JP2013531488A - エキセンジン−4の融合タンパク質およびその類似体、これらの調製方法および使用 - Google Patents
エキセンジン−4の融合タンパク質およびその類似体、これらの調製方法および使用 Download PDFInfo
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
Description
式I
Xaa10は、Leu、Ala、Ser、Leu、Ile、GluまたはLysであってよく、
Xaa12は、Lys、Leu、Thr、Ser、Leu、IleまたはCysであってよく、
Xaa13は、Gln、Thr、Ala、Val、Leu、IleまたはLysであってよく、
Xaa14は、Met、Tyr、Thr、Ala、Ser、IleまたはLysであってよく、
Xaa19は、Val、Cys、Ala、Ser、Leu、IleまたはLysであってよく、
Xaa20は、Arg、Thr、Tyr、Ser、Leu、IleまたはLysであってよく、
Xaa21は、Leu、Thr、Ala、Asp、Glu、HisまたはLysであってよく、
Xaa24は、Glu、Leu、Thr、Ala、Ser、LysまたはIleであってよく、
Xaa27は、Lys、Ala、Ser、Leu、Thr、IleまたはLysであってよく、
Xaa28は、Asp、Thr、Ala、Ser、Leu、IleまたはLysであってよく、
Xaa30は、Gly、Thr、Ala、Ser、Leu、IleまたはArgであってよく、
Xaa31は、Pro、Val、Ser、Ala、Leu、IleまたはLysであってよく、
Xaa32は、Ser、Thr、Glu、Ser、Asp、LysまたはIleであってよく、
Xaa33は、Thr、Ser、Ala、Met、Leu、IleまたはLysであってよく、
Xaa34は、Gly、Thr、Met、Ser、Ile、LeuまたはLysであってよく、
Xaa35は、Ala、Thr、Ala、Glu、Leu、IleまたはPheであってよく、
Xaa36は、Pro、Ala、Thr、Ser、Leu、IleまたはCysであってよく、
Xaa37は、Pro、Thr、Ser、Ala、His、LysまたはIleであってよく、
Xaa38は、Pro、Thr、Val、Ser、Leu、LysまたはIleであってよく、
Xaa39は、Ser、Tyr、Ala、Leu、Ser、IleまたはLysであってよい。
牛胎児血清(FCS)を添加したDMEM(Invitrogenから購入)全培養液10%(体積百分率)でチャイニーズハムスター卵巣細胞(CHO)を培養し、トランスフェクション前に、1ウェル当り3×105個の細胞で6ウェルプレートに均等に分散させる。トランスフェクションに関しては、LIPOFECTAMINE 2000の取扱指示を参照する。トランスフェクション48時間後、細胞を選択的基質(メチオニンスルホキシミン(MSX)25μm)で約1週間加圧培養すると、空細胞はすべて壊死する。生存細胞を96ウェルプレート(50細胞/ウェル)に播種してさらに加圧培養する。細胞をクローン化後に、培養上清中のタンパク質発現量を定量するELISA試験を行い、高発現(発現量が200mg/L超)のウェルを選別し、増幅培養のために24ウェルプレートに移す。再度ELISAを実施して上澄中のタンパク質発現量を定量し、参照文献(Cell Experimental Manual、Science Press、2003)に従って、高発現(発現量が200mg/L超)の細胞株を選別して増幅培養を継続する。懸濁培養液を徐々に熟成することによって、シードセルバンクを作製し、サブクローン化を実施してワーキングセルバンク(遺伝子操作したCHO細胞株からなる)を作製する。
上記で得た遺伝子操作したCHO細胞株を解凍して、容量が25cm2のT型培養瓶に5mLの細胞懸濁液で播種し、4〜5日間培養液を振とうさせた後、内容物を三角フラスコに入れて増幅し、7〜10日間さらに培養する。参照文献(Molecular Cloning、Science Press、2002)に記載の手順に従って、融合タンパク質を含む細胞培養液を分離し、タンパク質Aアフィニティークロマトグラフィー培地(MabSuRe(商標)、GE社)、アニオンクロマトグラフィー培地(Q Sepherose FF、GE社)、カチオンクロマトグラフィー培地(SP Sepherose FF、GE社)によって連続精製する。その後、精製した融合タンパク質をG−25ゲル濾過カラムによって製剤緩衝液に置換して得る。
精製した融合タンパク質を非還元条件下で電気泳動すると、転送装置(GE社)(電流:25mA、時間:2時間)によって、電気泳動バンドが、メタノールで活性したPVDF膜に転写される。PVDF膜を脱脂乳5wt%に入れて2時間密閉し、予め希釈したアルカリホスファターゼの添加によって標識した抗IgG2抗体を1時間培養し、TBSTで洗浄する。洗浄時では、TBSTを5分に1回新しいものに交換する必要がある。洗浄が終了した後に、ルミネセンス測定法用の基質CDP−star(登録商標)を添加し、フィルムを押圧し、露出させて撮像する。結果を図2に示す。融合タンパク質はIgG2抗体に対して陽性を示す。
精製した融合タンパク質は、高速電気泳動システム(Phast System、GE)を用い、等電点電気泳動によって分析する。分析には、pH3〜10に予め調製したゲルを使用した。焦点電気泳動を実施する場合は、予め調製したゲルをクマシー溶液で染色する。結果を図3に示す。融合タンパク質のメインバンドの等電点は5.8であり、期待値6.2に近い。
精製した融合タンパク質は、参照文献(Molecular Cloning、Science Press、2002)に記載の手順に従って、ゲルクロマトグラフィー(クロマトグラフ用カラムTSK3000sw)により、負荷量10μgで分析する。結果を図4に示す。融合タンパク質は、ゲルクロマトグラフィーで単一の対称ピークを示し、保持時間は8.5分である。
A.ヒトGLP1受容体発現CHO細胞におけるエキセンジン−4の融合タンパク質のcAMP分泌試験
GLP−1受容体発現CHO−hGLP1R細胞を用いて、融合タンパク質の生物学的活性を(国際公開第2007/017892号パンフレットに記載されるように)細胞レベルで試験し、下流効果のある産物(セカンドメッセンジャーcAMP)のモル濃度と、本発明のLAX09(すなわち、上に記載するようにして得られ、配列番号4で示すエキセンジン−4の融合タンパク質であり、以下同じである)のin vitroでの性能とを定量する。DMEM基質10体積%を含有するFBSを黒色透明の96ウェルプレートに添加し、薬剤濃度が0.01〜1000nMのエキセンジン−4およびLAX09をそれぞれ基質に添加する。30分培養すると細胞は崩壊することから、市販キット(Cisbio)によって細胞内のcAMP濃度を測定する。結果を表1に示す。
LAX09とヒトGLP−1受容体の持続発現が可能な遺伝子操作したCHO細胞株(CHO−hGLP1R、以下同じ)との結合活性を試験し、本発明のLAX09の精製試料の生物学的活性を定量する。
A.肥満糖尿病モデルのKK−Ayマウス単回注射による低血糖試験
糖尿病モデルのKK−Ayマウス(Beijing HFK Bioscience社(北京)から購入、以下同じ)を無作為化により、PBS対照群1群とさまざまな勾配のエキセンジン−4の融合タンパク質(LAX09)実験群3群とを含む4群に割り付ける。2時間絶食させた後に、尾静脈から薬剤を200μl/動物の用量で注射する。その後、0分、30分、60分、120分、180分および240分後のマウスの血糖値を測定する。結果を図6に示す。LAX09は、1mg/kgで血糖降下作用が最良となり、マウスの血糖値が10mmol/L未満に抑制されている。
5〜6週齢の糖尿病モデルのdb−dbマウスを無作為化により、PBS対照群1群とさまざまな勾配のエキセンジン−4の融合タンパク質(LAX09)実験群3群とを含む4群に割り付ける。2時間絶食させた後に、尾静脈から薬剤を200μl/動物の用量で注射する。その後、0分、30分、60分、120分、180分および240分後のマウスの血糖値を測定する。結果を図13に示す。1mg/kg群および0.1mg/kg群は、血糖降下作用が最良である。
Claims (17)
- リンカーを介して輸送タンパク質にペプチドホルモンを融合することによって得られる融合タンパク質であって、前記ペプチドホルモンはエキセンジン−4またはエキセンジン−4の類似体であり、前記ペプチドホルモンは血糖を下げることができ、前記輸送タンパク質は免疫グロブリンIgG2のFc部分であり、前記融合タンパク質は血糖を下げることができ、前記ペプチドホルモンは式Iで示す配列を含む融合タンパク質。
His−Xaa2−Glu−Gly−Thr−Phe−Thr−Ser−Asp−Xaa10−Ser−Xaa12−Xaa13−Xaa14−Glu−Glu−Glu−Ala−Xaa19−Xaa20−Xaa21−Phe−Ile−Xaa24−Trp−Leu−Xaa27−Xaa28−Gly−Xaa30−Xaa31−Xaa32−Xaa33−Xaa34−Xaa35−Xaa36−Xaa37−Xaa38−Xaa39
式I
[式中、Xaa2は、Gly、Thr、Ala、Ser、Leu、IleまたはLysであり、
Xaa10は、Leu、Ala、Ser、Leu、Ile、GluまたはLysであり、
Xaa12は、Lys、Leu、Thr、Ser、Leu、IleまたはCysであり、
Xaa13は、Gln、Thr、Ala、Val、Leu、IleまたはLysであり、
Xaa14は、Met、Tyr、Thr、Ala、Ser、IleまたはLysであり、
Xaa19は、Val、Cys、Ala、Ser、Leu、IleまたはLysであり、
Xaa20は、Arg、Thr、Tyr、Ser、Leu、IleまたはLysであり、
Xaa21は、Leu、Thr、Ala、Asp、Glu、HisまたはLysであり、
Xaa24は、Glu、Leu、Thr、Ala、Ser、LysまたはIleであり、
Xaa27は、Lys、Ala、Ser、Leu、Thr、IleまたはLysであり、
Xaa28は、Asp、Thr、Ala、Ser、Leu、IleまたはLysであり、
Xaa30は、Gly、Thr、Ala、Ser、Leu、IleまたはArgであり、
Xaa31は、Pro、Val、Ser、Ala、Leu、IleまたはLysであり、
Xaa32は、Ser、Thr、Glu、Ser、Asp、LysまたはIleであり、
Xaa33は、Thr、Ser、Ala、Met、Leu、IleまたはLysであり、
Xaa34は、Gly、Thr、Met、Ser、Ile、LeuまたはLysであり、
Xaa35は、Ala、Thr、Ala、Glu、Leu、IleまたはPheであり、
Xaa36は、Pro、Ala、Thr、Ser、Leu、IleまたはCysであり、
Xaa37は、Pro、Thr、Ser、Ala、His、LysまたはIleであり、
Xaa38は、Pro、Thr、Val、Ser、Leu、LysまたはIleであり、
Xaa39は、Ser、Tyr、Ala、Leu、Ser、IleまたはLysである。] - 前記ペプチドホルモンは、配列番号1で示すアミノ酸配列を有するエキセンジン−4である請求項1に記載の融合タンパク質。
- 前記リンカーは、(Gly)m−Xaa−(Gly)nで示す配列を有するペプチドであり、mは3〜8の整数であり、nは3〜8の整数であり、XaaはGly、Ser、AlaおよびThrからなる群から選択されるいずれか1つである請求項1に記載の融合タンパク質。
- mは4〜6の整数であり、nは4〜6の整数である請求項3に記載の融合タンパク質。
- 前記リンカーは、配列番号3で示すアミノ酸配列を有する請求項4に記載の融合タンパク質。
- 前記免疫グロブリンIgG2のFc部分は、ヒト由来である請求項1に記載の融合タンパク質。
- 配列番号4で示すアミノ酸配列を有する請求項1に記載の融合タンパク質。
- 請求項1〜7のいずれか1項に記載の融合タンパク質をコードするポリヌクレオチド配列。
- 請求項8に記載のポリヌクレオチド配列を含むベクター。
- 請求項9に記載のベクターが受容細胞をトランスフェクトすることによって生成される宿主細胞。
- 前記受容細胞はCHO細胞である請求項10に記載の宿主細胞。
- 前記受容細胞はNS0細胞である請求項10に記載の宿主細胞。
- 請求項1に記載の融合タンパク質の製造方法であって、
(1)請求項8に記載のポリヌクレオチド配列を転写して変換する工程と、
(2)プロテインA法を用いて請求項8に記載のポリヌクレオチド配列の翻訳生成物を精製する工程とを含む方法。 - 請求項1〜7のいずれか1項に記載の融合タンパク質と、薬理学的に許容できる賦型剤とを含む医薬組成物。
- 局所投与、エアロゾルまたは注射として投与される請求項14に記載の医薬組成物。
- 腹腔注射、皮下注射、筋肉注射および静脈注射で投与されることを特徴とする請求項15に記載の医薬組成物。
- 糖尿病および肥満症に対する薬剤の製造における請求項1〜7のいずれか1項に記載の融合タンパク質の使用。
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2004528014A (ja) * | 2000-12-07 | 2004-09-16 | イーライ・リリー・アンド・カンパニー | Glp−1融合タンパク質 |
WO2004035623A2 (en) * | 2002-10-02 | 2004-04-29 | Zealand Pharma A/S | Stabilized exendin-4 compounds |
WO2007012188A1 (en) * | 2005-07-27 | 2007-02-01 | Qinghua Wang | GLP/1/EXENDM 4 IgG Fc FUSION CONSTRUCTS FOR TREATMENT OF DIABETES |
CN1935846A (zh) * | 2005-09-14 | 2007-03-28 | 王庆华 | 一种用于治疗糖尿病的融合蛋白及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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SI2581389T1 (sl) | 2017-01-31 |
EP2581389B1 (en) | 2016-07-20 |
EA201290722A1 (ru) | 2013-05-30 |
EP2581389A1 (en) | 2013-04-17 |
CN101891823A (zh) | 2010-11-24 |
BR112012029689B1 (pt) | 2021-12-14 |
US8889619B2 (en) | 2014-11-18 |
US20130142795A1 (en) | 2013-06-06 |
EA023037B1 (ru) | 2016-04-29 |
JP5865359B2 (ja) | 2016-02-17 |
CN101891823B (zh) | 2012-10-03 |
WO2011153965A1 (zh) | 2011-12-15 |
KR101530065B1 (ko) | 2015-06-18 |
EP2581389A4 (en) | 2013-10-09 |
BR112012029689A2 (pt) | 2019-10-15 |
KR20120127729A (ko) | 2012-11-23 |
ES2597962T3 (es) | 2017-01-24 |
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