JP5222729B2 - ペプチダーゼに対する耐性が向上しているglp−1(グルカゴン様ペプチド−1)融合ペプチド - Google Patents
ペプチダーゼに対する耐性が向上しているglp−1(グルカゴン様ペプチド−1)融合ペプチド Download PDFInfo
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- JP5222729B2 JP5222729B2 JP2008531616A JP2008531616A JP5222729B2 JP 5222729 B2 JP5222729 B2 JP 5222729B2 JP 2008531616 A JP2008531616 A JP 2008531616A JP 2008531616 A JP2008531616 A JP 2008531616A JP 5222729 B2 JP5222729 B2 JP 5222729B2
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Description
I.小さな、脂肪族の、非極性のまたはわずかに極性の残基(Ala、Ser、Thr、ProおよびGly);
II.極性の、負電荷の残基(Asp、Asn、GluおよびGln)およびそれらのアミド;
III.極性の、正電荷の残基(His、ArgおよびLys);
IV.大きい、脂肪族の非極性の残基(Met、Leu、Ile、ValおよびCys)、ならびに;
V.大きな芳香族の残基(Phe、TryおよびTrp)。
Xaa7−Xaa8−Glu−Gly−Thr−Phe−Thr−Ser−Asp−Xaa16−Ser−Xaa18−Xaa19−Xaa20−Glu−Xaa22−Xaa23−Ala−Xaa25−Xaa26−Xaa27−Phe−Ile−Xaa3o−Trp−Leu−Xaa33−Xaa34−Xaa35−Xaa36−Xaa37
(式中、Xaa7は、L−ヒスチジン、D−ヒスチジン、脱アミノヒスチジン、2−アミノヒスチジン、3−ヒドロキシヒスチジン、ホモヒスチジン、N−アセチルヒスチジン、a−フルオロメチルヒスチジン、a−メチルヒスチジン、3−ピリジルアラニン、2−ピリジルアラニン、または4−ピリジルアラニンを表し;Xaa8は、Ala、Gly、Val、Leu、Ile、Lys、Aib、(1−アミノシクロプロピル)カルボン酸、(1−アミノシクロブチル)カルボン酸、(1−アミノシクロペンチル)カルボン酸、(1−アミノシクロヘキシル)カルボン酸、(1−アミノシクロヘプチル)カルボン酸または(1−アミノシクロオクチル)カルボン酸を表し(ここで、Xaa8はGlyを表すことが特に好ましい);Xaa16は、ValまたはLeuを表し;Xaaは、Ser、LysまたはArgを表し;Xaa19は、TyrまたはGlnを表し;Xaa20は、LeuまたはMetを表し;Xaa22は、Gly、GluまたはAibを表し;Xaa23は、Gln、Glu、LysまたはArgを表し;Xaa25は、AlaまたはValを表し;Xaa26は、Lys、GluまたはArgを表し;Xaa27は、GluまたはLeuを表し;Xaa30は、Ala、GluまたはArgを表し;Xaa33は、ValまたはLysを表し;Xaa34は、Lys、Glu、AsnまたはArgを表し;Xaa35は、GlyまたはAibを表し;Xaa36は、Arg、GlyもしくはLys、またはアミドを表すか、あるいは存在せず;ならびにXaa37は、Gly、Ala、Glu、Pro、もしくはLys、またはアミドを表すか、あるいは存在しない。)
のアミノ酸配列を含んでいる修飾されたGLP−1を含んでいる。
Xaa7−Xaa8−Glu−Gly−Thr−Phe−Thr−Ser−Asp−Val−Ser−Xaa8−Tyr−Leu−Glu−Xaa22−Xaa23−Ala−Ala−Xaa26−Glu−Phe−lle−Xaa30−Trp−Leu−Val−Xaa34−Xaa35−Xaa36−Xaa37
(式中、Xaa7は、L−ヒスチジン、D−ヒスチジン、脱アミノヒスチジン、2−アミノヒスチジン、−ヒドロキシヒスチジン、ホモヒスチジン、N−アセチルヒスチジン、a−フルオロメチルヒスチジン、a−メチルヒスチジン、3−ピリジルアラニン、2−ピリジルアラニンまたは4−ピリジルアラニンを表し; Xaa8は、Ala、Gly、Val、Leu、Ile、Lys、Aib、(1−アミノシクロプロピル)カルボン酸、(1−アミノシクロブチル)カルボン酸、(1−アミノシクロペンチル)カルボン酸、(1−アミノシクロヘキシル)カルボン酸、(1−アミノシクロヘプチル)カルボン酸または(1−アミノシクロオクチル)カルボン酸を表し; Xaa18は、Ser、LysまたはArgを表し; Xaa22は、Gly、GluまたはAibを表し; Xaa23は、Gln、Glu、LysまたはArgを表し; Xaa26は、Lys、GluまたはArgを表し;Xaa30は、Ala、GluまたはArgを表し; Xaa34は、Lys、GluまたはArgを表し;Xaa35は、GlyまたはAibを表し; Xaa36は、ArgもしくはLys、またはアミドを表すか、あるいは存在せず; Xaa37は、Gly、Ala、GluもしくはLys、またはアミドを表すか、あるいは存在していない。)
のアミノ酸配列を含んでいる修飾されたGLP−1ペプチドを含んでいる。
<実施例1>
−遺伝子コンストラクトの作製−
GLP−1(7−37)cDNAのコード配列を、図1aに示されたようなHincIIおよびEcoRIの制限酵素認識部位を含む配列として人工的に合成した。図1bに示されたようなGLP−1(7−37)のコード配列、IP2ならびにSfoI、EcoRIおよびXbaIの制限酵素認識部位を含むcDNA(図1b)を、別に合成した。GLP−1を分泌経路に向かわせるために、ストロメライシン3(stromelysin3、(登録番号NM_005940)の異種シグナル配列を用いた。つまり、ストロメライシンのシグナル配列およびリーダー配列をコードするcDNAを、逆転写PCRを用いてヒトRNAから増幅した。そして、図1aまたは図1bのコンストラクトを用いて、図1cおよび図1dに示されたコンストラクトをそれぞれ作製した。
−哺乳類細胞に対するトランスフェクション、クローン選抜およびGLP−1の発現−
細胞源:HEK293(ヒト胎児腎臓細胞株、カタログ番号ACC305、DSMZ Cell Culture Collection、ドイツ)、AtT20(マウスLAF1下垂体腫瘍細胞株、カタログ番号87021902、European Cell Culture Collection、英国)、hTERT−MSC細胞は、カセム(Kassem)教授(オーデンセ大学病院(University Hospital of Odense)、デンマーク)から生み出された。
−哺乳類細胞から分泌されたGLP−1ペプチドのウェスタンブロット解析−
GLP−1を分泌する細胞の細胞培養上清を、10%−20%の勾配のSDS PAGE(120V、90分)により分離して、PVDFメンブレン(Immobilon-P Membrane 0.45 μm ミリポアIPVH 00010)にセミドライブロッティング(2.0mA/cm2、60分)によりトランスファーした。メタノール固定と、ブロッキング(3%(w:v)BSAおよび0.1%(v:v)Tween−20を含むTBS)とを行った後、上記メンブレンを、1μg/mlの抗GLP−1抗体(HYB 147−12、Antibodyshop)を用いて、4℃で一晩、免疫ブロットした。洗浄して、0.02μg/mlの検出抗体(Anti Mouse IgG, HRP conjugated, パーキンエルマー PC 2855-1197)と一緒に、室温で4時間インキュベーションした後、化学発光検出を行いタンパク質の位置を明らかにした。
−ヒト細胞から分泌されたGLP−1ペプチドの血しょうにおけるインビトロでの安定性−
HEK293細胞およびhTERT−MSC細胞に、ストロメライシンの異種シグナル配列をコードするコンストラクトを一過的にトランスフェクションした。なお、上記異種シグナル配列は、以下のペプチドをコードする各GLP−1変異体と連結している。
2:GLP−1(7−37)−IP2(11AAだけ伸長)
3:GLP1(7−37)−IP2−GLP1(7−37)。
−GLP−1ペプチドのウェスタンブロット解析−
様々なGLP−1ペプチドを、固相により(syn)、または、E.coliを用いた組み換えにより(rec)合成的に製造した。GLP−1ペプチド(配列番号1(31ng)、ならびに、配列番号6、7および8(各10ng))を、10%−20%の勾配のSDS PAGE(120V、90分)により分離して、PVDFメンブレン(Immobilon-P Membrane 0,45μmミリポア IPVH 00010)にセミドライブロッティング(2.0mA/cm2、60分)によりトランスファーした。メタノール固定と、ブロッキング(3%(w:v)BSAおよび0.1%(v:v)Tween−20を含むTBS)とを行った後、上記メンブレンを、1μg/mlの抗GLP−1抗体(HYB 147−12, Antibodyshop)を用いて、4℃で一晩、免疫ブロットした。洗浄して、0.02μg/mlの検出抗体(Anti Mouse IgG, HRP conjugated, パーキンエルマー PC 2855-1197)と一緒に、室温で4時間インキュベーションした後、化学発光検出を行いタンパク質の位置を明らかにした。示されたペプチドのウェスタンブロットを図6に示す。以下の値を与えることができる。配列番号1(ID1syn)は、GLP−1(7−37)に対応し、31aaおよび3.3kDである;配列番号8(ID8syn、CM3)は、GLP−1(7−37)−IP2に対応し、46aaおよび5.1kDである;配列番号7(ID7rec、CM2)は、GLP−1(7−37)−IP2−RR−GLP2に対応し、83aaおよび9.4kDである;配列番号6(ID6syn、CM1)は、GLP−1(7−37)−IP2−RR−GLP1(7−37)に対応し、79aaおよび8.7kDである。
−GLP−1CMペプチドのインビトロでのヒト血しょうにおける安定性−
濃度20ng/mlの合成GLP−1ペプチド(配列番号1syn、配列番号6syn、配列番号7rec、配列番号8syn)を、ヒト血しょうと一緒に、37℃および5%CO2の環境下において3時間インキュベートした。血しょうのジペプチジルペプチダーゼ活性を、DPP−IV阻害剤(#DPP4, Biotrend)を用いて阻害した。活性型GLPを、GLP(活性)ELISA(#EGLP-35K、Biotrend)を用いて測定した。
−インビトロにおけるバイオアッセイ(環状AMPの産生)−
RIN−5細胞(ラットの島細胞種、ECACC 番号95090402)を、24ウェルプレートにおいて、4日間、70%の集密度に達するまで育てた。細胞をDMEM(E15−009、PAA)で2回洗浄してから、1%HSA(Aventis)、0.2mM IBMX(858455、シグマ)およびテストペプチドが添加されたDMEM(E15−009、PAA)を0.5ml加えた。25℃で20分間インキュベートした後、細胞を氷冷のPBSを用いて2回洗浄した。0.5%TritonX−100を含む0.1N HCLを添加して、細胞のcAMPを抽出した。cAMP(低pH)EIA(カタログ番号DE0355、R&D)を用いて、環状AMPを定量した。3×10−8Mの刺激については、配列番号1、配列番号6syn、配列番号6rec、配列番号7rec、配列番号8synを用いた。
−インビボでの生物活性−
11週齢のII型糖尿病のマウス(C57BL/Ks−Leprdb/db、Harlan)に、5μgのペプチドを、1日に二回(午前9時および午後5時)皮下注射した(1グループあたりn=5である)。一晩絶食させてから午前10時における血糖を、GLPCMペプチドを用いて処置する前(0日)および処置した後(2日、4日、7日、10日後)について、測定した。データを、0日における血糖値に対する相対値として示した。
−GLP1CMペプチドのインビトロでの安定性の測定(速度論的テスト方法)−
インキュベーション緩衝液(50mMトリエタノールアミン−HCl(pH7.8)、0.2%HSA)中のCM3、アラニンが置換されたCM3類似体(CM3−ANA01、CM3−ANA02、CM3−ANA03、CM3−ANA04)、C末端が短くなったCM3類似体(CM3−ANA06、CM3−ANA07)、またはC末端が伸長したCM3類似体(CM3−ANA09)からの1μMのペプチドのアリコートを、10%ヒト血しょうと一緒に、37℃および5%CO2の環境下において0、3、6および9時間インキュベートした。DPPIV阻害剤(#DPP、Biotrend)を添加することにより、ジペプチジルペプチダーゼ活性を停止させて、GLP−1(活性)ELISA(#EGLP-35K, Linco)を用いて、活性型GLP−1量を測定した。2以上の独立な実験のそれぞれにおいて、これを3回行い、結果を得た。
インビボでの研究−(免疫原性)
テスト物質であるCM1に免疫原性があるかどうかを明らかにするために、パラバイオサイエンス(Parabioscience(グローニンゲン、ドイツ))において、マウスの研究を実施した。22日間、5回繰り返して静脈注射された(70μgのペプチド/用量)BALB/cマウス(n=5)において、試験を行った。
−糖尿病マウスにおける用量と有効性とに関する研究−
2時間の絶食のあと、5つの異なる濃度のGLP−1、CM1、CM3、CM3−ANA01およびエキセンディン−4を用いて、糖尿病のC57BL/KsJ@Rj−db(db/db)マウスを処置した。6番目のグループを、生理食塩水のみを用いて処置した。1グループにつき7匹の動物を処置した。注射から1時間および4時間後に尾より採血し、この血液から血糖を直接決定した。
−db/dbマウスの長期間処置−
以下の4つのグループ(n=12)のC57BL/KsJ@Rj−db(db/db)マウスを調査した:
グループA;1日に1回、溶剤(0.9%生理食塩水)を用いて処置された、
グループB;1日に1回、24nmol/kgのテスト物質1(CM1rec)を用いて処置された、
グループC;1日に1回、24nmol/kgのテスト物質2(CM3−ANA01)を用いて処置された、
グループD;1日に1回、24nmol/kgの参照物質(エキセンディン−4)を用いて処置された。なお、エキセンディン−4は技術的に知られており、承認されている。しかしエキセンディン−4はGLP−1類似体ではない。
全てのグループの健康状態は良好であり、処置の副作用は見られなかった。
18週に及ぶ処置の後において、処置された全てのグループにおける体重は減少していた(図13)。相対的体重増加は、CM3−ANA01のグループにおいて有意に少ない。図13Aは、db/dbマウスの体重に対する、生理食塩水(A)、CM1(B)、CM3−ANA01(C)、またはエキセンディン(D)を用いた処置の効果を示す図である。1グループあたり12匹の動物の平均値をプロットされている。図13Bは、db/dbマウスの体重に対する、生理食塩水(A)、CM1(B)、CM3−ANA01(C)、またはエキセンディン(D)を用いた処置の効果を示す図である。122日に及ぶ処置の後に関する1グループあたり12匹の動物の相対的体重増加をプロットされている。テスト物質としてCM3−ANA01を用いて処置したときのみに(グループB)、体重増加量が有意に少なくなっていた(p<0.001)。
対照と比較して、CM1およびCM3−ANA01のグループにおいて、飼料消費が有意に低くなっていた。図14は、122日に及ぶ処置の間における、db/dbマウスの1週間の飼料消費に対する生理食塩水(A)、CM1(B)、CM3−ANA01(C)、またはエキセンディン(D)を用いた処置の効果を示す図である。マウス1匹あたりの相対的飼料消費は、グループBおよびCにおいて有意に減少している(p<0.001)。
血糖値を、様々な状況において決定した。非絶食時の血糖値(ペプチドの注射から1時間後)を図15Aに示す。すなわち、図15Aには、非絶食時の血糖値に対する生理食塩水(A)、CM1(B)、CM3−ANA01(C)、またはエキセンディン(D)を用いた処置の効果が示されている。生理食塩水(A)、または、24nmol/kgの濃度のCM1(B)、CM3−ANA01(C)、もしくはエキセンディン(D)ペプチドを皮下注射した。それから1時間後に尾より採血し、この血液から血糖を測定した。対照と比較して、ペプチドの皮下注射から1時間後の、非絶食時の血糖値は、グループBでは55%、グループでは51%、グループDでは60%に減少している(図15B)。処置されたグループにおける血糖は、極めて有意に減少している(p<0.0001)。
グルコース負荷テストを、グループA−Dのマウスに対する処置を8週行った後に、実施した。尾より採血することによって、12時間絶食させた動物の基準血糖値(0分)を決定した。その後、テスト物質を皮下注射し、20%のグルコース溶液を腹腔内注射した(1kgあたり1gのグルコース)。そして、グルコース注射から15、30、45、60、90、および120分後の血糖値を続けて決定した。全ての処置されたグループにおいて、グルコース負荷の有意な正規化が示された(図16A)。図16Aでは、生理食塩水(A)、CM1(B)、CM3−ANA01(C)、またはエキセンディン(D)を用いて8週間処置された後に、腹腔内注射によりグルコース負荷テスト(IPGTT)を実施している間の血糖値が絶対値で示されている。なお、上記絶対値は、各グループの平均値(n=12)である。
一晩(12時間)絶食させた後のマウスのインスリン量を決定した。18週間の処置の後、処置されたグループの全てのマウスは、処置されていない対照よりも有意に多くのインスリンを産生している。0.9%生理食塩水(グループA)、CM1ペプチド(グループB)、CM3−ANA01ペプチド(グループC)、またはエキセンディン−4(グループD)を用いて18週間処置した後の、マウスの血清中インスリン量に関するデータを、図17に示す。血液を採取した直後、プロテアーゼ阻害剤カクテルを用いて試料を処置することにより、インスリンが分解することを防いだ。インスリンマウスウルトラセンシティブELISA(Insulin Mouse Ultrasensitive ELISA(カタログ番号EIA-3440、DRG))を用いて、血清をインスリンについて分析した。スチューデントt−検定により、有意差を決定した。
赤血球(RBC)におけるヘモグロビンに非常に多くの血しょうグルコースが結合することによって、グリコシル化ヘモグロビンが形成される。RBCの寿命は120日であるため、グリコシル化ヘモグロビンは、グルコース制御の長期指標を与え、血しょうグルコース量よりも良好な指標として見られる。後眼窩洞(retro-orbital sinus)から全血液を回収した。そして、酵素HbA1cテストキット(Enzymatic HbA1c Test Kit (#DZ121A, Diazyme))を用いて分析して、グリコシル化ヘモグロビン量を決定した。グリコシル化ヘモグロビンをパラメーターとして用いた場合に、増加が有意に減少していることが、全ての処置されたグループにおいて見られた。
処置されたマウスの病状を調査した。検視の結果、処置されたグループと処置されていないグループAとの間の臓器については、膵臓の体積のこと以外は違いがないことが明らかになった。膵臓の重量を決定すると、処置された全グループの脾臓の重量が、極めて有意に重いことが明らかになった。0.9%生理食塩水(A、n=11)、CM1(B、n=12)、CM3−ANA01(C、n=12)、またはエキセンディン(D、n=12)を用いて、18週間処置した後の動物を乱切した日に決定された膵臓の重量を、図19に示す。
T細胞の再刺激によりIV型免疫原性を調べて、テストされた物質の可能性がある免疫原性効果を評価した。したがって、1グループあたり8匹の動物の脾臓を体外培養して、T細胞を単離し、異なる濃度の対応するテスト物質を用いて再刺激した。処置されていない対照と比べて、再刺激されたT細胞の増殖は、有意に増加していなかった。図20は、異なる濃度のテスト物質であるCM1(図20A)およびCM3−ANA01(図20B)、ならびに参照物質であるエキセンディン−4(図20C)に対する、インビトロにおける脾臓細胞の想起反応を示す図である。非放射性細胞増殖分析(細胞増殖のためのELISA(Cell Proliferation ELISA)、BrdU、化学発光法)を用いて、テスト物質であるCM1およびCM3−ANA01、ならびに参照物質であるエキセンディン−4を含んでいる溶液に対する、グループA−Dのマウスの脾臓細胞のインビトロにおける想起反応を、別々のマウスにおいて3回測定した。なお、上記溶液における各テスト物質の濃度を、初めは50μg/mlに調製し、その後3倍に希釈していった。刺激指数(SI)を、それぞれのペプチドが存在するときの反応、およびペプチドがないときの反応の指数として計算した。それぞれの処置されたグループおよび対照のグループの平均値±標準偏差を示す(グループA:n=3、グループB:n=6、グループC:n=7、グループD:n=6)。平均値を計算するために、SIが6.5よりも大きいマウスだけを分析した。なお、この6.5は5μg/mlのConAにより刺激した陽性対照培養物におけるSIである。
Claims (17)
- 配列番号31(HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGAADFPEEVAIAEELG)、
配列番号38(HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGAADFPEEVAIVEELG)、
配列番号8(HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIAEELG)、
配列番号12(HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELG)、
配列番号6(HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIAEELGRRHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG)、および
配列番号10(HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELGRRHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG)
から成る群から選ばれる配列から成る、ペプチド。 - 配列番号31から成るか、または、配列番号38から成る、請求項1に記載のペプチド。
- 請求項1または2に記載のペプチドのN末端のHis残基が化学的に修飾されている、ペプチド。
- 請求項1〜3のいずれか1項に記載のペプチドと、担体タンパク質を含んでいる、ペプチド。
- 前記担体タンパク質が、トランスフェリンまたはアルブミンである、請求項4に記載のペプチド。
- 固体状態のペプチド合成による、請求項1〜5の何れか1項に記載のペプチドの、製造方法。
- 請求項1〜5の何れか1項に記載のペプチドをコードする、核酸。
- 請求項7に記載の核酸を含んでいるベクター。
- 請求項1〜5のいずれか1項に記載のペプチドを発現することができる、ヒト胚性幹細胞を含まない、外因的に導入された請求項7に記載の核酸、または請求項8に記載のベクターを含んでいる、宿主細胞。
- 請求項1〜5のいずれか1項に記載のペプチドをコードする核酸を含有させるために形質転換した微生物細胞または動物細胞を発酵させて、上記ペプチドを回収する、請求項1〜5の何れか1項に記載のペプチドの、製造方法。
- 前記微生物細胞または動物細胞を、請求項1〜5のいずれか1項に記載のペプチドが上記細胞から排出される条件下において成長させる、請求項10に記載の製造方法。
- 請求項1〜5のいずれか1項に記載のペプチドを中性または塩の形態で製剤化される、請求項1〜5の何れか1項に記載のペプチドを含む、製剤。
- 前記塩が酢酸塩である、請求項12に記載の製剤。
- ヒトまたは動物の治療の場合に使用するための薬物としての、請求項1〜5の何れか1項に記載のペプチド。
- 1型または2型糖尿病、インスリン耐性、体重異常および疾病、またはそれに関連する症状を治療するための薬物を製造するための、(i)請求項1〜5の何れか1項に記載のペプチド、(ii)請求項7に記載の核酸、(iii)請求項8に記載のベクター、(iv)請求項9に記載の宿主細胞、あるいは(v)請求項12または13に記載の製剤。
- 神経変性疾患および神経変性病、またはそれらに関連する状態を治療するために使用するための、(i)請求項1〜5の何れか1項に記載のペプチド、(ii)請求項7に記載の核酸、(iii)請求項8に記載のベクター、(iv)請求項9に記載の宿主細胞、あるいは(v)請求項12または13に記載の製剤。
- アポトーシスに関係する疾患および病気、または状態を治療するために使用するための、(i)請求項1〜5の何れか1項に記載のペプチド、(ii)請求項7に記載の核酸、(iii)請求項8に記載のベクター、(iv)請求項9に記載の宿主細胞、あるいは(v)請求項12または13に記載の製剤。
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