JP5221959B2 - 代謝障害の状態を治療するためのil−22の使用 - Google Patents
代謝障害の状態を治療するためのil−22の使用 Download PDFInfo
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Description
肥満症、糖尿病、高脂血症、高血糖症および高インスリン血症を含む代謝障害は、世界中の多くの人々を苦しめる複雑な症候群である。遺伝要因および環境要因ならびに生活習慣が、代謝障害に寄与してきたと考えられている。これらの代謝障害は、冠状心臓病の発症に大きく寄与する。肥満症および糖尿病などの代謝障害に対する有効な治療法は存在しない。組換えインスリンは、I型糖尿病を効果的に制御するために広く使用されている。しかし、II型糖尿病については、組換えインスリンによる治療は、患者がインスリン抵抗性を発症しているので有効ではなかった。インスリン増感剤は、II型糖尿病のために開発されている。高脂血症については、現在の治療は、主にコレステロール合成を阻害することによって患者のコレステロールレベルを減少させることまたは脂質吸収を阻害することに焦点があてられている。
本発明は、一般に治療薬および治療の方法に関する。特に、本発明は、肥満症、糖尿病、高脂血症および高インスリン血症などの代謝障害の治療薬および治療の方法に関する。
従って、肥満症、糖尿病およびそれに関連する健康状態などの栄養的な障害に関連する病状に対する代替の治療薬および治療の方法を提供することが本発明の目的である。
物の体重を減量するときのIL−22の使用および哺乳動物の体重を減量するための薬剤を調製するときのIL−22の使用を提供する。別の態様において、本発明は、体重を減量するための薬剤を調製するためのIL−22の使用に関する。
以下は、本発明の様々な態様を説明する実施例である。本明細書中に引用されるすべての参考文献は、それらの全体が本明細書中に援用される。
ヒトおよびマウスのIL−22遺伝子クローニング
ヒトIL−22遺伝子クローニングは、Dumoutierらによる最初のクローニン
グに関する論文,PNAS 2000,97:10144に記載されているのと同様の手順を使用し、この論文の全体が本明細書中に援用される。簡潔には、ヒト末梢血単核球を、抗ヒトCD3mAb(Pharmingen Inc.,San Diego)を使用または使用せずに24時間培養した。全RNAを超遠心分離によって抽出し、cDNAを、Molocular Cloning,2nd edition(Sambrookら,Cold Spring Harbor Laboratory Press,1989)に記載されている方法に従ってプライマーであるdTを用いて合成した。配列番号1に示すような配列を有するヒトIL−22を、特異的プライマー対(5’−GCAGAATCTTCAGAACAGGTTC−3’(配列番号5)および5’−GGCATCTAATTGTTATTTCTAG−3’(配列番号6))を用いたPCRによって増幅した。増幅されたDNAを、pET21(+)ベクターにクローニングし、E.coliのBL21株において発現する。
組換えヒトIL−22(RHIL−22)および組換えマウスIL−22(RMIL−22)タンパク質発現
組換えタンパク質の発現は、Dumoutierらによる最初のクローニングに関する論文,PNAS vol:97:pl0144,2000に記載されているのと同じ方法を使用し、この論文の全体が、本明細書中に援用される。簡潔には、E.coliのBL21(+)株(Stratagene)を、発現宿主として使用した。宿主細胞を、アンピシリン(100mg/ml)、クロラムフェニコール(34mg/ml)およびグルコース2%を含むLuria−Bertani培地中で培養した。タンパク質の発現を、1mMイソプロピル−b−D−チオガラクトシドを用いて誘導した。細胞ペレットを、ホモジナイザーを用いて破砕し、IL−22封入体を、遠心分離によって得た。封入体を、TriszHCl 50mM、NaCl 100mM、EDTA 1mM、DTT 1mMおよびデオキシコール酸ナトリウム0.5%(wt/vol),pH8で洗浄した。
IL−22 100mg/ml、Tris−HCl 100mM、EDTA 2mM、L−アルギニン 0.5M、還元グルタチオン1mMおよび酸化グルタチオン0.1mM、pH8。この溶液を、4℃で24時間インキュベートした。次いでフォールディング混合物を、Superdex75(Amersham Pharmacia Biotech)ゲル濾過カラムを使用して精製した。このタンパク質を、TriszHCl 20m
MおよびNaCl 50mM、pH7を用いて溶出し、−80℃において保存した。
RMIL−22は正常マウスにおいて総血清トリグリセリドレベルを減少させた
正常マウス、C57BL6、8〜12週齢、雌、体重:20〜25g(n=10)を使用した。対照群に担体溶液(0.1%BSA,ウシ血清アルブミン,PBS,リン酸緩衝食塩水,pH7.0)を注射した。試験群にrmIL−22を注射した。その用量は、0、3、30、100、300μg/kg/dで、1日1回を7日間連続して皮下注射した。血液サンプルを、様々な時点で回収し、その血清を、総トリグリセリドレベルの測定のために解析した。
RMIL−22は後天性肥満マウス(正常老齢マウス)において総血清トリグリセリドレベルおよび腹膜後の脂肪重量を減少させた
18〜24月齢のC57BL6マウス、雌(n=10)、体重30〜40gを使用した。対照群に担体(0.1%BSA,ウシ血清アルブミン,PBS,リン酸緩衝食塩水,pH7.0)を注射した。試験群に、300μg/kg/dで皮下に1日に1回、9日間連続してrmIL−22を注射した。血液を様々な時点で回収し、その血清を、総トリグリセリドレベルを測定するために解析した。腹膜後の脂肪重量の測定のために、マウスを21日間処置した。動物を処置の最後に屠殺した。結果は、rmIL−22が、後天性肥満マウスにおいて総血清トリグリセリドレベルを著しく減少させることができることを示す。図2は、正常老齢マウスにおける血清トリグリセリドレベルに対するIL−22の効果を示す。マウスを、10日間、担体(点線)またはrmIL−22(100μg/kg/day、実線)のいずれかで処置した。マウスは、16月齢、C57BL6マウス、雌(体重:38+/−3gm,n=10)であった。点線は、対照群を示し、実線は、試験群を示す。結果は、平均+/−標準偏差である。
遺伝性肥満(OB/OB)マウスにおいて血清グルコース、トリグリセリド、インスリンレベルおよび体重を減少させるIL−22
ob/obマウス、8〜12週齢、雌、体重35〜50gを使用した。対照群に担体(0.1%BSA,ウシ血清アルブミン,PBS,リン酸緩衝食塩水,pH7.0)を注射した。試験群には、300μg/kg/dのrmIL−22を皮下に1日に1回、14日間連続して注射した。体重(BW)を記録した。グルコース、トリグリセリドおよびインスリンに対する血清レベルを測定した。
たob/obマウスの体重を示す。図4の点線は、対照群を示し、実線は、試験群を示す。担体で処置されたマウスでは、体重は、14日間の処置中に5%超増加した。rmIL−22で処置されたマウスでは、体重は、14日間の処置中に7%超減少した。このデータは、rmIL−22が、遺伝性肥満マウスにおいて体重の減少を引き起こすことができることを示す。図5は、ob/obマウスにおける血清トリグリセリドレベルに対するIL−22の効果を示す。破線は、担体で処置されたマウスを示し、実線は、2週間にわたってrmIL−22(300μg/kg/日)で処置されたマウス(n=10)を示す。このデータは、IL−22が、遺伝性肥満マウスにおいて総血清トリグリセリドレベルの減少を引き起こすことができることを示す。
マウスの耐糖能およびインスリン感受性を改善するRMIL−22
グルコース耐性試験およびインスリン感受性試験を、8〜12週齢のC57BL6マウス、雌、体重:20〜25gを使用して、rmIL−22処置あり、およびrmIL−22処置なしで実施した。対照群に担体(0.1%BSA,ウシ血清アルブミン,PBS,リン酸緩衝食塩水,pH7.0)を注射した。rmIL−22処置群にrmIL−22を300μg/kg/d、1日に1回、皮下に14日間連続して注射した。処置の最後にマウスを一晩絶食させた。グルコースを、各動物に2mg/g(体重)で腹腔内注射により投与した。血液グルコース濃度を、グルコース注射の30、60および120分後に測定した。図6は、IL−22が、耐糖能試験におけるマウスのグルコース利用を促進したことを示す。点線は、担体で処置されたマウスの血液グルコースレベルを示す。実線は、2週間にわたってrmIL−22(300μg/kg/日)で処置されたマウス(n=10)のグルコースレベルを示す。グルコースレベルは、60分および120分において2群間で有意に異なっている(p<0.01)。
and Nurse,Nature,290:140−142(1981);EP139,383)、Kluyveromyces宿主(米国特許第4,943,529号;Fleeら,Bio/Technology,9:968−975(1991)(例えば、K.lactis(MW98−8C,CBS683,CBS4574;Louvencourtら,J.Bacteriol.,154(2):737−742(1983))、K.fragilis(ATCC 12,424)、K.waltii(ATCC 56,500)、K.drosophilarum(ATCC 36,906;Van den
Bergら,BioTechnology,8:135−139(1990))、K.thermotolerans、K.marxianus;yarrowia(EP244,234))、Neurospora crassa(Caseら,Proc.Natl.Acad.Sci.USA,76:5259−5263(1979))、Schwanniomyces occidentalis(EP394,538)のようなschwanniomyces、Neurospora、penicillium、Tolypocladium(WO91/00357)のような糸状菌類、A.nidulans(Balanceら,Biochem.Biophys.Res.Commum.,112:284−289(1983);Tilburnら,Gene,26:205−221(1983);Yeltonら,Proc.Natl.Acad.Sci.USA,81:1470−1474(1984))、A.niger(Kelly and Hynes,EMBO J.,4:475−479(1985))のようなAspergillusである。メタノール上で生育することができる酵母(例えば、Hansenula,Candida,kloeckera,Pichia,Saccharomyces,Torulopsis,Rhodotorula)を含むメタノール資化性(methylotropic)酵母もまた適切である(C.Anthony,The Biochemistry of Methylotrophs,269(1982))。
ある。Agrobacterium tumefaciensの感染は、一部の植物細胞向きである(Shawら,Gene,23:315−330(1983)およびWO89/05859)。リン酸カルシウム沈殿法は、哺乳動物細胞向きである(Graham and van der Eb,Virology,52;456−457(1978))。酵母細胞の転換についての詳細な技術は、Van Solingenら,J.Bact,130:946−947(1977);およびHsiaoら,Proc.Natl.Acad.Sci.(USA),76:3829−3833(1979)に見ることができる。他の方法(例えば、核酸のマイクロインジェクション、エレクトロポレーション、無処置の細胞との細菌のプロトプラスト融合など)もまた、適切である。哺乳動物細胞の転換に関連する技術は、Keownら,Methods in Enzymology,185:527−537(1990);およびMansourら,Nature,336:348−352(1988)に見ることができる。
Laboratory Press,1989)。
養方法は、Urlaubら,Proc.Natl.Acad.Sci.USA,77:4216−4220(1980)に見ることができる。酵母細胞に適した選択遺伝子は、酵母プラスミドYrp7において発現されるtrpl遺伝子である(Stinchcombら,Nature,282:39−43(1979);Kingsmanら,Gene,7:141−152(1979);Tschumperら,Gene,10:157−166(1980))。Trpl遺伝子は、ATCC番号44047またはPEP4−1などのトリプトファン上で生育することができない酵母変異株を選択するために使用することができる(Jones,Genetics,85:22−33(1977))。
おける発現ベクターはまた、転写を終結するためおよびmRNAを安定化するためのDNA配列を含む。この種の配列は、通常、真核細胞における非翻訳領域の5’または3’末端またはウイルスのDNAもしくはcDNA由来である。他の方法、ベクターおよび宿主は、Gethingら,Nature,293:620−625(1981);Manteiら,Nature,281:40−46(1979);EP117,060;EP117,058に見ることができる。
Sciencesにおいて理解されるように使用してもよい。
などのセルロース調製物である。所望であれば、架橋ポリビニルピロリドン、寒天またはアルギン酸もしくはその塩(例えば、アルギン酸ナトリウム)などの崩壊剤を添加してもよい。
を含まない水を含む組成についての粉末形態であってもよい。
形態において、適切なヒト用量は、動物における毒性研究および効能研究によって認定されるように、ED50値もしくはID50値またはインビトロ研究もしくはインビボ研究から得られた他の適切な値から推測することができる。
実際の状況に従って適切な用量および注射の方法を選択する方法を知っているはずである。本発明における動物試験は、人体における有効量について信用できる使用法を提供する。異なる種間の調節原理は、Mordenti,J.and Chappell,W.“The use of interspecies scaling in toxicokinetics”In Toxicokinetics and New Drug
Development,Yacobiら;Pergamon Press,New York 1989,pp.42−96に見ることができる。
release of bioactive agents form lactide/glycolide polymer”,in: M.Chasin and R.Langer(Eds.),Biodegradable Polymers as Drug Delivery Sysytems(Marcel Dekker: New
York,1990),pp.1−41))。
調製物などのような他の調製技術もまた、本発明に含まれる。引用されたすべての参考文献は、それらの全体が本明細書中に援用される。
National Biomedical Research Foundationを参照のこと)。BLASTプログラムは、同定されたすべてのスコアの高いセグメント対の統計的有意性を評価し、好ましくは利用者に特異的な相同性パーセントなどの利用者に特異的な有意性の閾値を満たすそれらのセグメントを選択する。好ましくは、スコアの
高いセグメント対の統計的有意性を、Karlinの統計的有意性の式を使用して評価する(例えば、Karlin and Altschul,1990,Proc.Natl.Acad.Sci.USA 87:2267−2268を参照のこと)。
Claims (12)
- 肥満症の哺乳類の体重の減少のための薬剤の製造のためのIL−22の使用。
- 前記肥満症の哺乳類が後天性または先天性である、請求項1に記載の使用。
- 血中グルコース量を低下させる医薬を製造するためのIL−22とインスリンとの組合せの使用。
- 血清トリグリセリドレベルの減少のための薬剤の製造のためのIL−22の使用。
- 哺乳類に用いられる、請求項4に記載の使用。
- 前記医薬が哺乳類における体重の減少のために用いられる、請求項5に記載の使用。
- 前記医薬が哺乳類における血中グルコースレベルの減少のために用いられる、請求項5に記載の使用。
- 哺乳類における脂肪細胞の大きさの減少のための薬剤の製造のためのIL−22の使用。
- 前記医薬が肥満症の哺乳類に用いられる、請求項8に記載のIL−22の使用。
- インスリン感受性の増大のための薬剤の製造のためのIL−22の使用。
- 前記IL−22がヒトIL−22またはマウスIL−22である、請求項1〜10のいずれかに記載の使用。
- 前記IL−22が組換えヒトIL−22または組換えマウスIL−22である、請求項11に記載の使用。
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CA2748392C (en) * | 2009-01-12 | 2017-06-27 | Generon (Shanghai) Corporation | Use of interleukin-22 for the prevention and/or treatment of multiple organ dysfunction syndrome (mods) |
CN102260343A (zh) | 2010-05-25 | 2011-11-30 | 健能隆医药技术(上海)有限公司 | 重组人g-csf二聚体在治疗神经损伤疾病中的用途 |
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CN1679918A (zh) | 2005-10-12 |
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US20080069798A1 (en) | 2008-03-20 |
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US7666402B2 (en) | 2010-02-23 |
US20080069799A1 (en) | 2008-03-20 |
ATE504595T1 (de) | 2011-04-15 |
CA2592943C (en) | 2015-11-24 |
CN100515491C (zh) | 2009-07-22 |
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