JP2008511323A - 線維芽細胞成長因子21の突然変異タンパク質 - Google Patents
線維芽細胞成長因子21の突然変異タンパク質 Download PDFInfo
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Abstract
Description
腹部脂肪−男性の大半において胴囲が40インチ以上
高血糖−絶食後に1デシリットルあたり少なくとも110ミリグラム(110mg/dl)、
高トリグリセリド−血流中に少なくとも150mg/dL、低HDL−40mg/dl未満、及び130/85以上の血圧
酵母におけるFGF−21の突然変異タンパク質の発現及び精製
メタノール資化酵母、メチロトローフ酵母又は出芽酵母などの酵母においてFGF−21の突然変異タンパク質を発現させる。ピキア・パストリスにおける産生には、市販されているシステム(Invitrogen, Carlsbad, CA)によって、組換えタンパク質の高レベル発現を促進する強力なAOX1(アルコールオキシダーゼ)プロモーターを有するベクターが使用される。また、高レベルな構成的発現のために、GAP遺伝子(グリセルアルデヒド−3−リン酸デヒドロゲナーゼ)由来プロモーターを使用するベクターも利用できる。ピキアの多コピー型の発現ベクターにより、ゲノムに組み込まれる対象の遺伝子の複数のコピーをもつ株を得ることができる。組換えピキア株において対象となる遺伝子のコピーの数を増加することにより、タンパク質発現レベルを増加することができる。更に別の酵母発現系は、出芽酵母である。発現ベクターは、GAL1遺伝子由来のプロモーター及びエンハンサー配列を含む。GAL1プロモーターは、ガラクトースで誘導する際の強力な転写活性によって、最も広く使用される酵母プロモーターのうちの1つである。
マウス3T3−L1脂肪細胞におけるグルコース摂取
American Type Culture Collection(ATCC、Rockville、MD)から3T3−L1細胞を入手する。細胞をダルベッコ変法イーグル培地中に10%の鉄を富化したウシ胎児血清を含む増殖培地(GM)において培養する。標準的な脂肪細胞分化は、細胞が周密状態に達した2日後(0日とする)に、10%のウシ胎児血清、10μg/mlインスリン、1μMデキサメサゾン、及び0.5μMイソブチルメチルキサンチンを含む分化培地(DM)に細胞を8時間曝す。次いで、10%のウシ胎児血清、及び10μg/mlインスリンを含む再分化培地中で細胞を維持する。
ob/obマウスモデル
雄ob/obマウスを使用した肥満症モデルにおける実験を行い、媒体及びインスリン対照群と比較して、FGF−21で処置した後の血漿グルコースレベル及びトリグリセリドレベルを観察する。雄ob/obマウス(7週間目)の試験群には、媒体(0.9%のNaCl)のみ、又は、FGF−21の突然変異タンパク質(0.125mg/kg)(0.1mL、毎日一回)を皮下に7日間注射する。7日目の化合物を最後に注射した1時間後に断尾して採血し、標準的なプロトコルを使用して血漿グルコースレベルを測定する。媒体対照と比較して、血漿グルコースレベルを低下させるFGF−21の突然変異タンパク質の能力を表2に示す。表2は、媒体対照と比較して血漿グルコースレベルを低下させたことを示す。媒体対照と比較して、トリグリセリドレベルを低下させる本発明の突然変異タンパク質の能力を表3に示す。
FGF−21の突然変異タンパク質の薬理学的な安定性
本発明のFGF−21の突然変異タンパク質の安定性を、シミュレートされた生理学的及び薬理学的な条件下で解析する。生理学的な条件をシミュレートするために、突然変異タンパク質を、10mg/ml(pH 7.4)の標的タンパク質濃度において室温(RT)でのPBS中の安定性について解析する。PBS中での突然変異タンパク質の溶解性/物理安定性は、サイズ排除クロマトグラフィー及び/又は逆相クロマトグラフィーで測定される調製後のタンパク質の回収がRTにおいて90%以上の回収を生じる場合は良好であるとみなす。表4及び5に示すように、本発明の突然変異タンパク質はこの基準を満たす。
O型グリコシル化の分析
FGF−21の突然変異タンパク質は、メタノール資化酵母において発現し、Zorbax、330−SB C8、4.6×50 mm、40℃の3.5μm粒子カラムを使用して、HPLC(Waters 2695)により培養液から精製される(移動相C:10%のACN、及び、90%のH2Oにおける0.1%のTFA、移動相D:ACNにおける0.1%のTFA)。
Claims (26)
- ヒトFGF−21の突然変異タンパク質又はその生物活性ペプチドであって、Ser167に対するSer又はThr以外のアミノ酸置換を含み、アミノ酸の番号付けは配列番号1に基づき、前記突然変異タンパク質は、酵母において発現する場合、野生型ヒトFGF−21と比較してO型グリコシル化の能力が減少する突然変異タンパク質又はその生物活性ペプチド。
- 前記突然変異タンパク質が、Ser167Ala、Ser167Glu、Ser167Asp、Ser167Asn、Ser167Gln、Ser167Gly、Ser167Val、Ser167His、Ser167Lys、及びSer167Tyrからなる群から選択される請求項1に記載の突然変異タンパク質。
- 請求項1に記載の突然変異タンパク質をコードするヌクレオチド配列を含む単離されたポリヌクレオチド。
- 前記核酸がDNAである請求項6に記載のポリヌクレオチド。
- 請求項4に記載のDNAを含むベクター。
- 請求項5に記載のベクターを含む宿主細胞。
- ポリペチドを産生する工程であって、請求項6に記載の宿主細胞から、前記DNAによってコードされる前記ポリペチドを発現することを含む工程。
- 肥満症、2型糖尿病、インスリン抵抗性、インスリン過剰血症、グルコース不耐性、高血糖、又は代謝性症候群の1又は複数を呈する患者を治療するのに有用な医薬組成物であって、
(a)治療上有効量の請求項1に記載のFGF−21の突然変異タンパク質と、
(b)薬理学的に許容できる担体と、を含む医薬組成物。 - 肥満症、2型糖尿病、インスリン抵抗性、インスリン過剰血症、グルコース不耐性、高血糖、又は代謝性症候群の1又は複数を呈する患者を治療する方法であって、そのような治療を必要とする前記患者に、治療上有効量の請求項1に記載のFGF−21の突然変異タンパク質を投与することを含む方法。
- ヒトFGF−21の突然変異タンパク質又はその生物活性ペプチドであって、アルギニン19、チロシン20、ロイシン21、チロシン22、スレオニン23、アスパラギン酸24、アスパラギン酸25、アラニン26、グルタミン27、グルタミン28、アラニン31、ロイシン33、イソロイシン35、ロイシン37、バリン41、グリシン42、グリシン43、グルタミン酸50、グルタミン54、ロイシン58、バリン62、ロイシン66、グリシン67、リジン69、アルギニン72、フェニルアラニン73、グルタミン76、アルギニン77、アスパラギン酸79、グリシン80、アラニン81、ロイシン82、グリシン84、セリン85、プロリン90、アラニン92、セリン94、フェニルアラニン95、ロイシン100、アスパラギン酸102、チロシン104、チロシン107、セリン109、グルタミン酸110、プロリン115、ヒスチジン117、ロイシン118、プロリン119、アスパラギン121、リジン122、セリン123、プロリン124、ヒスチジン125、アルギニン126、アスパラギン酸127、アラニン129、プロリン130、グリシン132、アラニン134、アルギニン135、ロイシン137、プロリン138、又はロイシン139の2つ以上のアミノ酸に対するシステインの置換と共に、Ser167に対するSer又はThr以外のアミノ酸置換を含み、アミノ酸の番号付けは配列番号1に基づき、前記突然変異タンパク質は、酵母において発現する場合、野生型ヒトFGF−21と比較してO型グリコシル化の能力が減少する突然変異タンパク質又はその生物活性ペプチド。
- 請求項10に記載の突然変異タンパク質をコードするヌクレオチド配列を含む単離されたポリヌクレオチド。
- 前記核酸がDNAである請求項11に記載のポリヌクレオチド。
- 請求項12に記載のDNAを含むベクター。
- 請求項13に記載のベクターを含む宿主細胞。
- ポリペチドを産生する工程であって、請求項14に記載の宿主細胞から、前記DNAによってコードされる前記ポリペチドを発現することを含む工程。
- 肥満症、2型糖尿病、インスリン抵抗性、インスリン過剰血症、グルコース不耐性、高血糖、又は代謝性症候群の1又は複数を呈する患者を治療するのに有用な医薬組成物であって、
(a)治療上有効量の請求項10に記載のヒトFGF−21の突然変異タンパク質と、
(b)薬理学的に許容できる担体と、を含む医薬組成物。 - 肥満症、2型糖尿病、インスリン抵抗性、インスリン過剰血症、グルコース不耐性、高血糖、又は代謝性症候群の1又は複数を呈する患者を治療する方法であって、そのような治療を必要とする前記患者に、治療上有効量の請求項10に記載のヒトFGF−21の突然変異タンパク質を投与することを含む方法。
- ヒトFGF−21の突然変異タンパク質又はその生物活性ペプチドであって、グリシン42、グルタミン54、アルギニン77、アラニン81、ロイシン86、フェニルアラニン88、リジン122、ヒスチジン125、アルギニン126、プロリン130、アルギニン131、ロイシン139、アラニン145、ロイシン146、イソロイシン152、アラニン154、グルタミン156、グリシン161、セリン163、グリシン170、又はセリン172の1又は複数のアミノ酸位置に対する荷電及び/又は極性かつ無電荷のアミノ酸置換と共に、Ser167に対するSer又はThr以外のアミノ酸置換を含み、アミノ酸の番号付けは配列番号1に基づき、前記突然変異タンパク質は、酵母において発現する場合、野生型ヒトFGF−21と比較してO型グリコシル化の能力が減少する突然変異タンパク質又はその生物活性ペプチド。
- 請求項18に記載の突然変異タンパク質をコードするヌクレオチド配列を含む単離されるポリヌクレオチド。
- 前記核酸がDNAである請求項19に記載のポリヌクレオチド。
- 請求項20に記載のDNAを含むベクター。
- 請求項21に記載のベクターを含む宿主細胞。
- ポリペチドを産生する工程であって、請求項22に記載の宿主細胞から、前記DNAによってコードされる前記ポリペチドを発現することを含む工程。
- 肥満症、2型糖尿病、インスリン抵抗性、インスリン過剰血症、グルコース不耐性、高血糖、又は代謝性症候群の1又は複数を呈する患者を治療するのに有用な医薬組成物であって、
(a)治療上有効量の請求項18に記載のヒトFGF−21の突然変異タンパク質と、
(b)薬理学的に許容できる担体と、を含む医薬組成物。 - 肥満症、2型糖尿病、インスリン抵抗性、インスリン過剰血症、グルコース不耐性、高血糖、又は代謝性症候群の1又は複数を呈する患者を治療する方法であって、そのような治療を必要とする前記患者に、治療上有効量の請求項18に記載のFGF−21の突然変異タンパク質を投与することを含む方法。
- 前記突然変異タンパク質は、N末端から4個以下のアミノ酸が切断されている請求項1、10、又は18のいずれかに記載の突然変異タンパク質。
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PL1751184T3 (pl) | 2004-05-13 | 2010-02-26 | Lilly Co Eli | Białka fuzyjne FGF-21 |
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2005
- 2005-07-26 CA CA002575753A patent/CA2575753A1/en not_active Abandoned
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- 2005-07-26 SI SI200530852T patent/SI1789442T1/sl unknown
- 2005-07-26 DK DK05775749T patent/DK1789442T3/da active
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2018082699A (ja) * | 2008-06-04 | 2018-05-31 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2019187417A (ja) * | 2008-06-04 | 2019-10-31 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2012525847A (ja) * | 2009-05-05 | 2012-10-25 | アムジエン・インコーポレーテツド | Fgf21変異体およびその使用 |
JP2014530220A (ja) * | 2011-10-04 | 2014-11-17 | イーライ リリー アンド カンパニー | 線維芽細胞増殖因子21変異体 |
JP2021512634A (ja) * | 2018-02-08 | 2021-05-20 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | Fgf21バリアント、融合タンパク質及びそれらの適用 |
JP7475276B2 (ja) | 2018-02-08 | 2024-04-26 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | Fgf21バリアント、融合タンパク質及びそれらの適用 |
Also Published As
Publication number | Publication date |
---|---|
WO2006028595A3 (en) | 2007-01-18 |
EA011390B1 (ru) | 2009-02-27 |
DK1789442T3 (da) | 2009-11-16 |
SI1789442T1 (sl) | 2010-01-29 |
NO20071327L (no) | 2007-05-29 |
AU2005283025B2 (en) | 2011-06-30 |
ES2332057T3 (es) | 2010-01-25 |
AU2005283025A1 (en) | 2006-03-16 |
ATE444307T1 (de) | 2009-10-15 |
EP1789442B1 (en) | 2009-09-30 |
KR20070050454A (ko) | 2007-05-15 |
HRP20090597T1 (hr) | 2009-12-31 |
PL1789442T3 (pl) | 2010-02-26 |
US7582607B2 (en) | 2009-09-01 |
IL181573A0 (en) | 2007-07-04 |
KR100854198B1 (ko) | 2008-08-26 |
PT1789442E (pt) | 2009-11-11 |
CN101010338A (zh) | 2007-08-01 |
EP1789442A2 (en) | 2007-05-30 |
DE602005016946D1 (de) | 2009-11-12 |
BRPI0514790A (pt) | 2008-06-24 |
WO2006028595A2 (en) | 2006-03-16 |
JP4809352B2 (ja) | 2011-11-09 |
EA200700533A1 (ru) | 2007-08-31 |
CA2575753A1 (en) | 2006-03-16 |
MX2007002616A (es) | 2007-05-16 |
EP2161281A1 (en) | 2010-03-10 |
US20080103096A1 (en) | 2008-05-01 |
CN101010338B (zh) | 2011-06-15 |
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