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31. 发明授权

US06770742B1 Use of inhibitors for the treatment of disorders related to RTK hyperfunction, especially cancer 失效
标题翻译：使用抑制剂治疗与RTK亢进相关的疾病，特别是癌症
公开(公告)号：US06770742B1
公开(公告)日：2004-08-03
申请号：US09600826
申请日：2000-09-07
申请人： Axel Ullrich , Johannes Bange , Pjotr Knyazev
发明人： Axel Ullrich , Johannes Bange , Pjotr Knyazev
IPC分类号： C07K1400
CPC分类号： C07K14/71 , A61K38/00 , G01N33/574
摘要： The present invention concerns the use of inhibitors for the treatment and/or prophylaxis of diseases which are the consequence of increased receptor tyrosine kinase activity, particularly cancer. The use is particularly directed towards inhibition or lowering of the overexpression and/or altered activity of receptor tyrosine kinases (RTKs). In particular, this altered activity of receptor tyrosine kinase can be triggered by a mutation of FGFR-4, wherein this mutation is in particular a point mutation in the transmembrane domain of FGFR-4 and leads to an exchange of a hydrophobic amino acid for a hydrophilic amino acid. The invention further concerns the use of an inhibitor directed against FGFR-4, for the treatment and/or prophylaxis of cancer. Furthermore, the invention concerns a mutated FGFR-4, which leads to overexpression and/or altered activity in cells. Finally, the invention concerns a DNA and RNA sequence of a mutated FGFR-4 molecule. Finally, in addition the invention concerns a pharmaceutical composition, containing the inhibitor as described above and further a diagnostic and screening procedure.
摘要翻译：本发明涉及抑制剂用于治疗和/或预防由于受体酪氨酸激酶活性增加，特别是癌症引起的疾病的用途。该用途特别涉及抑制或降低受体酪氨酸激酶（RTK）的过表达和/或改变的活性。特别地，受体酪氨酸激酶的这种改变的活性可以由FGFR-4的突变引发，其中该突变特别是FGFR-4的跨膜结构域中的点突变，并导致疏水性氨基酸的交换亲水氨基酸。本发明还涉及使用针对FGFR-4的抑制剂来治疗和/或预防癌症。此外，本发明涉及突变的FGFR-4，其导致细胞中的过表达和/或改变的活性。最后，本发明涉及突变的FGFR-4分子的DNA和RNA序列。最后，本发明还涉及包含如上所述的抑制剂的药物组合物，并进一步进行诊断和筛选程序。

32. 发明授权

US06387371B1 Monoclonal antibodies directed to the HER2 receptor 有权
公开(公告)号：US06387371B1
公开(公告)日：2002-05-14
申请号：US09344073
申请日：1999-06-25
申请人： Robert M. Hudziak , H. Michael Shepard , Axel Ullrich , Brian M. Fendly
发明人： Robert M. Hudziak , H. Michael Shepard , Axel Ullrich , Brian M. Fendly
IPC分类号： A61K39395
CPC分类号： C07K16/32 , A61K38/00 , A61K39/395 , A61K47/6843 , A61K47/6849 , A61K2039/505 , C07K16/22 , C07K16/30 , C07K16/3015 , C07K2317/73 , A61K2300/00 , A61K38/217 , A61K38/2013 , A61K38/2006 , A61K38/191
摘要： A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or growth factor by treatment of the cells with antibodies which inhibit the growth factor receptor function, is disclosed. A method of treating tumor cells with antibodies which inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are rendered more susceptible to cytotoxic factors.

33. 发明授权

US06361984B1 MDK1 polypeptides 失效
标题翻译： MDK1多肽
公开(公告)号：US06361984B1
公开(公告)日：2002-03-26
申请号：US08438265
申请日：1995-05-09
申请人： Thomas Ciossek , Axel Ullrich , Birgit Millauer
发明人： Thomas Ciossek , Axel Ullrich , Birgit Millauer
IPC分类号： C12N900
CPC分类号： C07K16/40 , A61K38/00 , C07K14/71
摘要： The present invention relates to MDK1 polypeptides, nucleic acids encoding such polypeptides, cells, tissues and animals containing such nucleic acids, antibodies to such polypeptides, assays utilizing such polypeptides, and methods relating to all of the foregoing. Methods for treatment, diagnosis, and screening are provided for diseases or conditions characterized by an abnormality in a signal transduction disorder. The signal transduction pathway involves an interaction between a MDK1 receptor tyrosine kinase and a receptor for the kinase. The MDK1 receptor tyrosine kinase may be truncated and lack a kinase domain and may be selected from the group consisting of MDK1.T1, MDK1.T2, MDK1.&Dgr;1 and MDK1.&Dgr;2.
摘要翻译：本发明涉及MDK1多肽，编码这种多肽的核酸，含有这种核酸的细胞，组织和动物，这种多肽的抗体，利用这些多肽的测定法，以及与上述所有方法有关的方法。治疗，诊断和为特征为信号转导障碍异常的疾病或病症提供筛查。信号转导途径涉及MDK1受体酪氨酸激酶与激酶受体之间的相互作用。 MDK1受体酪氨酸激酶可能被截短并缺少激酶结构域，并且可以选自MDK1.T1，MDK1.T2，MDK1.DELTA1和MDK1.DELTA2。

34. 发明授权

US06333169B1 HER2 extracellular domain 失效
标题翻译： HER2细胞外结构域
公开(公告)号：US06333169B1
公开(公告)日：2001-12-25
申请号：US08422734
申请日：1995-04-14
申请人： Robert Michael Hudziak , H. Michael Shepard , Axel Ullrich
发明人： Robert Michael Hudziak , H. Michael Shepard , Axel Ullrich
IPC分类号： C12N1510
CPC分类号： C07K14/71 , A61K39/00
摘要： An extracellular portion of the HER2 molecule, essentially free of transmembrane and cytoplasmic portions, which is antigenic in animals. Isolated DNA encoding the extracellular portion; an expression vector containing the isolated DNA; and a cell containing the expression vector. A process for producing the extracellular domain. A vaccine containing the extracellular domain.
摘要翻译： HER2分子的细胞外部分，基本上不含跨膜和细胞质部分，其在动物中是抗原性的。编码胞外部分的分离DNA; 含有分离的DNA的表达载体; 和含有表达载体的细胞。一种产生细胞外结构域的方法。含有细胞外结构域的疫苗。

35. 发明授权

US5990141A Treatment of platelet derived growth factor related disorders such as cancers 失效
标题翻译：治疗血小板衍生生长因子相关疾病如癌症
公开(公告)号：US5990141A
公开(公告)日：1999-11-23
申请号：US370574
申请日：1995-01-06
申请人： Klaus Peter Hirth , Donna Pruess Schwartz , Elaina Mann , Laura Kay Shawver , Gyorgi Keri , Istvan Szekely , Tamas Bajor , Janis Haimichael , Laszlo Orfi , Alex Levitzki , Aviv Gazit , Axel Ullrich , Reiner Lammers , Fairooz F. Kabbinavar , Dennis Slamon , Peng Cho Tang
发明人： Klaus Peter Hirth , Donna Pruess Schwartz , Elaina Mann , Laura Kay Shawver , Gyorgi Keri , Istvan Szekely , Tamas Bajor , Janis Haimichael , Laszlo Orfi , Alex Levitzki , Aviv Gazit , Axel Ullrich , Reiner Lammers , Fairooz F. Kabbinavar , Dennis Slamon , Peng Cho Tang
IPC分类号： A61K9/00 , A61K31/165 , A61K31/167 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/421 , A61K31/425 , A61K31/44 , A61K31/47 , A61K31/495 , A61K31/505 , A61K31/535 , A61K45/06 , A61K47/10 , A61K47/26 , C07C255/23 , C07D231/38 , C07D239/91 , C07D241/38 , C07D241/42 , C07D487/04 , C07D498/04 , G01N33/50
CPC分类号： C07D231/38 , A61K31/165 , A61K31/167 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/421 , A61K31/425 , A61K31/44 , A61K31/47 , A61K31/495 , A61K31/505 , A61K31/535 , A61K45/06 , A61K47/10 , A61K47/26 , A61K9/0019 , C07C255/23 , C07D239/91 , C07D241/38 , C07D241/42 , C07D487/04 , G01N33/5011 , Y10S977/904 , Y10S977/911 , Y10S977/912 , Y10S977/915
摘要： The present invention concerns compounds which can inhibit platelet derived growth factor receptor (PDGF-R) activity, preferably such compounds also inhibit the activity other members of the PDGF-R super family and are selective for members of the PDGF-R super family. The PDGF-R super family includes PDGF-R and PDGF-R related kinases Flt, and KDR. The featured compounds are active on cell cultures to reduce the activity of the PDGF-R and preferably one or more PDGF-R related kinases. An example of a featured compound, A10 (see FIG. 1a), and its ability to inhibit growth of tumor cells in vivo is described below. Using the present application as guide other compounds able to inhibit PDGF-R and preferably Flt and/or KDR can be obtained. Such compounds are preferably used to treat patients suffering from cell proliferative disorders characterized by inappropriate PDGF-R activity.
摘要翻译：本发明涉及可以抑制血小板衍生生长因子受体（PDGF-R）活性的化合物，优选地，这些化合物也抑制PDGF-R超家族的其他成员的活性，并且对PDGF-R超家族的成员是选择性的。 PDGF-R超家族包括PDGF-R和PDGF-R相关的激酶Flt和KDR。特征化合物在细胞培养物中是有活性的，以降低PDGF-R，优选一种或多种PDGF-R相关激酶的活性。下面描述特征化合物A10（参见图1a）及其抑制体内肿瘤细胞生长的能力的实例。使用本申请作为指导，可以获得能够抑制PDGF-R，优选Flt和/或KDR的其它化合物。这些化合物优选用于治疗患有以不适当的PDGF-R活性为特征的细胞增殖性疾病的患者。

36. 发明授权

US5958959A Treatment of platelet derived growth factor related disorders such as cancers 失效
标题翻译：治疗血小板衍生生长因子相关疾病如癌症
公开(公告)号：US5958959A
公开(公告)日：1999-09-28
申请号：US457051
申请日：1995-06-01
申请人： Klaus Peter Hirth , Donna Pruess Schwartz , Elaina Mann , Laura Kay Shawver , Axel Ullrich , Reiner Lammers
发明人： Klaus Peter Hirth , Donna Pruess Schwartz , Elaina Mann , Laura Kay Shawver , Axel Ullrich , Reiner Lammers
IPC分类号： A61K9/00 , A61K31/165 , A61K31/167 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/421 , A61K31/425 , A61K31/44 , A61K31/47 , A61K31/495 , A61K31/505 , A61K31/535 , A61K45/06 , A61K47/10 , A61K47/26 , C07C255/23 , C07D231/38 , C07D239/91 , C07D241/38 , C07D241/42 , C07D487/04 , C07D498/04 , G01N33/50
CPC分类号： C07D231/38 , A61K31/165 , A61K31/167 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/421 , A61K31/425 , A61K31/44 , A61K31/47 , A61K31/495 , A61K31/505 , A61K31/535 , A61K45/06 , A61K47/10 , A61K47/26 , A61K9/0019 , C07C255/23 , C07D239/91 , C07D241/38 , C07D241/42 , C07D487/04 , G01N33/5011 , Y10S977/904 , Y10S977/911 , Y10S977/912 , Y10S977/915
摘要： The present invention concerns compounds which can inhibit platelet derived growth factor receptor (PDGF-R) activity, preferably such compounds also inhibit the activity other members of the PDFG-R superfamily and are selective for members of the PDGF-R superfamily. The PDGF-R superfamily includes PDGF-R and PDGF-R related kinases Flt, and KDR. The featured compounds are active on cell cultures to reduce the activity of the PDGF-R and preferably one or more PDGF-R related kinases. An example of a featured compound, A10 (see FIG. 1a), and its ability to inhibit growth of tumor cells in vivo is described below. Using the present application as guide other compounds able to inhibit PDGF-R and preferably Flt and/or KDR can be obtained. Such compounds are preferably used to treat patients suffering from cell proliferative disorders characterized by inappropriate PDGF-R activity.
摘要翻译：本发明涉及可以抑制血小板衍生生长因子受体（PDGF-R）活性的化合物，优选地，这些化合物还抑制PDFG-R超家族的其他成员的活性，并且对PDGF-R超家族的成员是选择性的。 PDGF-R超家族包括PDGF-R和PDGF-R相关的激酶Flt和KDR。特征化合物在细胞培养物中是有活性的，以降低PDGF-R，优选一种或多种PDGF-R相关激酶的活性。以下描述特征化合物A10（参见图1a）及其抑制体内肿瘤细胞生长的能力的实例。使用本申请作为指导，可以获得能够抑制PDGF-R，优选Flt和/或KDR的其它化合物。这些化合物优选用于治疗患有以不适当的PDGF-R活性为特征的细胞增殖性疾病的患者。

37. 发明授权

US5932602A Treatment of platelet derived growth factor related disorders such as cancers 失效
公开(公告)号：US5932602A
公开(公告)日：1999-08-03
申请号：US456735
申请日：1995-06-01
申请人： Klaus Peter Hirth , Laura Kay Shawver , Gyorgi Keri , Istvan Szekely , Janis Haimichael , Axel Ullrich , Reiner Lammers
发明人： Klaus Peter Hirth , Laura Kay Shawver , Gyorgi Keri , Istvan Szekely , Janis Haimichael , Axel Ullrich , Reiner Lammers
IPC分类号： A61K9/00 , A61K31/165 , A61K31/167 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/421 , A61K31/425 , A61K31/44 , A61K31/47 , A61K31/495 , A61K31/505 , A61K31/535 , A61K45/06 , A61K47/10 , A61K47/26 , C07C255/23 , C07D231/38 , C07D239/91 , C07D241/38 , C07D241/42 , C07D487/04 , C07D498/04 , G01N33/50 , A61K31/175
CPC分类号： C07D231/38 , A61K31/165 , A61K31/167 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/421 , A61K31/425 , A61K31/44 , A61K31/47 , A61K31/495 , A61K31/505 , A61K31/535 , A61K45/06 , A61K47/10 , A61K47/26 , A61K9/0019 , C07C255/23 , C07D239/91 , C07D241/38 , C07D241/42 , C07D487/04 , G01N33/5011 , Y10S977/904 , Y10S977/911 , Y10S977/912 , Y10S977/915
摘要： The present invention concerns compounds which can inhibit platelet derived growth factor receptor (PDGF-R) activity, preferably such compounds also inhibit the activity other members of the PDGF-R super family and are selective for members of the PDGF-R super family. The PDGF-R super family includes PDGF-R and PDGF-R related kinases Flt, and KDR. The featured compounds are active on cell cultures to reduce the activity of the PDGF-R and preferably one or more PDGF-R related kinases. An example of a featured compound, A10 (see FIG. 1a), and its ability to inhibit growth of tumor cells in vivo is described below. Using the present application as guide other compounds able to inhibit PDGF-R and preferably Flt and/or KDR can be obtained. Such compounds are preferably used to treat patients suffering from cell proliferative disorders characterized by inappropriate PDGF-R activity.

38. 发明授权

US5851999A FLK-1 is a receptor for vascular endothelial growth factor 失效
标题翻译： FLK-1是血管内皮生长因子受体
公开(公告)号：US5851999A
公开(公告)日：1998-12-22
申请号：US443861
申请日：1995-05-22
申请人： Axel Ullrich , Werner Risau , Birgit Millauer , Aviv Gazit , Alex Levitzki
发明人： Axel Ullrich , Werner Risau , Birgit Millauer , Aviv Gazit , Alex Levitzki
IPC分类号： G01N33/53 , A61K31/047 , A61K31/235 , A61K31/245 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/381 , A61K31/40 , A61K31/403 , A61K31/404 , A61K31/415 , A61K31/42 , A61K31/495 , A61K31/496 , A61K31/502 , A61K31/505 , A61K31/517 , A61K31/535 , A61K38/00 , A61K39/395 , A61P1/00 , A61P3/08 , A61P3/10 , A61P9/00 , A61P11/00 , A61P13/02 , A61P15/00 , A61P17/00 , A61P27/02 , A61P35/00 , C07C229/60 , C07C255/34 , C07C255/36 , C07C255/40 , C07C255/41 , C07C255/66 , C07C317/44 , C07C317/46 , C07C327/44 , C07D209/18 , C07D209/20 , C07D231/38 , C07D239/93 , C07D239/94 , C07D241/42 , C07D241/44 , C07D261/08 , C07D333/42 , C07D403/06 , C07D487/04 , C07D491/052 , C07D498/04 , C07H21/04 , C07K14/71 , C07K16/28 , C12N5/10 , C12N15/09 , C12N15/12 , C12P21/02 , C12P21/08 , C12R1/91 , G01N33/50 , G01N33/566 , G01N33/577 , G01N33/68 , A61K48/00 , C12N5/00 , C12N15/00
CPC分类号： C07D487/04 , A61K31/235 , A61K31/275 , A61K31/277 , A61K31/38 , A61K31/40 , A61K31/415 , A61K31/42 , A61K31/495 , A61K31/502 , A61K31/505 , A61K31/517 , A61K31/535 , C07C229/60 , C07C255/36 , C07C255/40 , C07C255/41 , C07C255/66 , C07C317/46 , C07C327/44 , C07D209/18 , C07D239/93 , C07D239/94 , C07D241/42 , C07D241/44 , C07K14/71 , C07K16/2863 , G01N33/5008 , G01N33/5011 , G01N33/502 , G01N33/5064 , G01N33/5091 , G01N33/6893 , A61K38/00 , C07K2319/32 , G01N2333/71 , G01N2500/04
摘要： The present invention relates to the use of ligands for the FLK-1 receptor for the modulation of angiogenesis and vasculogenesis. The invention is based, in part, on the demonstration that Flk-1 tyrosine kinase receptor expression is associated with endothelial cells and the identification of vascular endothelial growth factor (VEGF) as the high affinity ligand of Flk-1. These results indicate a major role for Flk-1 in the signaling system during vasculogenesis and angiogenesis. Engineering of host cells that express Flk-1 and the uses of expressed Flk-1 to evaluate and screen for drugs and analogs of VEGF involved in Flk-1 modulation by either agonist or antagonist activities is described. The invention also relates to the use of FLK-1 ligands, including VEGF agonists and antagonists, in the treatment of disorders, including cancer, by modulating vasculogenesis and angiogenesis.
摘要翻译：本发明涉及用于FLK-1受体的配体用于调节血管发生和血管发生的用途。本发明部分基于Flk-1酪氨酸激酶受体表达与内皮细胞相关的证据，以及作为Flk-1的高亲和力配体的血管内皮生长因子（VEGF）的鉴定。这些结果表明Flk-1在血管发生和血管发生过程中在信号系统中的主要作用。描述表达Flk-1的宿主细胞的工程和表达Flk-1的用途以通过激动剂或拮抗剂活性评价和筛选参与Flk-1调节的VEGF的类似物。本发明还涉及FLK-1配体，包括VEGF激动剂和拮抗剂在治疗疾病，包括癌症中的用途，通过调节血管生成和血管生成。

39. 发明授权

US5720954A Monoclonal antibodies directed to the HER2 receptor 失效
公开(公告)号：US5720954A
公开(公告)日：1998-02-24
申请号：US449383
申请日：1995-05-23
申请人： Robert M. Hudziak , H. Michael Shepard , Axel Ullrich , Brian M. Fendly
发明人： Robert M. Hudziak , H. Michael Shepard , Axel Ullrich , Brian M. Fendly
IPC分类号： A61K31/00 , A61K31/365 , A61K31/366 , A61K31/40 , A61K31/407 , A61K31/505 , A61K31/519 , A61K31/529 , A61K31/70 , A61K31/7008 , A61K33/24 , A61K38/00 , A61K38/21 , A61K39/395 , A61K45/00 , A61K47/48 , A61P35/00 , A61P43/00 , C07K1/22 , C07K14/00 , C07K14/485 , C07K14/495 , C07K14/52 , C07K14/525 , C07K14/54 , C07K14/545 , C07K14/55 , C07K14/555 , C07K14/57 , C07K14/705 , C07K14/715 , C07K16/00 , C07K16/22 , C07K16/28 , C07K16/30 , C07K16/32 , C07K19/00 , C12N5/10 , C12N15/02 , C12P21/08 , C12R1/91 , G01N33/573 , G01N33/574 , G01N33/577 , A61K39/00
CPC分类号： C07K16/32 , A61K39/395 , A61K47/48538 , A61K47/48561 , C07K16/22 , C07K16/30 , C07K16/3015 , A61K2039/505 , A61K38/00 , C07K2317/73
摘要： A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or growth factor by treatment of the cells with antibodies which inhibit the growth factor receptor function, is disclosed. A method of treating tumor cells with antibodies which inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are rendered more susceptible to cytotoxic factors.

40. 发明授权

US5677144A Recombinant DNA encoding CCK 2, a receptor tyrosine kinase 失效
标题翻译：编码CCK2的重组DNA，一种受体酪氨酸激酶
公开(公告)号：US5677144A
公开(公告)日：1997-10-14
申请号：US336343
申请日：1994-11-08
申请人： Axel Ullrich , Frauke Hildegard Elisabeth Alves
发明人： Axel Ullrich , Frauke Hildegard Elisabeth Alves
IPC分类号： A61K38/00 , C07K14/705 , C12N15/12 , C12N15/62
CPC分类号： A61K51/103 , C07K14/705 , C07K16/2863 , A61K38/00 , C07K2317/34 , C07K2319/00 , C12N2799/027
摘要： A recombinant nucleic acid molecule encoding a receptor tyrosine kinase identified herein as CCK-2, and specific functional fragments thereof are provided. Also, provided is a nucleic acid encoding a chimeric protein comprising all or a specific part of CCK-2, as well as a process of employing the disclosed nucleic acids to produce the proteins encoded thereby.
摘要翻译：提供了编码本文中鉴定为CCK-2的受体酪氨酸激酶的重组核酸分子及其特定功能片段。此外，提供了编码包含CCK-2的全部或特定部分的嵌合蛋白质的核酸，以及使用所公开的核酸产生由其编码的蛋白质的方法。

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