JP6181752B2 - 線維芽細胞増殖因子21変異体 - Google Patents
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/475—Growth factors; Growth regulators
- C07K14/50—Fibroblast growth factor [FGF]
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- A61K38/18—Growth factors; Growth regulators
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- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
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- Y10S530/812—Peptides or proteins is immobilized on, or in, an organic carrier
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Description
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTECHLEIREDGTVGCAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREDLKEDGYNVYQSEAHGLPLHLPGDKSPHRKPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLRLVEPSQLRSPSFE(配列番号1)であるFGF21変異体を提供する。
好ましくは、本発明は、2型糖尿病、肥満症、脂質異常症および/またはメタボリックシンドロームの治療に使用するための本発明のFGF21変異体を提供する。
本発明はまた、以下を提供する。
[1]
アミノ酸配列が
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTECHLEIREDGTVGCAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREDLKEDGYNVYQSEAHGLPLHLPGDKSPHRKPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLRLVEPSQLRSPSFE(配列番号1)である線維芽細胞増殖因子21(FGF21)変異体。
[2]
[1]に記載の変異体と少なくとも1つの医薬上許容される担体、希釈剤もしくは賦形剤とを含む医薬組成物。
[3]
2型糖尿病、肥満症、脂質異常症および/またはメタボリックシンドロームを治療する方法であって、それを必要とする患者に[1]に記載の変異体を投与することを含む方法。
[4]
療法に使用するための[1]に記載の変異体。
[5]
2型糖尿病、肥満症、脂質異常症および/またはメタボリックシンドロームの治療に使用するための[1]に記載の変異体。
CHOK1SV細胞中でのFGF21変異体の発現
本発明のFGF21変異体は、CHOK1SV細胞を使用して哺乳動物細胞発現系中で産生させる。FGF21変異体をコードする遺伝子をグルタミンシンテターゼ(GS)含有発現プラスミド骨格(pEE12.4をベースとするプラスミド)内にサブクローニングする。本発明のFGF21変異体をコードするcDNA配列は、組織培養培地中への所望の産物の分泌を強化するために好ましいシグナルペプチド配列のコーディング配列とインフレームで融合させる。好ましいシグナルペプチド配列は、アミノ酸配列の配列番号3、配列番号4、配列番号5および配列番号6に示したポリペプチドである。
3T3−L1−βKlotho線維芽細胞グルコース取込みアッセイ
3T3−L1−βKlotho線維芽細胞は、3T3−L1線維芽細胞から野生型βKlothoのコーディング配列およびブラスチシジン耐性マーカーを含有するCMV駆動哺乳動物発現ベクターのレトロウイルス形質導入によって生成する。ブラスチシジン耐性細胞は、15μMブラスチシジンの存在下で14日間にわたる増殖後に選択し、βKlotho変異体発現は抗βKlotho抗体を用いた免疫ブロットによって検証する。3T3−L1−βKlotho線維芽細胞は、10%仔ウシ血清および15μMのブラスチシジンを含むダルベッコ改変イーグル培地(DMEM)中で実験使用のためにプレーティングするまで保持する。
物理的安定性
FGF21変異体の物理的安定性は以下のように決定した。変異体を透析し、150mMのNaClを含む、または含まない10mMのヒスチジン(pH7)中の1〜2mg/mL中で調製し、SECによって分析してHMW(%)を決定した(表1:「初期」)。
R175およびE180発現の不均質性
均質変異体産物の産生は、一貫性のある明確に特徴付けられた産物をより良好に保証するので望ましい。産物の不均質性を評価するために、サンプルの10μLアリコートを90μLのDPBSと混合した。サンプルは、液体クロマトグラフィー質量分析法(LC−MS)によって、以下の条件を使用して分析した:移動相Aは0.05%のTFA、移動相Bはアセトニトリル中の0.04%のTFA、カラムはPLRPS 2.1×50mmカラム、注入量は15μLである。
ob/obマウスモデルにおけるグルコース低下
雄性ob/obマウスおよび年齢を適応させたob/m(痩身)コントロールは、到着時には7週齢であり、治療開始時の年齢は8〜9週齢であった。到着後、全マウスは1匹ずつ収容し、治療開始時まで1〜2週間順化させた。マウスはPurina社製齧歯類飼料5015で飼養し、自動給水装置から水道水を随意に与えた。マウスは、24℃(75°F)に設定した周囲温度を用いて12時間明暗周期で収容した。治療開始1〜2日前に、血液サンプルを尾部からの出血によって採取した。血中グルコース濃度はAccu−Check Avivia血糖計(Roche社)を使用して測定し、Meso Scale社製マウス/ラット用インスリンアッセイキットを使用するインスリンアッセイのために血清サンプルを収集した。治療開始日(第0日)に、治療前体重、血糖および血清インスリンに基づいてマウスを群にソーティングした(BRATソーティング・ソフトウエア)。第0日および第3日に、マウスに10mL/kgの用量で配列番号5のFGF21変異体のホモダイマー0.1〜30nmol/kgをSQ(皮下)投与した。投与ビヒクルは、0.03%のマウス血清アルブミン(MSA;Sigma A3139)を含有する無菌PBS(HyClone DPBS/改質−カルシウム−マグネシウム)であった。血糖を7日間にわたり毎日測定し、AUCを決定した。血糖降下についてのED50計算は、AUCに基づいた。犠死時に肝ホモジネートを収集し、肝トリグリセリドは日立社製Modular P臨床分析装置上で測定した。
配列番号1−FGF21変異体
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTECHLEIREDGTVGCAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREDLKEDGYNVYQSEAHGLPLHLPGDKSPHRKPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLRLVEPSQLRSPSFE
配列番号2−野生型FGF21(ホモサピエンス(Homo Sapiens))
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGTVGGAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHGLPLHLPGNKSPHRDPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLSMVGPSQGRSPSYAS
配列番号3−ヒトトランスフェリン(hTrf)シグナルペプチド
MRLAVGALLVCAVLGLCLA
配列番号4−ヒト線維芽細胞増殖因子結合タンパク質1(hFGFP−1)シグナルペプチド
MKICSLTLLSFLLLAAQVLLVEG
配列番号5−ウシリゾチームシグナルペプチド
MKALVILGFLFLSVAVQG
配列番号6−マウス軽鎖(mκ)シグナルペプチド
METDTLLLWVLLLWVPGSTG
配列番号7−FGF21変異体
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTECHLEIREDGTVGCAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREDLLEDGYNVYQSEAHGLPLHLPGDKSPHRKPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLRLVEPSQLLSPSFLG
配列番号8−(DNA)FGF21変異体
CACCCCATCCCTGACTCCAGTCCTCTCCTGCAATTCGGGGGCCAAGTCCGGCAGCGGTACCTGTACACCGACGACGCCCAGCAGACCGAGTGCCACCTGGAAATCCGGGAGGACGGCACCGTGGGCTGTGCCGCCGACCAGTCCCCTGAGTCCCTGCTGCAGCTGAAGGCCCTGAAGCCTGGCGTGATCCAGATCCTGGGCGTGAAAACCTCCCGGTTCCTGTGCCAGAGGCCTGATGGCGCCCTGTACGGCTCCCTGCACTTCGACCCTGAGGCCTGCTCCTTCCGGGAGGACCTGAAGGAAGATGGCTACAACGTGTACCAGTCCGAGGCTCACGGCCTGCCTCTGCATCTGCCTGGCGACAAGTCCCCCCACCGGAAGCCTGCTCCTAGGGGCCCTGCCAGATTCCTGCCACTGCCTGGCCTGCCTCCAGCTCTGCCTGAGCCTCCTGGCATCCTGGCCCCTCAGCCTCCAGACGTGGGCTCCTCCGACCCTCTGCGGCTGGTCGAGCCTTCCCAGCTGCGGAGCCCTAGCTTCGAG
Claims (4)
- アミノ酸配列が
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTECHLEIREDGTVGCAADQSPESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREDLKEDGYNVYQSEAHGLPLHLPGDKSPHRKPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLRLVEPSQLRSPSFE(配列番号1)である線維芽細胞増殖因子21(FGF21)変異体。 - 請求項1に記載の変異体と少なくとも1つの医薬上許容される担体、希釈剤もしくは賦形剤とを含む医薬組成物。
- 療法に使用するための請求項2に記載の医薬組成物。
- 2型糖尿病、肥満症、脂質異常症および/またはメタボリックシンドロームの治療に使用するための請求項2に記載の医薬組成物。
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PCT/US2013/044192 WO2013188182A1 (en) | 2012-06-11 | 2013-06-05 | Fibroblast growth factor 21 variants |
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CA2895517C (en) | 2012-12-27 | 2022-10-11 | Ngm Biopharmaceuticals, Inc. | Methods for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
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CA2937898A1 (en) | 2014-01-24 | 2015-07-30 | Ngm Biopharmaceuticals, Inc. | Antibodies that bind to beta klotho and uses thereof |
WO2015183890A2 (en) | 2014-05-28 | 2015-12-03 | Ngm Biopharmaceuticals, Inc. | Methods and compositions for the treatment of metabolic disorders and diseases |
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TW201731867A (zh) | 2015-12-02 | 2017-09-16 | 賽諾菲公司 | Fgf21變異體 |
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CN101520547B (zh) * | 2009-04-17 | 2011-05-18 | 东南大学 | 挠曲柱面反射式聚光镜制造方法 |
PL3248610T3 (pl) | 2009-05-05 | 2024-04-02 | Amgen Inc. | Mutanty fgf21 i ich zastosowania |
CA2760674A1 (en) * | 2009-05-05 | 2010-11-11 | Amgen Inc. | Fgf21 mutants and uses thereof |
US20120171125A1 (en) | 2009-08-07 | 2012-07-05 | Ucb Pharma, S.A. | Methods for Enhancing the Cognitive Function |
JP2013533227A (ja) * | 2010-06-08 | 2013-08-22 | ノヴォ ノルディスク アー/エス | Fgf21類似体および誘導体 |
AR087973A1 (es) * | 2011-10-04 | 2014-04-30 | Lilly Co Eli | Variantes del factor 21 del crecimiento de fibroblastos |
TWI513705B (zh) * | 2012-06-11 | 2015-12-21 | Lilly Co Eli | 纖維母細胞生長因子21蛋白質 |
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CA2871656A1 (en) | 2013-12-19 |
ZA201407938B (en) | 2016-08-31 |
US20150141327A1 (en) | 2015-05-21 |
JP2015521596A (ja) | 2015-07-30 |
KR20150006059A (ko) | 2015-01-15 |
US9422353B2 (en) | 2016-08-23 |
AU2013274639A1 (en) | 2014-11-06 |
EA201492064A1 (ru) | 2015-02-27 |
EP2859014B1 (en) | 2017-04-26 |
EP2859014A1 (en) | 2015-04-15 |
ES2632078T3 (es) | 2017-09-08 |
CN104364261A (zh) | 2015-02-18 |
CN104364261B (zh) | 2017-04-05 |
WO2013188182A1 (en) | 2013-12-19 |
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