JP2018162298A - オキシントモジュリン誘導体を含む糖尿病又は肥満性糖尿病の治療用組成物 - Google Patents
オキシントモジュリン誘導体を含む糖尿病又は肥満性糖尿病の治療用組成物 Download PDFInfo
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- JP2018162298A JP2018162298A JP2018123263A JP2018123263A JP2018162298A JP 2018162298 A JP2018162298 A JP 2018162298A JP 2018123263 A JP2018123263 A JP 2018123263A JP 2018123263 A JP2018123263 A JP 2018123263A JP 2018162298 A JP2018162298 A JP 2018162298A
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Abstract
Description
アラニン A アルギニン R
アスパラギン N アスパラギン酸 D
システイン C グルタミン酸 E
グルタミン Q グリシン G
ヒスチジン H イソロイシン I
ロイシン L リジン K
メチオニン M フェニルアラニン F
プロリン P セリン S
トレオニン T トリプトファン W
チロシン Y バリン V
R1-X1-X2-GTFTSD-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-R2(一般式1)
R1は、ヒスチジン、デスアミノ-ヒスチジル(desamino-histidyl)、N-ジメチル-ヒスチジル(N-dimethyl-histidyl)、β-ヒドロキシイミダゾプロピオニル(beta-hydroxyimidazopropionyl)、4-イミダゾアセチル(4-imidazoacetyl)、β-カルボキシイミダゾプロピオニル(beta-carboxy imidazopropionyl)又はチロシンであり、
X1は、アミノイソ酪酸(aminoisobutyric acid、Aib)、d-アラニン、グリシン、Sar(N-methylglycine)、セリン又はd-セリンであり、
X2は、グルタミン酸又はグルタミンであり、
X3は、ロイシン又はチロシンであり、
X4は、セリン又はアラニンであり、
X5は、リジン又はアルギニンであり、
X6は、グルタミン又はチロシンであり、
X7は、ロイシン又はメチオニンであり、
X8は、アスパラギン酸又はグルタミン酸であり、
X9は、グルタミン酸、セリン、α-メチル-グルタミン酸、又は欠失した配列であり、
X10は、グルタミン、グルタミン酸、リジン、アルギニン、セリン、又は欠失した配列であり、
X11は、アラニン、アルギニン、バリン、又は欠失した配列であり、
X12は、アラニン、アルギニン、セリン、バリン、又は欠失した配列であり、
X13は、リジン、グルタミン、アルギニン、α-メチル-グルタミン酸、又は欠失した配列であり、
X14は、アスパラギン酸、グルタミン酸、ロイシン、又は欠失した配列であり、
X15は、フェニルアラニン、又は欠失した配列であり、
X16は、イソロイシン、バリン、又は欠失した配列であり、
X17は、アラニン、システイン、グルタミン酸、リジン、グルタミン、α-メチル-グルタミン酸又は欠失した配列であり、
X18は、トリプトファン又は欠失した配列であり、
X19は、アラニン、イソロイシン、ロイシン、セリン、バリン、又は欠失した配列であり、
X20は、アラニン、リジン、メチオニン、グルタミン、アルギニン、又は欠失した配列であり、
X21はアスパラギン、又は欠失した配列であり、
X22は、アラニン、グリシン、トレオニン、又は欠失した配列であり、
X23は、システイン、リジン、又は欠失した配列であり、
X24は、アラニン、グリシン、及びセリンの組み合わせからなる2〜10個のアミノ酸を有するペプチド又は欠失した配列であり、及び
R2は、KRNRNNIA(配列番号35)、GPSSGAPPPS(配列番号36)、GPSSGAPPPSK(配列番号37)、HSQGTFTSDYSKYLD(配列番号38)、HSQGTFTSDYSRYLDK(配列番号39)、HGEGTFTSDLSKQMEEEAVK(配列番号40)又は欠失した配列である(ただし、前記一般式1のアミノ酸配列が、配列番号1と同一である場合は除く)。
R1-A-R3(一般式2)
R1-B-C-R4(一般式3)
R1は、前記一般式1で説明した構成と同一であり、
Aは、SQGTFTSDYSKYLDSRRAQDFVQWLMNT(配列番号41)、SQGTFTSDYSKYLDEEAVRLFIEWLMNT(配列番号42)、SQGTFTSDYSKYLDERRAQDFVAWLKNT(配列番号43)、GQGTFTSDYSRYLEEEAVRLFIEWLKNG(配列番号44)、GQGTFTSDYSRQMEEEAVRLFIEWLKNG(配列番号45)、GEGTFTSDLSRQMEEEAVRLFIEWAA(配列番号46)及びSQGTFTSDYSRQMEEEAVRLFIEWLMNG(配列番号47)からなる群から選択され、
Bは、SQGTFTSDYSKYLDSRRAQDFVQWLMNT(配列番号41)、SQGTFTSDYSKYLDEEAVRLFIEWLMNT(配列番号42)、SQGTFTSDYSKYLDERRAQDFVAWLKNT(配列番号43)、GQGTFTSDYSRYLEEEAVRLFIEWLKNG(配列番号44)、GQGTFTSDYSRQMEEEAVRLFIEWLKNG(配列番号45)、GEGTFTSDLSRQMEEEAVRLFIEWAA(配列番号46)、SQGTFTSDYSRQMEEEAVRLFIEWLMNG(配列番号47)、GEGTFTSDLSRQMEEEAVRLFIEW(配列番号48)、及びSQGTFTSDYSRYLD(配列番号49)からなる群から選択され、
Cは、アラニン、グリシン、及びセリンの組み合わせで構成された2〜10個のアミノ酸を有するペプチドであり、
D1は、セリン、グルタミン酸又はアルギニンであり、
D2は、アルギニン、グルタミン酸又はセリンであり、
D3は、アルギニン、アラニン又はバリンであり、
D4は、アルギニン、バリン又はセリンであり、
D5は、グルタミン、アルギニン又はリジンであり、
D6は、イソロイシン、バリン又はセリンであり、
D7は、メチオニン、アルギニン、又はグルタミンであり、
D8は、トレオニン、グリシン又はアラニンであり、
E1は、セリン、Aib、Sar、d-アラニン又はd-セリンであり、
E2は、セリン又はグルタミン酸であり、
E3は、アルギニン又はリジンであり、
E4は、グルタミン又はリジンであり、
E5は、アスパラギン酸又はグルタミン酸であり、
E6は、グルタミン、システイン又はリジンであり、
E7は、システイン、リジン又は欠失した配列であり、
R3は、KRNRNNIA(配列番号35)、GPSSGAPPPS(配列番号36)又はGPSSGAPPPSK(配列番号37)であり、
R4は、HSQGTFTSDYSKYLD(配列番号38)、HSQGTFTSDYSRYLDK(配列番号39)又はHGEGTFTSDLSKQMEEEAVK(配列番号40)であり、及び、
R5は、KRNRNNIA(配列番号35)、GPSSGAPPPS(配列番号36)、GPSSGAPPPSK(配列番号37)又は欠失した配列である(ただし、前記一般式2〜5のアミノ酸配列が、配列番号1と同一である場合は除く)。
R1は、ヒスチジン、デスアミノ-ヒスチジル、4-イミダゾアセチル又はチロシンであり、X1は、Aib(aminoISObutyric acid)、グリシン、セリン又はd-セリンであり、
X2は、グルタミン酸又はグルタミンであり、
X3は、ロイシン又はチロシンであり、
X4は、セリン又はアラニンであり、
X5は、リジン又はアルギニンであり、
X6は、グルタミン又はチロシンであり、
X7は、ロイシン又はメチオニンであり、
X8は、アスパラギン酸又はグルタミン酸であり、
X9は、グルタミン酸、α-メチル-グルタミン酸又は欠失した配列であり、
X10は、グルタミン、グルタミン酸、リジン、アルギニン、又は欠失した配列であり、
X11は、アラニン、アルギニン、又は欠失した配列であり、
X12は、アラニン、バリン、又は欠失した配列であり、
X13は、リジン、グルタミン、アルギニン、α-メチル-グルタミン酸又は欠失した配列であり、
X14は、アスパラギン酸、グルタミン酸、ロイシン又は欠失した配列であり、
X15は、フェニルアラニン又は欠失した配列であり、
X16は、イソロイシン、バリン、又は欠失した配列であり、
X17は、アラニン、システイン、グルタミン酸、グルタミン、α-メチル-グルタミン酸又は欠失した配列であり、
X18は、トリプトファン又は欠失した配列であり、
X19は、アラニン、イソロイシン、ロイシン、バリン、又は欠失した配列であり、
X20は、アラニン、リジン、メチオニン、アルギニン、又は欠失した配列であり、
X21は、アスパラギン又は欠失した配列であり、
X22は、トレオニン又は欠失した配列であり、
X23は、システイン、リジン又は欠失した配列であり、
X24は、グリシンで構成された2〜10個のアミノ酸を有するペプチド又は欠失した配列であり、及び
R2は、KRNRNNIA(配列番号35)、GPSSGAPPPS(配列番号36)、GPSSGAPPPSK(配列番号37)、HSQGTFTSDYSKYLD(配列番号38)、HSQGTFTSDYSRYLDK(配列番号39)、HGEGTFTSDLSKQMEEEAVK(配列番号40)、又は欠失した配列である(ただし、前記一般式6のアミノ酸配列が、配列番号1と同一である場合は除く)。
(1)両末端にアルデヒド、マレイミド又はスクシンイミド誘導体である官能基を有する非ペプチド性重合体を用いてオキシントモジュリン誘導体ペプチドのアミン基又はチオール基に共有結合によって連結する段階と、
(2)前記(1)の反応混合物からアミノ末端以外の位置に非ペプチド性重合体が共有結合したオキシントモジュリン誘導体ペプチドを含む連結体を分離する段階、及び、
(3)分離された連結体の非ペプチド性重合体の他方の末端に免疫グロブリンFc領域を共有結合によって連結し、非ペプチド性重合体の両端がそれぞれ免疫グロブリンFc領域及びオキシントモジュリン誘導体ペプチドと結合したペプチド結合体を生成する段階を含むことができる。
実施例1-1:GLP-1に対してcAMP反応を示す細胞株の生産
逆方向プライマー:5'-GAACGGTCCGGAGGACGTCGACTCTTAAGATAG-3 '(配列番号51)
ヒトグルカゴン受容体遺伝子のcDNA(OriGene Technologies、Inc.USA)でORFに対応する部分を鋳型にして、EcoRI切断部位とXhoI切断部位をそれぞれ含む正方向及び逆方向プライマーを用いてPCRを行い、PCR産物を得た。
逆プライマー:5'-CTAACCGACTCTCGGGGAAGACTGAGCTCGCC-3 '(配列番号53)
実施例2-1:オキシントモジュリン誘導体の合成
オキシントモジュリン誘導体のインビトロ活性を測定するために下記のアミノ酸配列を有するオキシントモジュリン誘導体を合成した(表1)。
実施例2-1で製造したペプチドの効果を測定するために、実施例1-1と1-2で製造した形質転換体を用いてインビトロ細胞活性を測定した。
先ず、MAL-10K-ALD PEG(NOF.,日本)をオキシントモジュリン誘導体(配列番号23)のアミノ酸配列24番システイン残基にペギル化させるために、オキシントモジュリン誘導体(配列番号23)とMAL-10K-ALD PEGのモル比を1:3、タンパク質の濃度を3mg/mLにして常温で3時間反応させた。この際、反応は50mM Tris緩衝液(pH8.0)にグアニジン1Mが添加された環境下で行われた。反応が終了した後、前記反応液をSOURCE Sを用いて、システインがモノペグ化されたオキシントモジュリン誘導体を精製した(カラム:SOURCE S、流速:2.0mL/分、勾配:A 0→100% 50分B(A:20mM クエン酸ナトリウム、pH3.0 + 45%エタノール、B:A + 1M KCl))。
先ず、MAL-10K-ALD PEGをオキシントモジュリン誘導体(配列番号25)のアミノ酸配列30番システイン残基にペグ化するために、オキシントモジュリン誘導体(配列番号25)とMAL-10K-ALD PEGのモル比を1:3、タンパク質の濃度を3mg/mLにして常温で3時間反応させた。この際、反応は50mM Tris緩衝液(pH8.0)にグアニジン1Mが添加された環境下で行われた。反応が終了した後、前記反応液をSOURCE Sを用いて、システインにモノペギル化されたオキシントモジュリン誘導体を精製した(カラム:SOURCE S、流速:2.0mL/分、勾配:A 0→100% 50分 B(A:20m Mクエン酸ナトリウム、pH3.0 + 45%エタノール、B:A + 1M KCl))。
先ず、MAL-10K-ALD PEGをオキシントモジュリン誘導体(配列番号27)のアミノ酸配列30番システイン残基にペグ化させるために、オキシントモジュリン誘導体(配列番号27)とMAL-10K-ALD PEGのモル比を1:3、タンパク質の濃度を3mg/mLにして常温で3時間反応させた。この際、反応は50mM Tris緩衝液(pH8.0)にグアニジン1Mが添加された環境下で行われた。反応が終了した後、該反応液をSOURCE Sを用いて、システインにモノペギル化されたオキシントモジュリン誘導体を精製した(カラム:SOURCE S、流速:2.0mL/分、勾配:A 0→100% 50分 B(A:20mM クエン酸ナトリウム、pH3.0 + 45%エタノール、B:A + 1M KCl))。
実施例6-1:試験方法
6週齢のマウス(C57BL/6、120-130g)は(株)オリエントバイオ(Orientbio、Korea)より購入した。購入したC57BL/6は、高脂肪の食餌によって、比較的容易に肥満が誘導でき、肥満及び糖尿病の試験に広く使用される動物である。HF DIOマウスは、糖尿病の研究に多く使用されるげっ歯類の一種であり、レプチン受容体の変異によって糖尿病を誘発させたdb/dbマウスなどとは異なり、遺伝子操作によってではなく高脂肪飼料の長期食餌によって、自然にヒトと類似した肥満性糖尿病症状を発現するので、本研究でも肥満性糖尿病に対する、本製剤の体重減少及び血糖の降下における効果を確認するために、本試験系を用いた。
各群(n=6)の全てに2週間生理食塩水又は薬物を投与した後、体重及び血糖値の改善に及ぼす影響について分析した。
本発明による持続型オキシントモジュリン誘導体の結合体が安定した(stable)肥満モデルである26週間高脂肪の食餌誘導した(HF DIO)マウスの血糖値の改善に及ぼす影響を調べるために、実施例6-1で分類したDIOマウスに持続型オキシントモジュリン誘導体を週1回2週間皮下投与した。毎日体重及び飼料摂取量を測定し、DIOマウスの尾部から血液を0、3、7、10、14日に採取し、血液内の血糖値の変化量を分析した(HITACHI 7020を使用)。体重と血糖値の変化は、図1〜2に示した。
実施例7-1:試験方法
オス7週齢BKS.Cg-+Leprdb/+Leprdb/OlaHsdmiceマウス(25±3g、Harlan U.S.A)は、Doo Yeol Biotech (Korea)より購入した。 BKS.Cg-+Leprdb/+ Leprdb/OlaHsdマウス(以下db/dbマウス)は、ob/obマウスとともに糖尿病の研究に最も多く使用されるげっ歯類であり、レプチン受容体の変異によってヒトと類似した糖尿病の症状を現すので、本研究でも糖尿病治療剤を開発するに当たり、本製剤の血糖降下効果を確認するために、本試験系を使用した。
本発明による持続型オキシントモジュリン誘導体の結合体が、レプチン受容体変異によって誘導された糖尿病モデルであるdb/dbマウスの血糖の改善に及ぼす影響を調べるために、実施例7-1で分類したdb/dbマウスに持続型オキシントモジュリン誘導体を週1回、4週間皮下投与した。週2回体重変化を測定し、db/dbマウスの尾部から血液を採取して(1、4週目-毎日、2、3週目-週2回)血糖変化量(HITACHI 7020を使用)を測定した。
Claims (10)
- オキシントモジュリン誘導体を有効成分として含む糖尿病、肥満性糖尿病、若しくは糖尿病合併症の予防又は治療用組成物。
- 前記オキシントモジュリン誘導体が、配列番号2〜34からなる群から選択されたアミノ酸配列を有するものである、請求項1に記載の組成物。
- 前記オキシントモジュリン誘導体が、免疫グロブリン断片、抗体、エラスチン、アルブミン、ピブロネクチンからなる群から選択されたものが連結された結合体の形態である、請求項1に記載の組成物。
- 前記結合体が、配列番号2〜34からなる群から選択されたアミノ酸配列を有するオキシントモジュリン誘導体及び免疫グロブリンFc領域が非ペプチド性重合体によって連結されたものである、請求項3に記載の組成物。
- 前記非ペプチド性重合体が、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコールとプロピレングリコールの共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、ポリサッカライド、デキストラン、ポリビニルエチルエーテル、ポリ乳酸(polylactic acid、PLA)、ポリ乳酸グリコール(polylactic-glycolic acid、PLGA)、脂質ポリマー、キチン類、ヒアルロン酸、及びこれらの組み合わせからなる群から選択されたものである、請求項4に記載の組成物。
- 前記非ペプチド性重合体の両末端がそれぞれ免疫グロブリンFc領域及びオキシントモジュリンのアミン基又はチオール基に結合するものである、請求項4に記載の組成物。
- 前記薬剤学的組成物が、糖尿病、肥満性糖尿病、若しくは糖尿病合併症の予防又は治療効果を奏する薬学的製剤がさらに含まれるものである、請求項1に記載の組成物。
- 前記糖尿病が、インスリン依存性1型糖尿病及びインスリン非依存性2型糖尿病である、請求項1に記載の組成物。
- 前記肥満性糖尿病が、肥満により発生するものである、請求項1に記載の組成物。
- オキシントモジュリン誘導体を薬学的有効量で、個体に投与する段階を含む、糖尿病、肥満性糖尿病若しくは糖尿病合併症を治療する方法。
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