公开(公告)号：WO1997011716A1

公开(公告)日：1997-04-03

申请号：PCT/US1996015651

申请日：1996-09-27

Applicant: YALE UNIVERSITY ,  ARTAVANIS-TSAKONAS, Spyridon ,  FORTINI, Mark, E. ,  MATSUNO, Kenji

Inventor： YALE UNIVERSITY

IPC: A61K38/17

CPC classification number: C12N5/0623 ,  A61K35/12 ,  A61K38/00 ,  C07K14/47 ,  C12N5/0018 ,  C12N5/0601 ,  C12N2501/42

Abstract: The present invention is directed to methods for the expansion of non-terminally differentiated cells ("precursor cells") using agonists of Notch function, by inhibiting the differentiation of the cells without inhibiting proliferation (mitotic activity) such that an expanded population of non-terminally differentiated cells is obtained. The cells are preferably stem or progenitor cells. These expanded cells can be used in cell replacement therapy to provide desired cell populations and help in the regeneration of diseased and/or injured tissues. The expanded cell populations can also be made recombinant and used for gene therapy, or can be used to supply functions associated with a particular precursor cell or its progeny cell.

Abstract translation: 本发明涉及使用Notch功能的激动剂来扩增非终末分化的细胞（“前体细胞”）的方法，通过抑制细胞的分化而不抑制增殖（有丝分裂活性），使得扩增的非 - 得到终末分化的细胞。 细胞优选是干细胞或祖细胞。 这些扩展的细胞可用于细胞替代疗法以提供所需的细胞群体并有助于病变和/或损伤组织的再生。 扩增的细胞群体也可以重组并用于基因治疗，或可用于提供与特定前体细胞或其后代细胞相关的功能。

公开(公告)号：WO1994007474A1

公开(公告)日：1994-04-14

申请号：PCT/US1993009338

申请日：1993-09-30

Applicant: YALE UNIVERSITY ,  ARTAVANIS-TSAKONAS, Spyridon ,  FEHON, Richard, Grant ,  ZAGOURAS, Panayiotis ,  BLAUMUELLER, Christine, Marie

Inventor： YALE UNIVERSITY

IPC: A61K31/00

CPC classification number: A61K31/70 ,  A61K38/00 ,  C07K14/43581 ,  C07K14/47 ,  C07K14/705 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/20 ,  C07K2319/23 ,  C07K2319/70 ,  C07K2319/95 ,  C12N15/62 ,  G01N33/57411 ,  G01N33/57415 ,  G01N33/57419 ,  G01N33/57484 ,  G01N33/6893 ,  Y10S436/811 ,  Y10S436/813 ,  Y10S436/815

Abstract: The present invention relates to therapeutic and diagnostic methods and compositions based on Notch proteins and nucleic acids. Figure 17 displays the sequences of human Notch DNA and the encoded human Notch protein. The invention provides for treatment of disorders of cell fate or differentiation by administration of a therapeutic compound of the invention. Such therapeutic compounds (termed herein "Therapeutics") include Notch proteins and analogs and derivatives (including fragments) thereof, antibodies thereto, nucleic acids encoding the Notch proteins, analogs, or derivatives, Notch antisense nucleic acids, as well as toporythmic proteins and derivatives which bind to or otherwise interact with Notch proteins, their encoding nucleic acids or antibodies. In a preferred embodiment, a Therapeutic of the invention is administered to treat a cancerous condition, or to prevent progression from a pre-neoplastic or non-malignant state into a neoplastic or a malignant state.

Abstract translation: 本发明涉及基于Notch蛋白和核酸的治疗和诊断方法和组合物。 图17显示人Notch DNA和编码的人Notch蛋白的序列。 本发明通过施用本发明的治疗化合物来治疗细胞命运或分化的病症。 此类治疗化合物（本文称为“治疗学”）包括Notch蛋白及其类似物及其衍生物（包括片段），其抗体，编码Notch蛋白，类似物或衍生物的核酸，Notch反义核酸以及拓扑蛋白和衍生物 其与Notch蛋白质，其编码核酸或抗体结合或以其它方式相互作用。 在优选的实施方案中，施用本发明的治疗剂以治疗癌症，或预防从肿瘤前或非恶性状态进展为肿瘤或恶性状态。

公开(公告)号：WO2013147793A1

公开(公告)日：2013-10-03

申请号：PCT/US2012/031213

申请日：2012-03-29

Applicant: FLEMING, Robert, J. ,  ARTAVANIS-TSAKONAS, Spyridon

Inventor： FLEMING, Robert, J. ,  ARTAVANIS-TSAKONAS, Spyridon

IPC: A61P35/00 ,  A61K39/395 ,  C07K14/00

CPC classification number: C07K14/705 ,  A61K38/00 ,  C07K14/43581 ,  C07K16/28 ,  C07K2317/30 ,  C07K2317/76 ,  C07K2319/30

Abstract: Provided herein are polypeptides and derivatives thereof that contain sequences of a Serrate protein and that inhibit Notch pathway function. Also provided herein are nucleic acids that encode the polypeptides, vectors and cells for producing the polypeptides, and related pharmaceutical compositions and kits. Additionally provided are antibodies which bind to the Notch inhibitory region of a Serrate protein. Therapeutic methods are also provided.

Abstract translation: 本文提供含有Serrate蛋白序列并抑制Notch途径功能的多肽及其衍生物。 本文还提供了编码多肽的核酸，用于产生多肽的载体和细胞，以及相关的药物组合物和试剂盒。 另外提供了结合丝氨酸蛋白的Notch抑制区的抗体。 还提供了治疗方法。

公开(公告)号：WO02102987A3

公开(公告)日：2003-05-22

申请号：PCT/US0219189

申请日：2002-06-18

Applicant: GEN HOSPITAL CORP ,  ARTAVANIS-TSAKONAS SPYRIDON ,  LAKE ROBERT J

Inventor： ARTAVANIS-TSAKONAS SPYRIDON ,  LAKE ROBERT J

IPC: A61K38/00 ,  A61K38/17 ,  A61K39/395 ,  A61K48/00 ,  C07K14/47 ,  C07K16/18 ,  C07K16/24 ,  C12N15/85 ,  C12Q1/68 ,  G01N33/50 ,  G01N33/53 ,  G01N33/574 ,  C12N5/00

CPC classification number: C07K16/18 ,  A61K38/1709 ,  A61K48/00 ,  A61K2039/505 ,  C07K14/47 ,  C07K16/24 ,  C07K2317/32 ,  C12Q1/6883 ,  C12Q2600/158 ,  G01N33/5041 ,  G01N33/574 ,  G01N2800/52

Abstract: The invention is directed to methods of modulating Notch signal transduction and to complexes of the protein Mastermind with proteins identified as interacting with Mastermind by a two-hybrid screen as well as a complex ofMastermind (Mam) with Mipl, or a complex ofMam with Mip30, or a complex ofMam with Mip6. Methods of screening the complexes for efficacy in treating and/or preventing certain diseases and disorders, particularly hyperproliferative and cancerous conditions are also provided. The invention includes nucleic acid and amino acid sequences of Mip30 or Mip6, as well as fragments and derivatives thereof.

Abstract translation: 本发明涉及调节Notch信号转导的方法和Mastermind蛋白与通过双杂交筛选鉴定为与Mastermind相互作用的蛋白质的复合物，以及Mplermind（Mam）与Mipl的复合物，或Mam与Mip30的复合物， 或Mam与Mip6的复合体。 还提供了筛选复合物以治疗和/或预防某些疾病和病症，特别是过度增殖和癌性病症方面的方法。 本发明包括Mip30或Mip6的核酸和氨基酸序列，以及其片段和衍生物。

公开(公告)号：WO1996027610A1

公开(公告)日：1996-09-12

申请号：PCT/US1996003172

申请日：1996-03-07

Applicant: YALE UNIVERSITY ,  IMPERIAL CANCER RESEARCH TECHNOLOGY, LTD. ,  ISH-HOROWICZ, David ,  HENRIQUE, Domingos, M., P. ,  LEWIS, Julian, H. ,  MYAT, Anna, M. ,  ARTAVANIS-TSAKONAS, Spyridon ,  MANN, Robert, S. ,  GRAY, Grace, E.

Inventor： YALE UNIVERSITY ,  IMPERIAL CANCER RESEARCH TECHNOLOGY, LTD.

IPC: C07K14/00

CPC classification number: C07K14/465 ,  A61K38/00 ,  C07K14/43504 ,  C07K14/43581 ,  C07K14/46 ,  C07K14/463 ,  C07K14/705

Abstract: The present invention relates to nucleotide sequences of vertebrate Serrate genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the Serrate protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of a vertebrate Serrate which comprise one or more domains of the Serrate protein, including but not limited to the intracellular domain, extracellular domain, DSL domain, cysteine rich domain, transmembrane region, membrane-associated region, or one or more EGF-like repeats of a Serrate protein, or any combination of the foregoing. Antibodies to vertebrate Serrate, its derivatives and analogs, are additionally provided. Methods of production of the vertebrate Serrate proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided.In specific examples, isolated Serrate genes, from chick, mouse, Xenopus and human, are provided.

Abstract translation: 本发明涉及脊椎动物Serrate基因的核苷酸序列，及其编码蛋白质的氨基酸序列，以及衍生物（例如片段）及其类似物。 在一个具体实施方案中，所述丝氨酸蛋白是人蛋白质。 本发明还涉及脊椎动物血清酸的片段（及其衍生物和类似物），其包含一个或多个丝氨酸蛋白结构域，包括但不限于细胞内结构域，细胞外结构域，DSL结构域，富含半胱氨酸的结构域，跨膜区， 膜相关区域，或一种或多种丝氨酸蛋白质的EGF样重复序列，或上述的任何组合。 脊椎动物的抗体Serrate，其衍生物和类似物也被提供。 还提供了脊椎动物的生产方法。例如，通过重组方法，提供了丝氨酸蛋白质，衍生物和类似物。 提供了治疗和诊断方法和药物组合物。在具体实施例中，提供了来自小鸡，小鼠，非洲爪蟾和人的分离的Serrate基因。

公开(公告)号：WO1994008037A1

公开(公告)日：1994-04-14

申请号：PCT/US1993009333

申请日：1993-09-30

Applicant: YALE UNIVERSITY ,  MEDICAL RESEARCH COUNCIL ,  ARTAVANIS-TSAKONAS, Spyridon ,  STIFANI, Stefani ,  REDHEAD, Nicola, J. ,  HILL, Robert, E.

Inventor： YALE UNIVERSITY ,  MEDICAL RESEARCH COUNCIL

IPC: C12P21/06

CPC classification number: C07K14/47 ,  C07K16/18

Abstract: The present invention relates to nucleotide sequences of the human transducin-like Enhancer of split ("TLE") genes, and amino acid sequences of their encoded TLE proteins. The invention further relates to fragments and other derivatives, and analogs, of human TLE proteins, as well as antibodies thereto. Nucleic acids encoding such fragments or derivatives are also within the scope of the invention. Production of the foregoing proteins and derivatives, e.g., by recombinant methods, is provided. Binding partners of TLE proteins are also provided. In particular, the invention provides sequences of four distinct human homologs of the Drosophila TLE gene, and sequences of their unique encoded TLE proteins. In specific embodiments, the invention relates to derivatives and analogs of the human TLE proteins which are functionally active, or which comprise one or more domains of a human TLE protein, including but not limited to the "Q domain", "GP domain", "CcN domain", "SP domain", "WD-40 domain", or a WD-40 repeat, casein kinase II (CK II) site, cdc2 kinase (cdc2) site, or nuclear localization sequence motif, consensus sequences for any of the foregoing, or any combination of the foregoing.

Abstract translation: 本发明涉及分裂（“TLE”）基因的人转导素样增强子的核苷酸序列，以及它们编码的TLE蛋白的氨基酸序列。 本发明还涉及人TLE蛋白的片段和其它衍生物和类似物，以及其抗体。 编码这种片段或衍生物的核酸也在本发明的范围内。 提供了上述蛋白质和衍生物的生产，例如通过重组方法。 还提供了TLE蛋白的结合伙伴。 特别地，本发明提供了果蝇TLE基因的四个不同的人类同源物的序列，以及它们唯一编码的TLE蛋白的序列。 在具体实施方案中，本发明涉及功能上有活性或包含人TLE蛋白的一个或多个结构域的人TLE蛋白的衍生物和类似物，包括但不限于“Q域”，“GP结构域”， “CcN域”，“SP结构域”，“WD-40结构域”或WD-40重复，酪蛋白激酶II（CK II）位点，cdc2激酶（cdc2）位点或核定位序列基序， 或上述的任何组合。

公开(公告)号：WO2002102987A2

公开(公告)日：2002-12-27

申请号：PCT/US2002/019189

申请日：2002-06-18

Applicant: THE GENERAL HOSPITAL CORPORATION ,  ARTAVANIS-TSAKONAS, Spyridon ,  LAKE, Robert, J.

Inventor： ARTAVANIS-TSAKONAS, Spyridon ,  LAKE, Robert, J.

IPC: C12N

CPC classification number: C07K16/18 ,  A61K38/1709 ,  A61K48/00 ,  A61K2039/505 ,  C07K14/47 ,  C07K16/24 ,  C07K2317/32 ,  C12Q1/6883 ,  C12Q2600/158 ,  G01N33/5041 ,  G01N33/574 ,  G01N2800/52

Abstract: The invention is directed to methods of modulating Notch signal transduction and to complexes of the protein Mastermind with proteins identified as interacting with Mastermind by a two-hybrid screen as well as a complex ofMastermind (Mam) with Mipl, or a complex ofMam with Mip30, or a complex ofMam with Mip6. Methods of screening the complexes for efficacy in treating and/or preventing certain diseases and disorders, particularly hyperproliferative and cancerous conditions are also provided. The invention includes nucleic acid and amino acid sequences of Mip30 or Mip6, as well as fragments and derivatives thereof.

Abstract translation: 本发明涉及调节Notch信号转导的方法和Mastermind蛋白与通过双杂交筛选鉴定为与Mastermind相互作用的蛋白质的复合物，以及Mplermind（Mam）与Mipl的复合物，或Mam与Mip30的复合物， 或Mam与Mip6的复合体。 还提供了筛选复合物以治疗和/或预防某些疾病和病症，特别是过度增殖和癌性病症方面的方法。 本发明包括Mip30或Mip6的核酸和氨基酸序列，以及其片段和衍生物。

公开(公告)号：WO1997001571A1

公开(公告)日：1997-01-16

申请号：PCT/US1996011178

申请日：1996-06-28

Applicant: IMPERIAL CANCER RESEARCH TECHNOLOGY, LTD. ,  YALE UNIVERSITY ,  ISH-HOROWICZ, David ,  HENRIQUE, Domingo, M., P. ,  LEWIS, Julian, H. ,  ARTAVANIS-TSAKONAS, Spyridon ,  GRAY, Grace, E.

Inventor： IMPERIAL CANCER RESEARCH TECHNOLOGY, LTD. ,  YALE UNIVERSITY

IPC: C07H17/00

CPC classification number: C07K14/47 ,  A61K38/00 ,  C07K14/705 ,  C07K2319/00

Abstract: The present invention relates to nucleotide sequences of vertebrate Delta genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the vertebrate Delta protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of Delta which comprise one or more domains of the Delta protein, including but not limited to the intracellular domain, extracellular domain, DSL domain, domain amino-terminal to the DSL domain, transmembrane region, or one or more EGF-like repeats of a Delta protein, or any combination of the foregoing. Antobidies to Delta, its derivatives and analogs, are additionally provided. Methods of production of the Delta proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. In specific examples, isolated Delta genes, from Xenopus, chick, mouse, and human, are provided.

Abstract translation: 本发明涉及脊椎动物Delta基因的核苷酸序列及其编码的蛋白质的氨基酸序列以及衍生物（例如片段）及其类似物。 在具体实施方案中，脊椎动物Delta蛋白是人蛋白质。 本发明还涉及包含Delta蛋白的一个或多个结构域的Delta的片段（及其衍生物和类似物），包括但不限于细胞内结构域，细胞外结构域，DSL结构域，DSL结构域的氨基末端， 跨膜区域，或一种或多种Delta蛋白质的EGF样重复序列，或上述的任何组合。 另外提供了对三角洲，其衍生物和类似物的安慰剂。 还提供了通过重组方法生产Delta蛋白质，衍生物和类似物的方法。 提供了治疗和诊断方法和药物组合物。 在具体实例中，提供了来自爪蟾，小鸡，小鼠和人的孤立的Delta基因。

公开(公告)号：WO1994007522A1

公开(公告)日：1994-04-14

申请号：PCT/US1993009339

申请日：1993-09-30

Applicant: YALE UNIVERSITY ,  ARTAVANIS-TSAKONAS, Spyridon ,  STIFANI, Stefano

Inventor： YALE UNIVERSITY

IPC: A61K37/02

CPC classification number: C07K14/47 ,  A61K38/00 ,  A61K48/00 ,  C07K14/4722 ,  G01N33/57407 ,  G01N33/57411 ,  G01N33/57415 ,  G01N33/5743 ,  G01N33/6881 ,  G01N2333/4719 ,  Y10S436/813

Abstract: The present invention relates to therapeutic and diagnostic methods and compositions based on transducin-like Enhancer of split ("TLE") proteins and nucleic acids, sequences of which are shown. The invention provides for treatment of disorders of cell fate or differentiation by administration of a therapeutic compound of the invention. Such therapeutic compounds (termed herein "Therapeutics") include transducin-like Enhancer of split proteins and analogs and derivatives (including fragments) thereof, antibodies thereto, nucleic acids encoding the transducin-like Enhancer of split proteins, ananlogs, or derivatives, transducin-like Enhancer of split antisense nucleic acids, as well as proteins and their derivatives which bind to or otherwise interact with transducin-like Enhancer of split proteins and their encoding nucleic acids and antibodies. Diagnostic methods and methods of inhibiting transducing-like Enhancer of split expression are also provided.

Abstract translation: 本发明涉及基于转导素样增强子（“TLE”）蛋白和核酸的治疗和诊断方法和组合物，其序列如图所示。 本发明提供了通过施用本发明的治疗化合物治疗细胞命运或分化的病症。 这样的治疗化合物（本文称为“治疗剂”）包括分裂蛋白的转导素样增强子及其类似物和衍生物（包括片段），其抗体，编码分解蛋白的转导素样增强子的核酸，ananlog或衍生物， 如分裂反义核酸的增强子，以及与裂解蛋白的转导素样增强子及其编码核酸和抗体结合或以其它方式相互作用的蛋白质及其衍生物。 还提供了诊断方法和抑制分裂表达的转导增强子的方法。

公开(公告)号：WO1992010518A1

公开(公告)日：1992-06-25

申请号：PCT/US1991009055

申请日：1991-11-27

Applicant: YALE UNIVERSITY ,  ROTHBERG, Jonathan, Marc ,  ARTAVANIS-TSAKONAS, Spyridon

Inventor： YALE UNIVERSITY

IPC: C07K13/00

CPC classification number: C07K14/47 ,  A61K38/00 ,  C07K14/485

Abstract: An isolated and substantially pure form of the SLIT protein and sequence elements thereof, antibodies thereto and diagnostics and therapeutics utilizing such proteins and antibodies. A method for treating neurodegenerative disease, traumatic injury to a neural tissue or affecting the angiogenic process in a patient comprising administering to the patient an effective amount of the SLIT protein.

Abstract translation: 分离且基本上纯的形式的SLIT蛋白及其序列元件，其抗体以及利用这些蛋白质和抗体的诊断和治疗。 一种用于治疗神经变性疾病，神经组织的创伤性损伤或影响患者的血管发生过程的方法，包括向患者施用有效量的SLIT蛋白。