JP4603261B2 - ヒト化カルシトニン遺伝子関連ペプチド受容体をコードする単離dna分子、関連する非ヒトトランスジェニック動物及びアッセイ方法 - Google Patents
ヒト化カルシトニン遺伝子関連ペプチド受容体をコードする単離dna分子、関連する非ヒトトランスジェニック動物及びアッセイ方法 Download PDFInfo
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Description
A=Ala=アラニン:コドンGCA,GCC,GCG,GCU
C=Cys=システイン:コドンUGC,UGU
D=Asp=アスパラギン酸:コドンGAC,GAU
E=Glu=グルタミン酸:GAA,GAG
F=Phe=フェニルアラニン:コドンUUC,UUU
G=Gly=グリシン:コドンGGA,GGC,GGG,GGU
H=His=ヒスチジン:コドンCAC,CAU
I=Ile=イソロイシン:コドンAUA,AUC,AUU
K=Lys=リジン:コドンAAA,AAG
L=Leu=ロイシン:コドンUUA,UUG,CUA,CUC,CUG,CUU
M=Met=メチオニン:コドンAUG
N=Asn=アスパラギン:コドンAAC,AAU
P=Pro=プロリン:コドンCCA,CCC,CCG,CCU
Q=Gln=グルタミン:コドンCAA,CAG
R=Arg=アルギニン:コドンAGA,AGG,CGA,CGC,CGG,CGU
S=Ser=セリン:コドンAGC,AGU,UCA,UCC,UCG,UCU
T=Thr=スレオニン:コドンACA,ACC,ACG,ACU
V=Val=バリン:コドンGUA,GUC,GUG,GUU
W=Trp=トリプトファン:コドンUGG
Y=Tyr=チロシン:コドンUAC,UAU。
マーモセット及びカニクイザルRAMP1cDNAクローニング−ポリメラーゼ連鎖反応(PCR)を使用して前頭脳cDNAから部分マーモセットRAMP1cDNAとカニクイザルcDNAを単離した。PCRプライマーはヒトRAMP1(5’−CTGCCAGGAGGCTAACTACG−3’[配列番号25]及び5’−CACGATGAAGGGGTAGAGGA−3’[配列番号26])に基づいて設計した。増幅反応は45秒94℃、45秒58℃、1分72℃を40サイクルとし、PLATINUM Taq PCRCNAポリメラーゼ(Invitrogen)に製造業者が推奨しているプロトコールに従った。潜在エラーを防ぐために多重サブクローンを配列決定した。
Claims (13)
- 配列番号1及び3から構成される群から選択されるヌクレオチド配列からなる、ヒト化RAMP1蛋白質をコードする精製核酸分子。
- 組換え宿主細胞でヒト化RAMP1蛋白質を発現させるための発現ベクターであって、前記発現ベクターが請求項1に記載の精製核酸分子を含む前記発現ベクター。
- 組換えヒト化RAMP1蛋白質を発現する宿主細胞であって、前記宿主細胞が請求項2に記載の発現ベクターを含む前記宿主細胞。
- 組換え宿主細胞におけるヒト化RAMP1蛋白質の発現方法であって、
(a)請求項2に記載の発現ベクターを適切な宿主細胞にトランスフェクトする段階、および
(b)前記ヒト化RAMP1蛋白質を前記発現ベクターから発現させる条件下で段階(a)の宿主細胞を培養する段階
を含む前記方法。 - 他の蛋白質を実質的に含まないヒト化RAMP1蛋白質であって、配列番号1及び3から構成される群から選択されるヌクレオチド配列によってコードされる前記ヒト化RAMP1蛋白質。
- 組換え宿主細胞内に含まれるDNA発現ベクターの産物である請求項5に記載のヒト化RAMP1蛋白質。
- 請求項6に記載のヒト化RAMP1蛋白質、及び機能的CRLR蛋白質を含む実質的に純粋な膜調製物。
- 前記蛋白質が配列番号2及び4から構成される群から選択されるアミノ酸配列からなる請求項5に記載のヒト化RAMP1蛋白質。
- 組換え宿主細胞内に含まれるDNA発現ベクターの産物である請求項8に記載のヒト化RAMP1蛋白質。
- 請求項9に記載のヒト化RAMP1蛋白質、及び機能的CRLR蛋白質を含む実質的に純粋な膜調製物。
- CRLR蛋白質が配列番号10、12及び14から構成される群から選択されるアミノ酸配列からなる請求項10に記載の膜調製物。
- CGRP受容体蛋白質のモジュレーターの同定方法であって、
(a)配列番号1及び3から構成される群から選択されるヌクレオチド配列によってコードされるヒト化RAMP1蛋白質とCRLR蛋白質を含むCGRP受容体に試験化合物を接触させる段階と、
(b)前記試験化合物がCGRP受容体蛋白質に及ぼす効果を測定する段階を含む前記方法。 - 段階(a)のヒト化RAMP1蛋白質が組換え宿主細胞内に含まれるDNA発現ベクターの産物である請求項12に記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32529501P | 2001-09-27 | 2001-09-27 | |
PCT/US2002/030501 WO2003027252A2 (en) | 2001-09-27 | 2002-09-26 | Isolated dna molecules encoding humanized calcitonin gene-related peptide receptor, related non-human transgenic animals and assay methods |
Publications (3)
Publication Number | Publication Date |
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JP2005503809A JP2005503809A (ja) | 2005-02-10 |
JP2005503809A5 JP2005503809A5 (ja) | 2005-12-22 |
JP4603261B2 true JP4603261B2 (ja) | 2010-12-22 |
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JP2003530824A Expired - Fee Related JP4603261B2 (ja) | 2001-09-27 | 2002-09-26 | ヒト化カルシトニン遺伝子関連ペプチド受容体をコードする単離dna分子、関連する非ヒトトランスジェニック動物及びアッセイ方法 |
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US (1) | US7193070B2 (ja) |
EP (1) | EP1438325B1 (ja) |
JP (1) | JP4603261B2 (ja) |
AT (1) | ATE453661T1 (ja) |
CA (1) | CA2461917C (ja) |
DE (1) | DE60234944D1 (ja) |
WO (1) | WO2003027252A2 (ja) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2476773C (en) | 2002-01-25 | 2013-05-28 | G2 Therapies Ltd | Monoclonal antibodies against extracellular loops of c5ar |
US7842808B2 (en) | 2002-06-05 | 2010-11-30 | Bristol-Myers Squibb Company | Anti-migraine spirocycles |
US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
US20040063735A1 (en) | 2002-06-05 | 2004-04-01 | Chaturvedula Prasad V. | Calcitonin gene related peptide receptor antagonists |
WO2004097421A2 (en) * | 2003-04-29 | 2004-11-11 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with calcitonin receptor-like receptor (calcrl) |
TW200524601A (en) | 2003-12-05 | 2005-08-01 | Bristol Myers Squibb Co | Heterocyclic anti-migraine agents |
EP1689493A4 (en) | 2003-12-05 | 2008-04-23 | Bristol Myers Squibb Co | ANTAGONISTS OF THE CALCITONIN GENE RELATED PEPTIDE RECEPTOR |
EP1701611B1 (en) * | 2003-12-24 | 2011-05-18 | G2 Inflammation Pty Ltd | Transgenic non-human mammal comprising a polynucleotide encoding human or humanized c5ar |
TW200533398A (en) | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
US7384931B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7384930B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7449586B2 (en) | 2004-12-03 | 2008-11-11 | Bristol-Myers Squibb Company | Processes for the preparation of CGRP-receptor antagonists and intermediates thereof |
FR2882628B1 (fr) * | 2005-03-04 | 2011-03-18 | Centre Nat Rech Scient | Souris transgeniques et leurs applications comme modele experimental |
US7834007B2 (en) | 2005-08-25 | 2010-11-16 | Bristol-Myers Squibb Company | CGRP antagonists |
BRPI0618705B8 (pt) | 2005-11-14 | 2021-05-25 | Labrys Biologics Inc | anticorpos antagonistas humanizados direcionados contra peptídeo relacionado ao gene da calcitonina, composição farmacêutica e uso dos mesmos |
JP2009201355A (ja) * | 2006-06-02 | 2009-09-10 | Osaka Univ | 高血圧モデル非ヒト動物 |
ES2570153T3 (es) | 2006-08-22 | 2016-05-17 | Novo Nordisk As | Anticuerpos anti-C5aR con propiedades mejoradas |
JP2010536326A (ja) * | 2007-04-26 | 2010-12-02 | アキリオン ファーマシューティカルズ,インコーポレーテッド | Hcvのキメラns4aタンパク質を発現する細胞およびアッセイ法におけるその使用 |
AU2009217224B2 (en) | 2008-02-20 | 2014-09-11 | G2 Inflammation Pty Ltd | Humanized anti-C5aR antibodies |
EP2265287B1 (en) | 2008-03-04 | 2018-09-05 | Teva Pharmaceuticals International GmbH | Methods of treating chronic pain |
JO3382B1 (ar) * | 2008-12-23 | 2019-03-13 | Amgen Inc | أجسام مضادة ترتبط مع مستقبل cgrp بشري |
EP2470207A1 (en) | 2009-08-28 | 2012-07-04 | Rinat Neuroscience Corporation | Methods for treating visceral pain by administering antagonist antibodies directed against calcitonin gene-related peptide |
EP2718322B1 (en) | 2011-06-06 | 2018-08-08 | Novo Nordisk A/S | Therapeutic antibodies |
JP6267986B2 (ja) * | 2014-02-13 | 2018-01-24 | 株式会社特殊免疫研究所 | ヒトの特定分子と結合する分子標的物質のinvivo評価法 |
JP6568099B2 (ja) | 2014-03-21 | 2019-08-28 | テバ・ファーマシューティカルズ・インターナショナル・ゲーエムベーハーTeva Pharmaceuticals International GmbH | カルシトニン遺伝子関連ペプチドに対するアンタゴニスト抗体及びその使用方法 |
US10556945B2 (en) | 2014-03-21 | 2020-02-11 | Teva Pharmaceuticals International Gmbh | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
MX2017003247A (es) | 2014-09-15 | 2017-11-30 | Amgen Inc | Proteina de union a antigenos, bi-especificos del receptor anti-cgrp/receptor pac1 y usos de las mismas. |
JOP20200116A1 (ar) | 2015-04-24 | 2017-06-16 | Amgen Inc | طرق لعلاج أو الوقاية من الصداع النصفي |
KR20220031944A (ko) | 2016-09-23 | 2022-03-14 | 테바 파마슈티컬스 인터내셔널 게엠베하 | 불응성 편두통의 치료 |
US11407838B2 (en) | 2018-04-02 | 2022-08-09 | Amgen Inc. | Erenumab compositions and uses thereof |
Family Cites Families (5)
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US4882609A (en) * | 1984-11-19 | 1989-11-21 | Max-Planck Gesellschaft Zur Forderung Der Wissenschafter E.V. | Semiconductor devices with at least one monoatomic layer of doping atoms |
US4908678A (en) * | 1986-10-08 | 1990-03-13 | Semiconductor Energy Laboratory Co., Ltd. | FET with a super lattice channel |
US5081513A (en) * | 1991-02-28 | 1992-01-14 | Xerox Corporation | Electronic device with recovery layer proximate to active layer |
US5606177A (en) * | 1993-10-29 | 1997-02-25 | Texas Instruments Incorporated | Silicon oxide resonant tunneling diode structure |
US6255150B1 (en) * | 1997-10-23 | 2001-07-03 | Texas Instruments Incorporated | Use of crystalline SiOx barriers for Si-based resonant tunneling diodes |
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- 2002-09-26 EP EP02763731A patent/EP1438325B1/en not_active Expired - Lifetime
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WO2003027252A2 (en) | 2003-04-03 |
JP2005503809A (ja) | 2005-02-10 |
EP1438325A4 (en) | 2005-02-23 |
ATE453661T1 (de) | 2010-01-15 |
DE60234944D1 (de) | 2010-02-11 |
WO2003027252A3 (en) | 2003-06-19 |
EP1438325B1 (en) | 2009-12-30 |
EP1438325A2 (en) | 2004-07-21 |
CA2461917C (en) | 2012-01-17 |
US7193070B2 (en) | 2007-03-20 |
US20040197859A1 (en) | 2004-10-07 |
CA2461917A1 (en) | 2003-04-03 |
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