィー担体を使用することができ、それは、DEAE−Sepharose CL−6B、DEAE−Sepharose FF、Q−Sepharose FF、Q−Sepharose HP、Q−Sepharose XL、DEAE−Sephacel、DEAE−Sephadex、QAE−Sephadex、DEAE−Toyopearl、QAE−Toyopearl、Mini−Q、Mono−Q、Mono−P、Source 15Q、Source 30Q、ANX−Sepharoseなどからなる群より選択され得る。好ましくは、陰イオン交換クロマトグラフィーは、Q−SepharoseまたはDEAE−Sepharoseにおいて(例えば、4.0〜9.0のpH範囲において)行われる。
(a)熱処理(例えば、10分間の65〜70℃)によってGOT1を精製する工程;
(b)塩誘導沈殿(例えば、硫酸アンモニウム沈殿)によってGOT1を精製する工程;
(c)混合モードクロマトグラフィー(例えば、4.0〜8.0のpH範囲でのPPA HyperCel)によってGOT1を精製する工程;
(d)陽イオン交換クロマトグラフィー(例えば、4.0〜7.0のpH範囲でのSP−SepharoseまたはCM−Sepharose)によってGOT1を精製する工程;および
(e)陰イオン交換クロマトグラフィー(例えば、4.0〜9.0のpH範囲でのQ−SepharoseまたはDEAE−Sepharose)によってGOT1を精製する工程。
実施例
還元条件および非還元条件下のSDS−PAGEによる純度:rGOT1の純度の測定は、還元条件および非還元条件下における界面活性剤ドデシル硫酸ナトリウム(SDS)の存在下でのプレキャストポリアクリルアミドゲルにおける垂直電気泳動によって行った。還元タンパク質および非還元タンパク質のサンプルを、ポリアクリルアミドゲルプレートにおいて分子サイズに従って分離した。
E.coli BL21(DE3)pET28/GOT1(Δhis)由来の構築物をGOT1遺伝子増幅のための主要な鋳型として使用した。開始メチオニンをコードする最初のATGコドンを除く完全な遺伝子(配列番号4)が増幅されるようにプライマーをデザインした。プライマー配列は、以下のとおりであった:順方向SUMO2:5’−GCACCTCCGTCAGTCTTTG−3’配列番号6 逆方向SUMO2:3’−CTACTGGATTTTGGTGACTGCTTCATGGAT−5’配列番号7。
a)フラスコ内での接種材料の調製(培養)用(g/L):リン酸水素二ナトリウム(17.0)、リン酸二水素カリウム(1.82)、硫酸アンモニウム(3.0)、硫酸マグネシウム七水和物(0.5)、D(+)−グルコース一水和物(15.0)および微量要素原液(0.16mL);
b)発酵用(g/L):第二リン酸アンモニウム(4.0)、硫酸マグネシウム七水和物(0.5)、リン酸二水素カリウム(13.3)、クエン酸一水和物(1.6)、D(+)−グルコース一水和物(30.0)および微量要素原液e)(0.25mL);
c)供給液A(g/L):D(+)−グルコース一水和物(700.0)、硫酸マグネシウム七水和物(20.7)および微量要素原液e)(2.2mL/L);
d)供給液B(g/L):第二リン酸アンモニウム(360.0)およびリン酸二水素カリウム(306.7);および
e)微量要素(微量元素)原液(g/L):塩化鉄(III)六水和物(30.0)、塩化カルシウム二水和物(4.05)、硫酸亜鉛(II)七水和物(6.75)、硫酸マンガン(II)一水和物(1.5)、硫酸銅(II)五水和物(3.0)、塩化コバルト(II)六水和物(1.14)、モリブデン酸ナトリウム二水和物(0.3)およびホウ酸(0.69)。
バイオマスの凍結片(1570〜1830g)をバッグから取り出した。緩衝液W−A02が入った容器内で3mL/グラムの細胞ペーストで4〜8℃の温度において細胞を再構成した。高圧ホモジナイザーを900barの圧力で3サイクル使用して、細胞を破壊した。懸濁液を遠心分離し、沈殿物を廃棄し、タンパク質溶液を次の工程に使用した。懸濁液をウォーターバス内で撹拌しながら加熱し、温度が50℃に達したら、アルファ−ケトグルタレートおよびピリドキサール5−リン酸水和物を、10mM(アルファ−ケトグルタレート)および20μM(ピリドキサール5−リン酸)の最終濃度まで加えた。温度を65〜70℃に上昇させ、溶液を10±1分間インキュベートした。2〜10℃に冷却した後、変性した材料を遠心分離によって除去した。上清をデカントして回収した。加熱処理後のタンパク質溶液に1mMのDTTを加えた。100,000UのSUMOプロテアーゼを加え、切断のために温度を4〜10℃で10〜24時間維持した。脱SUMO化の後、そのタンパク質溶液に固体硫酸アンモニウムを300g/Lの濃度まで加えた。この溶液を室温において20分間撹拌し、遠心分離した。ペレットを廃棄し、撹拌し続けながら、上清の流体にさらなる量の硫酸アンモニウム(130g/L)を加えた。4〜10℃で20分間貯蔵した後、最終的なペレットを遠心分離によって回収し、20ml/gのペレットになるようにPBS緩衝液に溶解した。
3つのクロマトグラフィー工程を用いて、rGOT1中間体材料を精製した:PPA Hyper Cel樹脂(ベッド高15.3〜15.8cm)の媒体を使用する混合モード相互作用、CM−Sepharose FF(ベッド高9.4〜9.9cm)およびQ Sepharose FF(ベッド高9.2〜10.2cm)を使用するイオン交換クロマトグラフィー。
陰イオン交換クロマトグラフィーからのタンパク質溶液を、30kDa膜を用いて15〜20mg/mlに濃縮した。20mM酢酸ナトリウムpH5.0への緩衝液交換のために100膜分離体積を使用した。最終的なタンパク質濃度は、10±2mg/mlであった。膜透過圧は、0.3〜0.6であった。純度は、>99%であると見出され、製剤化されたGOTを、還元条件と非還元条件の両方のSDS−PAGE(図8)、RP−HPLC(図9)およびSE−HPLC(図10)によって解析した。RP−HPLC解析の結果を本明細書の下記の表1に要約する。
Claims (36)
- グルタミン酸オキサロ酢酸トランスアミナーゼ1(GOT1)ポリペプチド分子を含むタンパク質調製物であって、前記GOT1ポリペプチド分子の100%が、前記GOT1ポリペプチドの1位にアラニンを有し、前記GOT1ポリペプチド分子は、前記調製物中のタンパク質の少なくとも95%を構成する、タンパク質調製物。
- 前記タンパク質が、前記調製物中の分子の少なくとも98%を構成する、請求項1に記載のタンパク質調製物。
- 活性な作用物質として請求項1または2に記載のタンパク質調製物、および薬学的に許容され得る担体を含む、薬学的組成物。
- 前記GOT1が、配列番号2と少なくとも90%相同なアミノ酸配列を含む、請求項1または3に記載の調製物または薬学的組成物。
- 前記GOT1が、配列番号2に示されているアミノ酸配列からなる、請求項1または3に記載の調製物または薬学的組成物。
- 目的のポリペプチドおよび低分子ユビキチン様修飾因子(SUMO)を含む融合タンパク質であって、前記目的のポリペプチドのN末端は、前記SUMOのC末端に翻訳段階で融合され、前記融合タンパク質は、異種親和性タグを欠く、融合タンパク質。
- グルタミン酸オキサロ酢酸トランスアミナーゼ1(GOT1)および低分子ユビキチン様修飾因子(SUMO)を含むGOT1融合タンパク質であって、前記GOT1のN末端は、前記SUMOのC末端に翻訳段階で融合され、前記融合タンパク質は、親和性タグを欠く、グルタミン酸オキサロ酢酸トランスアミナーゼ1(GOT1)融合タンパク質。
- 前記GOT1が、1位にアラニンを含む、請求項7に記載の融合タンパク質。
- 前記親和性タグが、ポリヒスチジンタグである、請求項6または7に記載の融合タンパク質。
- 前記GOT1のアミノ酸配列が、配列番号2と少なくとも90%相同である、請求項7に記載の融合タンパク質。
- 前記SUMOのアミノ酸配列が、配列番号5と少なくとも90%相同である、請求項6または7に記載の融合タンパク質。
- 配列番号1と少なくとも90%相同なアミノ酸配列を含む、請求項7に記載の融合タンパク質。
- 配列番号1に示されているアミノ酸配列からなる、請求項7に記載の融合タンパク質。
- 前記SUMOが、酵母SUMOである、請求項6または7に記載の融合タンパク質。
- 前記酵母SUMOが、Saccharomyces cerevisiaeのmif two 3のサプレッサー(Smt3)である、請求項14に記載の融合タンパク質。
- 請求項6〜15のいずれか1項に記載の融合タンパク質をコードする、単離されたポリヌクレオチド。
- 配列番号3と少なくとも90%相同な核酸配列を含む、請求項16に記載の単離されたポリヌクレオチド。
- 請求項16または17のいずれか1項に記載の単離されたポリヌクレオチドを含む、核酸構築物。
- 過剰なグルタメートに関連する疾患または状態の処置を必要とする被験体において過剰なグルタメートに関連する疾患または状態を処置する方法であって、治療有効量の請求項1〜5のいずれか1項に記載の調製物または薬学的組成物を前記被験体に投与することによって前記疾患または状態を処置する工程を含む、方法。
- 過剰なグルタメートに関連する疾患または状態の処置において使用するための、請求項1に記載のタンパク質調製物。
- 過剰なグルタメートに関連する疾患または状態の処置において使用するための、請求項3に記載の薬学的組成物。
- 前記疾患または状態が、脳の疾患または状態である、請求項19〜21のいずれか1項に記載の方法、調製物または組成物。
- 前記脳の疾患が、中枢神経系の癌である、請求項19〜21のいずれか1項に記載の方法、調製物または組成物。
- 前記癌が、神経膠芽腫である、請求項23に記載の方法、調製物または組成物。
- 前記脳の状態が、脳虚血である、請求項22に記載の方法、調製物または組成物。
- 前記疾患が、神経変性疾患である、請求項19〜21のいずれか1項に記載の方法、調製物または組成物。
- ポリペプチドを精製する方法であって、前記方法は、
(a)前記ポリペプチドおよびSUMOを含む融合タンパク質を宿主細胞において発現させる工程であって、前記ポリペプチドのN末端は、前記SUMOのC末端に翻訳段階で融合され、前記融合タンパク質は、異種親和性タグを欠く、工程;
(b)前記融合タンパク質から前記SUMOを除去する工程;および
(c)前記宿主細胞から前記ポリペプチドを単離することによって、前記ポリペプチドを精製する工程
を含む、方法。 - 工程(b)が、工程(c)の前に実施される、請求項27に記載の方法。
- 前記ポリペプチドが、GOT1である、請求項27に記載の方法。
- 前記除去する工程が、SUMOプロテアーゼを用いて実施される、請求項27または29に記載の方法。
- 前記単離する工程が、熱沈殿、塩誘導沈殿、混合モードクロマトグラフィー、陽イオン交換クロマトグラフィーおよび陰イオン交換クロマトグラフィーからなる群より選択される手法を用いて実施される、請求項27に記載の方法。
- 前記単離する工程が、熱沈殿、塩誘導沈殿、混合モードクロマトグラフィー、陽イオン交換クロマトグラフィーおよび陰イオン交換クロマトグラフィーを用いて実施される、請求項31に記載の方法。
- 前記単離する工程が、
(a)熱処理によって前記GOT1を精製する工程;
(b)塩誘導沈殿によって前記GOT1を精製する工程;
(c)混合モードクロマトグラフィーによって前記GOT1を精製する工程;
(d)陽イオン交換クロマトグラフィーによって前記GOT1を精製する工程;および
(e)陰イオン交換クロマトグラフィーによって前記GOT1を精製する工程
によって実施され、ここで、工程(e)は、工程(d)の後に行われ、工程(d)は、工程(c)の後に行われ、工程(c)は、工程(b)の後に行われ、工程(b)は、工程(a)の後に行われる、請求項29に記載の方法。 - 前記塩誘導沈殿が、硫酸アンモニウムによって誘導される沈殿を含む、請求項31〜33のいずれか1項に記載の方法。
- 前記宿主細胞が、細菌、酵母、哺乳動物細胞および昆虫細胞からなる群より選択される、請求項27〜34のいずれか1項に記載の方法。
- 前記宿主細胞が、細菌細胞である、請求項35に記載の方法。
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US20180071369A1 (en) | 2018-03-15 |
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