JP2022522723A - アルブミンと結合したSlit3タンパク質のLRRD2を含む筋肉疾患の予防または治療用組成物 - Google Patents
アルブミンと結合したSlit3タンパク質のLRRD2を含む筋肉疾患の予防または治療用組成物 Download PDFInfo
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Abstract
Description
HSA-Slit3 LRRD2融合タンパク質(HSA-Slit3 LRRD2fusion protein)の製造
PC DNA 3.1ベクターSPシスタチンS-HSA-Slit3 LRR D2-FLAG DNA 1.6mg/mlをExpi293F懸濁液細胞にトランスフェクションさせて発現を行った。125mlの293F細胞懸濁液で細胞を4.5~5×106細胞/mlまで培養し、培地のみを新しく交換した後、エクスピフェタミン(Expifectamine)400μlとOpti-mem7.5ml(Aサンプル)を常温で5分間反応し、DNA150μg、Opti-mem7.5ml(Bサンプル)を常温で5分間反応後、AとBサンプルを互いに混合し、20分間常温で反応してトランスフェクションを行った。24時間後、エンハンサー1と2を混合して処理した後、7日間培養した。
様々な形態のHSA-Slit3 LRRD2融合タンパク質(HSA-Slit3LRRD2 fusion protein)の受容体結合能確認
2-1.様々な形態のHSA-Slit3 LRRD2融合タンパク質の製造
実施例1の製造方法に基づいて、下記表2に示すように12種の様々なHSA-Slit3 LRRD2融合タンパク質を製造した。リンカーは、(GGGGS)3(配列番号6)を使用した。
Slit3 LRRD2は、Robo1またはRobo2受容体と結合し、Slit-Roboシステムを介して筋肉母細胞のM-カデリンに結合されていたβ-カテニンを放出させて(release)β-カテニンを活性化し、ミオゲニンの発現を増加させることにより、筋肉母細胞の分化を誘導して筋肉の形成を促進する。したがって、本実施例では、実施例2-1で製造された12種のHSA-Slit3 LRRD2融合タンパク質の受容体結合能を確認した。12種のHSA-Slit3 LRRD2融合タンパク質とRobo1受容体の結合能は、ELISAシステムを使用して定量した。詳細条件は、次の通りである。
マウスにおいてSlit3 LRRD2及びHSA-Slit3 LRRD2融合タンパク質の薬物動態研究
本実施例では、実施例2の結果に基づいて、受容体結合能が最も優れたLRRD2-3を選定し、薬物動態研究を行った。
本実施例で使用されたカルバマゼピン(carbamazepine)は、Sigma Aldrichから購入し、アセトニトリルとメタノールは、HPLCグレードでJ.T.Bakerから購入した。
本実施例では、体重30~32.5g範囲のICR系雄性マウス(6週齢、(株)オリエントバイオ、城南、大韓民国)を使用した。マウスは、実験前に4時間絶食し、投与後4時間まで絶食を維持した。飼育場は、12時間ずつ明暗を与えて適正温度(20~25℃)及び湿度(40~60%)を維持した。
薬物動態試験の場合、絶食させたマウスにSlit3 LRRD2とHSA-Slit3 LRRD2(LRRD2-3)をそれぞれ10mg/kg及び35mg/kgの容量で尾静脈を介してそれぞれ投与した。投与後、それぞれ0.05、0.12、0.33、1、3、7、10、24、48、及び72時間にマウスを手で固定した後、ヘパリンコーティングされた毛細管で右側の眼窩静脈叢から血液70μLを採血した。取られた血液は、5分間遠心分離した後、血漿を分離して分析前まで-20℃で冷凍保管した。
血漿試料のうち、Slit3 LRRD2の濃度は、HPLC/MS/MSシステムを用いて定量した。試料前処理の前、血漿試料は、Ni-NTAマグネティックビードを用いて精製した。精製されたSlit3 LRRD2及びHSA-Slit3 LRRD2(LRRD2-3)に6Mの尿素と18mMのジチオトレイトール(DTT)を加えて変性させた後、225mMのヨードアセトアミドを用いてアルキル化を誘導した。以後、シグネチャーペプチド(signature peptide)を得るため、850ngの組換えブタトリプシン(V5117、Promega、Madison、WI、USA)を加えて24時間37℃に設定されたウォーターバス(water bath)で反応させた。反応後に生成されたトリプシン消化物70μLにMeOHに溶解した3%のギ酸50μLを加えた後、ボルテックスミキサー(vortex mixer)を用いて10分間混合試料を懸濁し、13,500rpmで10分間遠心分離して上澄み液160μLを取って分析容器に移し、そのうち5μLをHPLC/MS/MSシステムに注入して分析を行った。
-カラム:ZORBAX(登録商標)C8 3.5μm、2.1*50mm(Agilent)
-移動相(Mobile phase):
-流速:300μL/min
-温度:カラムで20℃、及び自動サンプル機トレイ(autosampler tray)で10℃
-ランタイム:5分
-検出:タンデム四重極型質量分析計(API 4000,QTRAP(登録商標),Applied Biosystems/MDS SCIEX,Foster City,CA,USA)
-カーテンガス(curtain gas):20psi
-イオンソースガス 1(ion source gas 1):50psi
-イオンソースガス 2(ion source gas 2):60psi
-イオンスプレー電圧(ionspray voltage):5500V
-温度:600℃
-多重反応モニタリング(multiple-reaction-monitoring、MRM)モード:陽性
時間による血漿中のCNC00000の濃度を前記実施例3-4に記載されたLC-MS/MS分析法を用いて求め、WinNonlin4.2(Pharsight Corp.,Cary,NC,USA)のソフトウェアのノンコンパートメント解析(non-compartmental analysis)で薬物動態的パラメータ(PK parameters)を計算した。最高濃度(Cmax)と最高濃度到達時間(Tmax)は、血中薬物濃度に対して時間による曲線から経時的に求め、消失速度定数(Ke)は、ログスケール(log scale)の最終段階(terminal phase)において線形回帰分析によって計算した。半減期(T1/2)は、LN2をKeで除して求め、血中薬物濃度に対して時間曲線下面積(AUC0-∞)及び血中薬物モーメントに対して時間曲線下面積(AUMC0-∞)は、線形台形法(linear trapezoidal rule)と標準面積外挿法(standard area extrapolation method)により計算した。クリアランス(clearance、CL)と分布容積(steady state volume of distribution、Vss)は、次の[式1]~[式3]により計算した。
時間による血漿内のSlit3 LRRD2及びHSA-Slit3 LRRD2(LRRD2-3)の濃度は、図4及び表5と6に示し、薬物動態パラメータは、表7に示した。これに関連したパラメータとすべての値は、個体毎に算出した後、平均で示した。時間による血中濃度パターンと動物実験記録紙を参考して異常のある個体群は、データの分析から排除し、データの解釈に使用された実験群は、少なくともn=3以上となるようにした。
HSA-結合Slit3 LRRD2の生体効能確認
9週齢のBalbc-nudeマウスを9週齢で卵巣切除した後、11週齢から4週間アルブミンと結合しないSlit3 LRRD2またはHSA-Slit3 LRRD2融合タンパク質(LRRD2-3)を処理した。各薬物は、1日1回、毎週5回静脈注射により投与し、Slit3 LRRD2は、毎日10mg、HSA-結合Slit3 LRRD2(LRRD2-3)は、毎日37.13mg(Slit3 LRRD2は、毎日10mgに該当)注射した。投与完了後、ヒラメ筋(Soleus muscle)を採取して筋肉の重さを測定し、その結果を下記表8に示した。
(1)[この発明をサポートした国家研究開発事業]
[課題固有番号] 2017-1229(HI15C0377010017)
[省庁名] 保健福祉部
[研究管理専門機関] 韓国保健産業振興院
[研究事業名] 疾病中心仲介重点研究
[研究課題名] 骨形成促進作用を持つ巨核細胞分泌因子の発掘
[寄与率] 75/100
[主管機関] ソウル峨山病院
[研究期間] 2017.09.07~2018.09.06
(2)[この発明をサポートした国家研究開発事業]
[課題固有番号] 2013-2234(HI13C1634060018)
[省庁名] 保健福祉部
[研究管理専門機関] 韓国保健産業振興院
[研究事業名] 疾病中心仲介重点研究
[研究課題名] Slit3 LRRD2の薬物動態研究及びSlit3 TGマウスを用いたin vivo毒性の検証
[寄与率] 25/100
[主管機関] 忠南大学校産学協力団
[研究期間] 2013.11.01~2019.06.30
HSA-Slit3 LRRD2融合タンパク質(HSA-Slit3 LRRD2fusion protein)の製造
PC DNA 3.1ベクターSPシスタチンS-HSA-Slit3 LRR D2-FLAG DNA 1.6mg/mlをExpi293F懸濁液細胞にトランスフェクションさせて発現を行った。125mlの293F細胞懸濁液で細胞を4.5~5×106細胞/mlまで培養し、培地のみを新しく交換した後、エクスピフェタミン(Expifectamine)400μlとOpti-mem7.5ml(Aサンプル)を常温で5分間反応し、DNA150μg、Opti-mem7.5ml(Bサンプル)を常温で5分間反応後、AとBサンプルを互いに混合し、20分間常温で反応してトランスフェクションを行った。24時間後、エンハンサー1と2を混合して処理した後、7日間培養した。
様々な形態のHSA-Slit3 LRRD2融合タンパク質(HSA-Slit3LRRD2 fusion protein)の受容体結合能確認
2-1.様々な形態のHSA-Slit3 LRRD2融合タンパク質の製造
実施例1の製造方法に基づいて、下記表2に示すように12種の様々なHSA-Slit3 LRRD2融合タンパク質を製造した。リンカーは、(GGGGS)3(配列番号6)を使用した。
Slit3 LRRD2は、Robo1またはRobo2受容体と結合し、Slit-Roboシステムを介して筋肉母細胞のM-カデリンに結合されていたβ-カテニンを放出させて(release)β-カテニンを活性化し、ミオゲニンの発現を増加させることにより、筋肉母細胞の分化を誘導して筋肉の形成を促進する。したがって、本実施例では、実施例2-1で製造された12種のHSA-Slit3 LRRD2融合タンパク質の受容体結合能を確認した。12種のHSA-Slit3 LRRD2融合タンパク質とRobo1受容体の結合能は、ELISAシステムを使用して定量した。詳細条件は、次の通りである。
マウスにおいてSlit3 LRRD2及びHSA-Slit3 LRRD2融合タンパク質の薬物動態研究
本実施例では、実施例2の結果に基づいて、受容体結合能が最も優れたLRRD2-3を選定し、薬物動態研究を行った。
本実施例で使用されたカルバマゼピン(carbamazepine)は、Sigma Aldrichから購入し、アセトニトリルとメタノールは、HPLCグレードでJ.T.Bakerから購入した。
本実施例では、体重30~32.5g範囲のICR系雄性マウス(6週齢、(株)オリエントバイオ、城南、大韓民国)を使用した。マウスは、実験前に4時間絶食し、投与後4時間まで絶食を維持した。飼育場は、12時間ずつ明暗を与えて適正温度(20~25℃)及び湿度(40~60%)を維持した。
薬物動態試験の場合、絶食させたマウスにSlit3 LRRD2とHSA-Slit3 LRRD2(LRRD2-3)をそれぞれ10mg/kg及び35mg/kgの容量で尾静脈を介してそれぞれ投与した。投与後、それぞれ0.05、0.12、0.33、1、3、7、10、24、48、及び72時間にマウスを手で固定した後、ヘパリンコーティングされた毛細管で右側の眼窩静脈叢から血液70μLを採血した。取られた血液は、5分間遠心分離した後、血漿を分離して分析前まで-20℃で冷凍保管した。
血漿試料のうち、Slit3 LRRD2の濃度は、HPLC/MS/MSシステムを用いて定量した。試料前処理の前、血漿試料は、Ni-NTAマグネティックビードを用いて精製した。精製されたSlit3 LRRD2及びHSA-Slit3 LRRD2(LRRD2-3)に6Mの尿素と18mMのジチオトレイトール(DTT)を加えて変性させた後、225mMのヨードアセトアミドを用いてアルキル化を誘導した。以後、シグネチャーペプチド(signature peptide)を得るため、850ngの組換えブタトリプシン(V5117、Promega、Madison、WI、USA)を加えて24時間37℃に設定されたウォーターバス(water bath)で反応させた。反応後に生成されたトリプシン消化物70μLにMeOHに溶解した3%のギ酸50μLを加えた後、ボルテックスミキサー(vortex mixer)を用いて10分間混合試料を懸濁し、13,500rpmで10分間遠心分離して上澄み液160μLを取って分析容器に移し、そのうち5μLをHPLC/MS/MSシステムに注入して分析を行った。
-カラム:ZORBAX(登録商標)C8 3.5μm、2.1*50mm(Agilent)
-移動相(Mobile phase):
-流速:300μL/min
-温度:カラムで20℃、及び自動サンプル機トレイ(autosampler tray)で10℃
-ランタイム:5分
-検出:タンデム四重極型質量分析計(API 4000,QTRAP(登録商標),Applied Biosystems/MDS SCIEX,Foster City,CA,USA)
-カーテンガス(curtain gas):20psi
-イオンソースガス 1(ion source gas 1):50psi
-イオンソースガス 2(ion source gas 2):60psi
-イオンスプレー電圧(ionspray voltage):5500V
-温度:600℃
-多重反応モニタリング(multiple-reaction-monitoring、MRM)モード:陽性
時間による血漿中のCNC00000の濃度を前記実施例3-4に記載されたLC-MS/MS分析法を用いて求め、WinNonlin4.2(Pharsight Corp.,Cary,NC,USA)のソフトウェアのノンコンパートメント解析(non-compartmental analysis)で薬物動態的パラメータ(PK parameters)を計算した。最高濃度(Cmax)と最高濃度到達時間(Tmax)は、血中薬物濃度に対して時間による曲線から経時的に求め、消失速度定数(Ke)は、ログスケール(log scale)の最終段階(terminal phase)において線形回帰分析によって計算した。半減期(T1/2)は、LN2をKeで除して求め、血中薬物濃度に対して時間曲線下面積(AUC0-∞)及び血中薬物モーメントに対して時間曲線下面積(AUMC0-∞)は、線形台形法(linear trapezoidal rule)と標準面積外挿法(standard area extrapolation method)により計算した。クリアランス(clearance、CL)と分布容積(steady state volume of distribution、Vss)は、次の[式1]~[式3]により計算した。
時間による血漿内のSlit3 LRRD2及びHSA-Slit3 LRRD2(LRRD2-3)の濃度は、図4及び表5と6に示し、薬物動態パラメータは、表7に示した。これに関連したパラメータとすべての値は、個体毎に算出した後、平均で示した。時間による血中濃度パターンと動物実験記録紙を参考して異常のある個体群は、データの分析から排除し、データの解釈に使用された実験群は、少なくともn=3以上となるようにした。
HSA-結合Slit3 LRRD2の生体効能確認
9週齢のBalbc-nudeマウスを9週齢で卵巣切除した後、11週齢から4週間アルブミンと結合しないSlit3 LRRD2またはHSA-Slit3 LRRD2融合タンパク質(LRRD2-3)を処理した。各薬物は、1日1回、毎週5回静脈注射により投与し、Slit3 LRRD2は、毎日10mg、HSA-結合Slit3 LRRD2(LRRD2-3)は、毎日37.13mg(Slit3 LRRD2は、毎日10mgに該当)注射した。投与完了後、ヒラメ筋(Soleus muscle)を採取して筋肉の重さを測定し、その結果を下記表8に示した。
(1)[この発明をサポートした国家研究開発事業]
[課題固有番号] 2017-1229(HI15C0377010017)
[省庁名] 保健福祉部
[研究管理専門機関] 韓国保健産業振興院
[研究事業名] 疾病中心仲介重点研究
[研究課題名] 骨形成促進作用を持つ巨核細胞分泌因子の発掘
[寄与率] 75/100
[主管機関] ソウル峨山病院
[研究期間] 2017.09.07~2018.09.06
(2)[この発明をサポートした国家研究開発事業]
[課題固有番号] 2013-2234(HI13C1634060018)
[省庁名] 保健福祉部
[研究管理専門機関] 韓国保健産業振興院
[研究事業名] 疾病中心仲介重点研究
[研究課題名] Slit3 LRRD2の薬物動態研究及びSlit3 TGマウスを用いたin vivo毒性の検証
[寄与率] 25/100
[主管機関] 忠南大学校産学協力団
[研究期間] 2013.11.01~2019.06.30
Claims (14)
- アルブミンと結合したSlit3タンパク質のLRRD2を含む、融合タンパク質。
- 前記アルブミンは、ヒト血清アルブミン(human serum albumin)である、請求項1に記載の融合タンパク質。
- 前記ヒト血清アルブミンは、前記Slit3タンパク質のLRRD2のN-末端に結合されている、請求項2に記載の融合タンパク質。
- 前記ヒト血清アルブミンは、配列番号2のアミノ酸配列を含み、前記Slit3タンパク質のLRRD2は、配列番号3のアミノ酸配列を含む、請求項3に記載の融合タンパク質。
- 前記アルブミンと前記Slit3タンパク質のLRRD2の間にリンカーをさらに含む、請求項1に記載の融合タンパク質。
- 前記リンカーは、(GGGGS)nであり、ここで、nは1~10の整数である、請求項5に記載の融合タンパク質。
- 請求項1~請求項6のいずれか一項に記載の融合タンパク質を暗号化する、核酸分子。
- 請求項7に記載の核酸分子を含む、組換えベクター。
- 請求項6に記載の組換えベクターを含む、形質転換体。
- 請求項9に記載の形質転換体を培養する段階を含む、アルブミンと結合したSlit3タンパク質のLRRD2を含む、融合タンパク質の製造方法。
- 請求項1~請求項6のいずれか一項に記載の融合タンパク質を含む、筋肉疾患の予防または治療用薬学組成物。
- 注射剤として投与される、請求項11に記載の筋肉疾患の予防または治療用薬学組成物。
- 前記筋肉疾患は、緊張減退症(atony)、筋萎縮症(muscular atrophy)、筋ジストロフィー(muscular dystrophy)、筋無力症、悪液質(cachexia)及び筋肉減少症(sarcopenia)からなる群から選ばれるいずれか一つ以上である、請求項11に記載の筋肉疾患の予防または治療用薬学組成物。
- 請求項1~請求項6のいずれか一項に記載の融合タンパク質を含む、Slit3タンパク質のLRRD2の生体内半減期増進用組成物。
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CN104119446A (zh) * | 2013-04-26 | 2014-10-29 | 李华顺 | 含有富含亮氨酸重复序列的融合蛋白及其制法和应用 |
CN106589130B (zh) * | 2015-10-14 | 2019-11-01 | 阿思科力(苏州)生物科技有限公司 | 一种Slit2D2-HSA重组蛋白及其在治疗脓毒症中的应用 |
US10336812B2 (en) * | 2016-05-10 | 2019-07-02 | Janssen Biotech, Inc. | GDF15 fusion proteins and uses thereof |
KR102011957B1 (ko) * | 2016-06-08 | 2019-08-19 | 재단법인 아산사회복지재단 | Slit-robo 시스템을 이용한 근감소증 예방 또는 치료용 조성물 |
CN108929383B (zh) * | 2017-05-26 | 2021-10-15 | 阿思科力(苏州)生物科技有限公司 | 重组Slit2D2(C386S)-HSA融合蛋白及其在预防和/或治疗肺部炎症中的应用 |
KR102353524B1 (ko) * | 2019-02-27 | 2022-01-20 | 주식회사 대웅제약 | 알부민이 결합된, Slit3 단백질의 LRRD2를 포함하는 골 관련 질환 예방 또는 치료용 조성물 |
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2020
- 2020-02-27 KR KR1020200024592A patent/KR102406899B1/ko active IP Right Grant
- 2020-02-27 BR BR112021016973A patent/BR112021016973A2/pt unknown
- 2020-02-27 EP EP20763321.5A patent/EP3950707A4/en active Pending
- 2020-02-27 CN CN202080017137.1A patent/CN113544142A/zh active Pending
- 2020-02-27 US US17/434,388 patent/US20220125889A1/en active Pending
- 2020-02-27 JP JP2021550267A patent/JP7295261B2/ja active Active
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Patent Citations (2)
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CN104119448A (zh) * | 2013-04-26 | 2014-10-29 | 李华顺 | 含有富含亮氨酸重复序列的融合蛋白及其制法和应用 |
WO2017213435A1 (ko) * | 2016-06-08 | 2017-12-14 | 재단법인 아산사회복지재단 | Slit-robo 시스템을 이용한 근감소증 예방 또는 치료용 조성물 |
Non-Patent Citations (1)
Title |
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J CLIN INVEST., vol. 128, no. 4, JPN6022030685, 2018, pages 1429 - 1441, ISSN: 0004971771 * |
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KR102406899B1 (ko) | 2022-06-10 |
KR20200104829A (ko) | 2020-09-04 |
US20220125889A1 (en) | 2022-04-28 |
EP3950707A4 (en) | 2022-12-28 |
EP3950707A1 (en) | 2022-02-09 |
JP7295261B2 (ja) | 2023-06-20 |
WO2020175931A1 (ko) | 2020-09-03 |
CN113544142A (zh) | 2021-10-22 |
BR112021016973A2 (pt) | 2021-11-30 |
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