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    Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
    21.
    发明授权
    Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids 失效
    基于缺口蛋白和核酸的治疗和诊断方法和组合物

    公开(公告)号：US06083904A

    公开(公告)日：2000-07-04

    申请号：US532384

    申请日：1995-09-22

    申请人： Spyridon Artavanis-Tsakonas

    发明人： Spyridon Artavanis-Tsakonas

    IPC分类号： G01N33/53 ,  A01N37/18 ,  A61K31/70 ,  A61K38/00 ,  A61K38/17 ,  A61K39/395 ,  A61K48/00 ,  A61P1/16 ,  A61P17/00 ,  A61P25/00 ,  A61P35/00 ,  A61P43/00 ,  C07H21/04 ,  C07K14/435 ,  C07K14/47 ,  C07K14/705 ,  C12N1/21 ,  C12N15/09 ,  C12N15/62 ,  C12P21/02 ,  C12R1/19 ,  G01N33/574 ,  G01N33/68

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

    摘要： The present invention relates to therapeutic and diagnostic methods and compositions based on Notch proteins and nucleic acids. 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 and their encoding nucleic acids and 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. In other embodiments, a Therapeutic is administered to treat a nervous system disorder or to promote tissue regeneration and repair. In one embodiment, Therapeutics which antagonize, or inhibit, Notch function (hereinafter "Antagonist Therapeutics") are administered for therapeutic effect. In another embodiment, Therapeutics which promote Notch function (hereinafter "Agonist Therapeutics") are administered for therapeutic effect. Diagnostic methods and methods of inhibiting Notch expression are also provided.

    摘要翻译： 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。 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。 此类治疗化合物（本文称为“治疗学”）包括Notch蛋白及其类似物和衍生物（包括其片段），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蛋白质及其编码核酸和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状况，或预防从肿瘤前或非恶性状态进展为肿瘤或恶性状态。 在其它实施方案中，施用治疗剂以治疗神经系统疾病或促进组织再生和修复。 在一个实施方案中，施用拮抗或抑制Notch功能的治疗剂（以下称为“拮抗剂治疗剂”）用于治疗效果。 在另一个实施方案中，施用促进Notch功能的治疗剂（以下称为“激动剂治疗剂”）用于治疗效果。 还提供了抑制Notch表达的诊断方法和方法。

    Human notch and delta, binding domains in toporythmic proteins, and methods based thereon
    22.
    发明授权
    Human notch and delta, binding domains in toporythmic proteins, and methods based thereon 失效
    人类缺口和δ，拓扑蛋白中的结合结构域，以及基于此的方法

    公开(公告)号：US5789195A

    公开(公告)日：1998-08-04

    申请号：US465500

    申请日：1995-06-05

    申请人： Spyridon Artavanis-Tsakonas ,  Marc Alan Telander Muskavitch ,  Richard Grant Fehon ,  Ilaria Rebay ,  Christine Marie Blaumueller ,  Scott Brockwell Shepard

    发明人： Spyridon Artavanis-Tsakonas ,  Marc Alan Telander Muskavitch ,  Richard Grant Fehon ,  Ilaria Rebay ,  Christine Marie Blaumueller ,  Scott Brockwell Shepard

    IPC分类号： A61K38/00 ,  C07K14/705 ,  C07K16/18 ,  C12N15/12 ,  C12N15/05

    CPC分类号： C07K16/18 ,  C07K14/705 ,  A61K38/00 ,  C07K2319/00 ,  Y10S530/839

    摘要： The present invention relates to nucleotide sequences of the human Notch and Delta genes, and amino acid sequences of their encoded proteins, as well as fragments thereof containing an antigenic determinant or which are functionally active. The invention is also directed to fragments (termed herein "adhesive fragments"), and the sequences thereof, of the proteins ("toporythmic proteins") encoded by toporythmic genes which mediate homotypic or heterotypic binding to toporythmic proteins. Toporythmic genes, as used herein, refers to the genes Notch, Delta, and Serrate, as well as other members of the Delta/Serrate family which may be identified, e.g., by the methods described herein. Analogs and derivatives of the adhesive fragments which retain-binding activity are also provided. Antibodies to human Notch and to adhesive fragments are additionally provided. In specific embodiments, the adhesive fragment of Notch is that fragment comprising the Notch sequence most homologous to Drosophila Notch EGF-like repeats 11 and 12; the adhesive fragment of Delta mediating heterotypic binding is that fragment comprising the sequence most homologous to Drosophila Delta amino acids 1-230; the adhesive fragment of Delta mediating homotypic binding is that fragment comprising the sequence most homologous to Drosophila Delta amino acids 32-230; and the adhesive fragment of Serrate is that fragment comprising the sequence most homologous to Drosophila Serrate amino acids 85-283.

    摘要翻译： 本发明涉及人Notch和Delta基因的核苷酸序列及其编码蛋白质的氨基酸序列，以及其含有抗原决定簇或其功能活性的片段。 本发明还涉及由介导与拓扑蛋白质的同型或异型结合的拓扑学基因编码的蛋白质（“拓扑蛋白”）的片段（称为“粘合片段”）及其序列。 如本文所用的拓扑学基因是指Notch，Delta和Serrate基因以及Delta / Serrate家族的其他成员，例如通过本文所述的方法鉴定。 还提供了保留结合活性的粘合剂片段的类似物和衍生物。 另外提供人类Notch和粘合剂片段的抗体。 在具体实施方案中，Notch的粘合片段是包含与果蝇Notch EGF样重复序列11和12最相似的Notch序列的片段; Delta介导异型结合的粘合片段是包含与果蝇Delta氨基酸1-230最相似的序列的片段; Delta介导同型结合的粘合片段是包含与果蝇三角洲氨基酸32-230最相似的序列的片段; 并且Serrate的粘合片段是包含与果糖果丝氨酸85-283最相似序列的片段。

    Manipulation of non-terminally differentiated cells using the Notch pathway
    24.
    发明申请
    Manipulation of non-terminally differentiated cells using the Notch pathway 审中-公开
    使用Notch途径操纵非终末分化细胞

    公开(公告)号：US20050158859A1

    公开(公告)日：2005-07-21

    申请号：US10746237

    申请日：2003-12-22

    申请人： Spyridon Artavanis-Tsakonas ,  Mark Fortini ,  Kenji Matsuno

    发明人： Spyridon Artavanis-Tsakonas ,  Mark Fortini ,  Kenji Matsuno

    IPC分类号： A61K35/12 ,  A61K38/00 ,  C07K14/47 ,  C12N5/00 ,  C12N5/07 ,  A61K48/00 ,  C12N5/08 ,  C12N15/85

    CPC分类号： C07K14/47 ,  A61K35/12 ,  A61K38/00 ,  C12N5/0018 ,  C12N5/0601 ,  C12N2501/42

    摘要： 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.

    摘要翻译： 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患病和/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。

    Activated forms of notch and methods based thereon
    25.
    发明授权
    Activated forms of notch and methods based thereon 失效
    基于此的活化形式的缺口和方法

    公开(公告)号：US06692919B1

    公开(公告)日：2004-02-17

    申请号：US09121457

    申请日：1998-07-23

    申请人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    发明人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    IPC分类号： G01N3353

    CPC分类号： G01N33/5032 ,  C07K14/705 ,  G01N33/68 ,  G01N2500/10

    摘要： The present invention is directed to methods for detecting or measuring Notch activation by observing or measuring the appearance of Notch on the cell surface or by observing or measuring Notch cleavage products that are indicative of Notch activation. The present invention is also directed to methods for detecting a molecule that modulates Notch activation by observing or measuring a change in the amount of Notch expressed on the cell surface or a change in the amount or pattern of Notch cleavage products. The present invention is also directed to a substantially purified activated heterodimeric form of Notch and components thereof and pharmaceutical compositions and kits thereof. The present invention is based, at least in part, on the discovery that Notch in its active form, i.e., the form that mediates signal transduction and that binds Notch ligands such as Delta, is a heterodimer of an about 180 kDa subunit (NEC) and an about 110 kDa subunit (NTM), which are tethered together through a reducing agent-sensitive linkage, in particular, a non-covalent, metal ion-dependent linkage.

    摘要翻译： 本发明涉及通过观察或测量Notch在细胞表面上的外观或通过观察或测量Notch切割产物来表征Notch活化来检测或测量Notch活化的方法。 本发明还涉及通过观察或测量在细胞表面表达的Notch量的变化或Notch切割产物的量或图案的变化来检测调节Notch活化的分子的方法。 本发明还涉及基本上纯化的Notch及其组分的活化异二聚体形式及其药物组合物和试剂盒。 本发明至少部分地基于以下发现：Notch以其活性形式即介导信号转导并且结合Notch配体如Delta的形式是约180kDa亚基的异二聚体（N < EC>）和约110kDa的亚基（N TM），其通过还原剂敏感性连接键连在一起，特别是非共价金属离子依赖性连接。

    Activated forms of notch and methods based thereon
    26.
    发明授权
    Activated forms of notch and methods based thereon 失效
    基于此的活化形式的缺口和方法

    公开(公告)号：US06436650B1

    公开(公告)日：2002-08-20

    申请号：US08899232

    申请日：1997-07-23

    申请人： Spyridon Artavanis-Tsakonas ,  Huilin Qi

    发明人： Spyridon Artavanis-Tsakonas ,  Huilin Qi

    IPC分类号： G01N33567

    CPC分类号： G01N33/5032 ,  C07K14/705 ,  G01N33/68 ,  G01N2500/10

    摘要： The present invention is directed to methods for detecting or measuring Notch activation by observing or measuring the appearance of Notch on the cell surface or by observing or measuring Notch cleavage products that are indicative of Notch activation. The present invention is also directed to methods for detecting a molecule that modulates Notch activation by observing or measuring a change in the amount of Notch expressed on the cell surface or a change in the amount or pattern of Notch cleavage products. The present invention is also directed to a substantially purified activated heterodimeric form of Notch and components thereof and pharmaceutical compositions and kits thereof. The present invention is based, at least in part, on the discovery that Notch in its active form, i.e., the form that mediates signal transduction and that binds Notch ligands such as Delta, is a heterodimer of an about 180 kDa subunit (NEC) and an about 110 kDa subunit (NTM), which are tethered together through a reducing agent-sensitive linkage.

    摘要翻译： 本发明涉及通过观察或测量Notch在细胞表面上的外观或通过观察或测量Notch切割产物来表征Notch活化来检测或测量Notch活化的方法。 本发明还涉及通过观察或测量在细胞表面表达的Notch量的变化或Notch切割产物的量或图案的变化来检测调节Notch活化的分子的方法。 本发明还涉及基本上纯化的Notch及其组分的活化异二聚体形式及其药物组合物和试剂盒。 本发明至少部分地基于以下发现：Notch以其活性形式即介导信号转导并且结合Notch配体如Delta的形式是约180kDa亚基（NEC）的异源二聚体的发现， 和约110kDa亚基（NTM），其通过还原剂敏感性连接物连接在一起。

    Human Notch and Delta binding domains in toporythmic proteins, and methods based thereon
    28.
    发明授权
    Human Notch and Delta binding domains in toporythmic proteins, and methods based thereon 失效
    拓扑学蛋白质中的人类Notch和Delta结合结构域，以及基于此的方法

    公开(公告)号：US5648464A

    公开(公告)日：1997-07-15

    申请号：US264534

    申请日：1994-06-23

    申请人： Spyridon Artavanis-Tsakonas ,  Richard Grant Fehon ,  Ilaria Rebay ,  Christine Marie Blaumueller

    发明人： Spyridon Artavanis-Tsakonas ,  Richard Grant Fehon ,  Ilaria Rebay ,  Christine Marie Blaumueller

    IPC分类号： A61K38/00 ,  C07K14/705 ,  C07K16/18 ,  C07K14/435

    CPC分类号： C07K16/18 ,  C07K14/705 ,  A61K38/00 ,  C07K2319/00 ,  Y10S530/839

    摘要： The present invention relates to nucleotide sequences of the human Notch and Delta genes, and amino acid sequences of their encoded proteins, as well as fragments thereof containing an antigenic determinant or which are functionally active. The invention is also directed to fragments (termed herein "adhesive fragments"), and the sequences thereof, of the proteins ("toporythmic proteins") encoded by toporythmic genes which mediate homotypic or heterotypic binding to toporythmic proteins. Toporythmic genes, as used herein, refers to the genes Notch, Delta, and Serrate, as well as other members of the Delta/Serrate family which may be identified, e.g., by the methods described herein. Analogs and derivatives of the adhesive fragments which retain binding activity are also provided. Antibodies to human Notch and to adhesive fragments are additionally provided. In specific embodiments, the adhesive fragment of Notch is that fragment comprising the Notch sequence most homologous to Drosophila Notch EGF-like repeats 11 and 12; the adhesive fragment of Delta mediating heterotypic binding is that fragment comprising the sequence most homologous to Drosophila Delta amino acids 1-230; the adhesive fragment of Delta mediating homotypic binding is that fragment comprising the sequence most homologous to Drosophila Delta amino acids 32-230; and the adhesive fragment of Serrate is that fragment comprising the sequence most homologous to Drosophila Serrate amino acids 85-283.

    摘要翻译： 本发明涉及人Notch和Delta基因的核苷酸序列及其编码蛋白质的氨基酸序列，以及其含有抗原决定簇或其功能活性的片段。 本发明还涉及由介导与拓扑蛋白质的同型或异型结合的拓扑学基因编码的蛋白质（“拓扑蛋白”）的片段（称为“粘合片段”）及其序列。 如本文所用的拓扑学基因是指Notch，Delta和Serrate基因以及Delta / Serrate家族的其他成员，例如通过本文所述的方法鉴定。 还提供了保留结合活性的粘合剂片段的类似物和衍生物。 另外提供人类Notch和粘合剂片段的抗体。 在具体实施方案中，Notch的粘合片段是包含与果蝇Notch EGF样重复序列11和12最相似的Notch序列的片段; Delta介导异型结合的粘合片段是包含与果蝇Delta氨基酸1-230最相似序列的片段; Delta介导同型结合的粘合片段是包含与果蝇三角洲氨基酸32-230最相似的序列的片段; 并且Serrate的粘合片段是包含与果糖果丝氨酸85-283最相似序列的片段。

    Activated amino- and carboxy-terminal forms of Notch
    30.
    发明授权
    Activated amino- and carboxy-terminal forms of Notch 失效
    Notch的活性氨基和羧基末端形式

    公开(公告)号：US08222213B2

    公开(公告)日：2012-07-17

    申请号：US12789148

    申请日：2010-05-27

    申请人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    发明人： Spyridon Artavanis-Tsakonas ,  Huilin Qi ,  Matthew D. Rand

    IPC分类号： A61K38/00 ,  G01N33/567 ,  C07K1/00

    CPC分类号： G01N33/5032 ,  C07K14/705 ,  G01N33/68 ,  G01N2500/10

    摘要： The present invention is directed to methods for detecting or measuring Notch activation by observing or measuring the appearance of Notch on the cell surface or by observing or measuring Notch cleavage products that are indicative of Notch activation. The present invention is also directed to methods for detecting a molecule that modulates Notch activation by observing or measuring a change in the amount of Notch expressed on the cell surface or a change in the amount or pattern of Notch cleavage products. The present invention is also directed to a substantially purified activated heterodimeric form of Notch and components thereof and pharmaceutical compositions and kits thereof. The present invention is based, at least in part, on the discovery that Notch in its active form, i.e., the form that mediates signal transduction and that binds Notch ligands such as Delta, is a heterodimer of an about 180 kDa subunit (NEC) and an about 110 kDa subunit (NTM), which are tethered together through a reducing agent-sensitive linkage, in particular, a non-covalent, metal ion-dependent linkage.

    摘要翻译： 本发明涉及通过观察或测量Notch在细胞表面上的外观或通过观察或测量Notch切割产物来表征Notch活化来检测或测量Notch活化的方法。 本发明还涉及通过观察或测量在细胞表面表达的Notch量的变化或Notch切割产物的量或图案的变化来检测调节Notch活化的分子的方法。 本发明还涉及基本上纯化的Notch及其组分的活化异二聚体形式及其药物组合物和试剂盒。 本发明至少部分地基于以下发现：Notch以其活性形式即介导信号转导并且结合Notch配体如Delta的形式是约180kDa亚基（NEC）的异源二聚体的发现， 和约110kDa的亚基（NTM），其通过还原剂敏感性连接键连在一起，特别是非共价金属离子依赖性连接。