公开(公告)号：US06835544B2

公开(公告)日：2004-12-28

申请号：US09742684

申请日：2000-12-19

申请人： Lawrence W. Mathews ,  Wylie W. Vale, Jr. ,  Kunihiro Tsuchida

发明人： Lawrence W. Mathews ,  Wylie W. Vale, Jr. ,  Kunihiro Tsuchida

IPC分类号： G01N3353

CPC分类号： C07K14/71 ,  A61K38/00 ,  C07K2319/00

摘要： In accordance with the present invention, there are provided novel receptor proteins characterized by having the following domains, reading from the N-terminal end of said protein: an extracellular, ligand-binding domain, a hydrophobic, trans-membrane domain, and an intracellular, receptor domain having serine kinase-like activity. The invention receptors optionally further comprise a second hydrophobic domain at the amino terminus thereof. The invention receptor proteins are further characterized by having sufficient binding affinity for at least one member of the activin/TGF-&bgr; superfamily of polypeptide growth factors such that concentrations of ≦10 nM of said polypeptide growth factor occupy ≧50% of the binding sites of said receptor protein. A presently preferred member of the invention superfamily of receptors binds specifically to activins, in preference to inhibins, transforming growth factor-&bgr;, and other non-activin-like proteins. DNA sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed.

摘要翻译： 根据本发明，提供了新的受体蛋白，其特征在于具有以下结构域，从所述蛋白质的N-末端读取：细胞外，配体结合结构域，疏水性，跨膜结构域和细胞内， 受体结构域具有丝氨酸激酶样活性。本发明受体任选地还包含在其氨基末端的第二疏水结构域。 本发明受体蛋白的进一步特征在于对多肽生长因子的激活素/ TGF-β超家族的至少一个成员具有足够的结合亲和力，使得所述多肽生长因子的<= 10nM的浓度占结合物的50％ 所述受体蛋白的位点。 本发明目前优选的受体超家族成员特异性结合激活素，优于抑制素，转化生长因子-β和其他非激活素样蛋白。 还公开了编码这种受体的DNA序列，使用其的测定法，以及由其衍生的抗体。

公开(公告)号：US06482608B1

公开(公告)日：2002-11-19

申请号：US09580734

申请日：2000-05-26

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： C12N510

CPC分类号： C07K14/72 ,  A61K38/00 ,  C07K14/723

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of 10 nM of CRF occupy 50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新型G蛋白偶联受体蛋白（CRF-R），其特征在于对促皮质激素释放因子（CRF）具有足够的结合亲和力，使得10nM CRF的浓度占结合物的50％ 所述受体蛋白的位点。 还公开了编码这种受体的核酸序列，使用其的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US5728545A

公开(公告)日：1998-03-17

申请号：US110286

申请日：1993-08-23

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson

IPC分类号： G01N33/53 ,  C07K14/72 ,  C12N15/09 ,  C12N15/12 ,  C12P21/02 ,  C12P21/08 ,  C12Q1/68 ,  C12R1/91 ,  G01N33/566 ,  C07H21/04 ,  C12N15/11

CPC分类号： C07K14/72

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of .ltoreq.10 nM of CRF occupy .gtoreq.50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. The invention CRF-R can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新颖的G蛋白偶联受体蛋白（CRF-R），其特征在于对促肾上腺皮质激素释放因子（CRF）具有足够的结合亲和力，使得CRF的<10nM浓度占据> =所述受体蛋白的结合位点的50％。 还公开了编码这种受体的核酸序列，使用其的测定法，以及由其衍生的抗体。 本发明CRF-R可以以各种方式使用，例如在生物测定中用于制备其抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US5510458A

公开(公告)日：1996-04-23

申请号：US162178

申请日：1993-12-14

申请人： Wayne D. Kornreich ,  Jean F. Hernandez ,  Jean E. Rivier ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

发明人： Wayne D. Kornreich ,  Jean F. Hernandez ,  Jean E. Rivier ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/00 ,  C07K14/575 ,  C07K14/695

CPC分类号： C07K14/57509 ,  A61K38/00 ,  Y10S930/26

摘要： Disclosed are improved CRF peptide antagonists such as those having the formula: Y-D-Phe-Xaa.sub.13 -Leu-Leu-Arg-Xaa.sub.17 -Xaa.sub.18 -Leu-Xaa.sub.20 -Nle-Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Xaa.sub.26 -Leu-Xaa.sub.28 -Xaa.sub.29 -Gln-Xaa.sub.31 -Xaa.sub.32 -Xaa.sub.33 -Xaa.sub.34 -Arg-Xaa.sub.36 -Xaa.sub.37 -Nle-Xaa.sub.39 -Xaa.sub.40 -Xaa.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; Xaa.sub.13 is His, Tyr or Glu; Xaa.sub.17 is CML, Glu, Asn or Lys; Xaa.sub.18 is Val, Nle or Met; Xaa.sub.20 is Glu, D-Glu, Aib or D-Ala; Xaa.sub.22 is Ala, Aib, Thr, Asp or Glu; Xaa.sub.23 is Arg, Orn, Har or Lys; Xaa.sub.24 is Ala or Aib; Xaa.sub.25 is Asp or Glu; Xaa.sub.26 is Gln, Asn or Lys; Xaa.sub.28 is Ala or Aib; Xaa.sub.29 is Gln, Aib or Glu, Xaa.sub.31 is Ala or Aib; Xaa.sub.32 is His, Aib, Gly, Tyr or Ala; Xaa.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; Xaa.sub.34 is Asn or Aib; Xaa.sub.36 is Lys, Orn, Arg, Har or Leu; Xaa.sub.37 is Leu or Tyr; Xaa.sub.39 is Glu, Aib or Asp; Xaa.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and Xaa.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln, wherein CML may be substituted for Leu. Specific CRF antagonists disclosed include D-Phe.sup.12, D-Ala.sup.20, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, Nle.sup.21,38, Aib.sup.34 !-rCRF (12-41) , D-Phe.sup.12, CML.sup.17, Nle.sup.21,38 !-rCRF(12-41) , D-Phe.sup.12, Aib.sup.20, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, Aib.sup.29, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, CML.sup.14, Nle.sup.21,38, Aib.sup.24,28,31 !-rCRF(12-41) and D-Phe.sup.12, CML.sup.15, Aib.sup.24,28,31 !-rCRF(12-41).

摘要翻译： PCT No.PCT / US92 / 05101 Sec。 371日期：1993年12月14日 102（e）日期1993年12月14日PCT提交1992年6月12日PCT公布。 出版物WO92 / 22576 日期为1992年12月23日。公开的是改进的CRF肽拮抗剂，例如具有下式的那些：YD-Phe-Xaa13-Leu-Leu-Arg-Xaa17-Xaa18-Leu-Xaa20-Nle-Xaa22-Xaa23-Xaa24-Xaa25- Xaa26-Leu-Xaa28-Xaa29-Gln-Xaa31-Xaa32-Xaa33-Xaa34-Arg-Xaa36-Xaa37-Nle-Xaa39-Xaa40-Xaa41-NH2，其中Y是Ac或氢; Xaa13是His，Tyr或Glu; Xaa17是CML，Glu，Asn或Lys; Xaa18是Val，Nle或Met; Xaa20是Glu，D-Glu，Aib或D-Ala; Xaa22是Ala，Aib，Thr，Asp或Glu; Xaa23是Arg，Orn，Har或Lys; Xaa24是Ala或Aib; Xaa25是Asp或Glu; Xaa26是Gln，Asn或Lys; Xaa28是Ala或Aib; Xaa29是Gln，Aib或Glu，Xaa31是Ala或Aib; Xaa32是His，Aib，Gly，Tyr或Ala; Xaa33是Ser，Aib，Asn，Leu，Thr或Ala; Xaa34是Asn或Aib; Xaa36是Lys，Orn，Arg，Har或Leu; Xaa37是Leu或Tyr; Xaa39是Glu，Aib或Asp; Xaa40是Ile，Aib，Thr，Glu，Ala，Val，Leu，Nle，Phe，Nva，Gly或Gln; Xaa41是Ala，Ile，Gly，Val，Leu，Nle，Phe，Nva或Gln，其中CML可以被Leu取代。 公开的具体CRF拮抗剂包括[D-Phe12，D-Ala20，Nle21,38] -rCRF（12-41），[D-Phe12，Nle21,38，Aib34] -rCRF（12-41），[D-Phe12， C-17，Nle 21,38] -rCRF（12-41），[D-Phe12，Aib20，Nle21,38] -rCRF（12-41），[D-Phe12，Aib29，Nle21,38] -rCRF（12-41 ），[D-Phe12，CML14，Nle21,38，Aib24,28,31] -rCRF（12-41）和[D-Phe12，CML15，Aib24,28,31] -rCRF（12-41）。

公开(公告)号：US07893213B2

公开(公告)日：2011-02-22

申请号：US11747869

申请日：2007-05-11

申请人： Lawrence S. Mathews ,  Wylie W. Vale, Jr. ,  Kunihiro Tsuchida

发明人： Lawrence S. Mathews ,  Wylie W. Vale, Jr. ,  Kunihiro Tsuchida

IPC分类号： C07K16/18 ,  A61K39/395

CPC分类号： C07K14/71 ,  A61K38/00 ,  C07K2319/00

摘要： In accordance with the present invention, there are provided novel receptor proteins characterized by having the following domains, reading from the N-terminal end of said protein: an extracellular, ligand-binding domain, a hydrophobic, trans-membrane domain, and an intracellular, receptor domain having serine kinase-like activity. The invention receptors optionally further comprise a second hydrophobic domain at the amino terminus thereof. The invention receptor proteins are further characterized by having sufficient binding affinity for at least one member of the activin/TGF-β superfamily of polypeptide growth factors such that concentrations of ≦10 nM of said polypeptide growth factor occupy ≧50% of the binding sites of said receptor protein. A presently preferred member of the invention superfamily of receptors binds specifically to activins, in preference to inhibins, transforming growth factor-β, and other non-activin-like proteins. DNA sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed.

摘要翻译： 根据本发明，提供了新的受体蛋白，其特征在于具有以下结构域，从所述蛋白质的N-末端读取：细胞外，配体结合结构域，疏水性，跨膜结构域和细胞内 ，具有丝氨酸激酶样活性的受体结构域。 本发明受体任选地还包含在其氨基末端的第二疏水结构域。 本发明受体蛋白的进一步特征在于对活化素/ TGF-β1的至少一个成员具有足够的结合亲和力; 多肽生长因子的超家族，使得所述多肽生长因子的浓度为10nM占所述受体蛋白质结合位点的≥50％。 本发明目前优选的受体超家族成员特异性结合激活素，优于抑制素，转化生长因子-β和其它非激活素样蛋白。 还公开了编码这种受体的DNA序列，使用其的测定法，以及由其衍生的抗体。

公开(公告)号：US06838274B2

公开(公告)日：2005-01-04

申请号：US09919473

申请日：2001-07-31

申请人： Wylie W. Vale, Jr. ,  Teresa M. Reyes ,  Paul E. Sawchenko ,  Jean E. Rivier ,  Kathy A. Lewis ,  John B. Hogenesch ,  Joan M. Vaughan ,  Marilyn H. Perrin

发明人： Wylie W. Vale, Jr. ,  Teresa M. Reyes ,  Paul E. Sawchenko ,  Jean E. Rivier ,  Kathy A. Lewis ,  John B. Hogenesch ,  Joan M. Vaughan ,  Marilyn H. Perrin

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K38/22 ,  A61K39/00 ,  A61P3/00 ,  A61P5/06 ,  A61P9/04 ,  A61P9/10 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/26 ,  A61P25/28 ,  A61P29/00 ,  C07K14/435 ,  C07K14/52 ,  C07K14/575 ,  C07K16/24 ,  C12N1/21 ,  C12N5/10 ,  C12N15/12 ,  C12N15/16 ,  C12P21/08 ,  C12R1/19 ,  C12N15/63

CPC分类号： C07K14/57509 ,  A61K38/00 ,  A61K39/00

摘要： A human urocortin-related peptide with significant sequence homology to the CRF neuropeptide family was identified. A mouse cDNA was isolated from whole brain poly (A+) RNA that encodes a predicted 38 amino acid peptide protein designated herein as urocortin II. Both human URP and mouse Ucn II are structurally related to the other known mammalian family members, CRF and urocortin (Ucn). These peptides are involved in the regulation of the hypothalamic-pituituary-adrenal axis under basal and stress conditions, suggesting a similar role for URP and Ucn II. Synthesized Ucn-II and URP peptide binds with higher affinity to CRF-R2 than to CRF-R1 Ucn II and human URP appear to be involved in the regulation of body temperature and appetite and may play a role in other stress related phenomenon. These findings identify Ucn II and human URP as a new members of the CRF family of neuropeptides, which are expressed centrally and bind to CRF-R2.

摘要翻译： 鉴定出与CRF神经肽家族具有显着序列同源性的人尿皮质素相关肽。 从编码本文称为尿皮质素II的预测的38个氨基酸的肽蛋白质的全脑poly（A +）RNA中分离出小鼠cDNA。 人URP和小鼠Ucn II都与其他已知的哺乳动物家族成员CRF和尿皮质素（Ucn）结构相关。 这些肽在基础和应激条件下参与下丘脑 - 垂体 - 肾上腺轴的调节，表明URP和Ucn II具有类似的作用。 合成的Ucn-II和URP肽以比CRF-R1 Ucn II更高的亲和力结合，并且人URP似乎参与体温和食欲的调节，并且可能在其他压力相关现象中起作用。 这些发现将Ucn II和人类URP鉴定为CRF家族的新成员，它们集中表达并结合CRF-R2。

公开(公告)号：US06638905B2

公开(公告)日：2003-10-28

申请号：US09191724

申请日：1998-11-12

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： A61K3817

CPC分类号： C07K14/72 ,  A61K38/00 ,  C07K14/723

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of 10 nM of CRF occupy 50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新型G蛋白偶联受体蛋白（CRF-R），其特征在于对促皮质激素释放因子（CRF）具有足够的结合亲和力，使得10nM CRF的浓度占结合物的50％ 所述受体蛋白的位点。 还公开了编码这种受体的核酸序列，使用其的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US06399315B1

公开(公告)日：2002-06-04

申请号：US08482746

申请日：1995-06-07

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： G01N3353

CPC分类号： C07K14/723 ,  A61K38/00 ,  C07K14/72

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of ≦10 nM of CRF occupy ≧50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新颖的G蛋白偶联受体蛋白（CRF-R），其特征在于对促皮质激素释放因子（CRF）具有足够的结合亲和力，使得CRF的<= 10nM的浓度占据≥50 所述受体蛋白的结合位点的百分比。 还公开了编码这种受体的核酸序列，使用其的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US06495343B1

公开(公告)日：2002-12-17

申请号：US08374009

申请日：1995-01-17

申请人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

发明人： Marilyn H. Perrin ,  Ruoping Chen ,  Kathy A. Lewis ,  Wylie W. Vale, Jr. ,  Cynthia J. Donaldson ,  Paul Sawchenko

IPC分类号： C12P2102

CPC分类号： C07K14/723 ,  A61K38/00 ,  C07K14/72

摘要： In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of ≦10 nM of CRF occupy ≧50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

摘要翻译： 根据本发明，提供了新颖的G蛋白偶联受体蛋白（CRF-R），其特征在于对促皮质激素释放因子（CRF）具有足够的结合亲和力，使得CRF的<= 10nM的浓度占据≥50 所述受体蛋白的结合位点的百分比。 还公开了编码这种受体的核酸序列，使用它们的测定法，以及由其衍生的抗体。 本发明CRF-Rs可以以各种方式使用，例如在生物测定中用于生产抗体，在含有这种蛋白质和/或抗体的治疗组合物中。

公开(公告)号：US6023011A

公开(公告)日：2000-02-08

申请号：US68754

申请日：1993-05-28

申请人： Wylie W. Vale, Jr. ,  Mary P. Stenzel-Poore

发明人： Wylie W. Vale, Jr. ,  Mary P. Stenzel-Poore

IPC分类号： A01K67/027 ,  C07K14/47 ,  C12N15/85 ,  C12N5/00 ,  C12N15/00 ,  C12N15/09 ,  C12N15/63

CPC分类号： C12N15/8509 ,  A01K67/0275 ,  C07K14/47 ,  A01K2217/05 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0356 ,  A01K2267/0362

摘要： In accordance with the present invention, there are provided CRF overproducing transgenic mice which exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis, such as elevated plasma levels of ACTH and glucocorticoids. The transgenic mice of the present invention represent a genetic model of CRF overproduction, providing a valuable tool for investigating the long term effects of CRF excess and dysregulation in the central nervous system.