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    Non-cytotoxic protein conjugates
    1.
    发明授权
    Non-cytotoxic protein conjugates 有权
    非细胞毒性蛋白偶联物

    公开(公告)号：US09139635B2

    公开(公告)日：2015-09-22

    申请号：US13072865

    申请日：2011-03-28

    申请人： Keith Foster ,  John Chaddock ,  Charles Penn ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    发明人： Keith Foster ,  John Chaddock ,  Charles Penn ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    IPC分类号： A61K38/48 ,  C07K14/575 ,  A61K31/711 ,  A61K47/48 ,  C07K14/33 ,  C12N9/64 ,  C12N15/62

    CPC分类号： C07K14/575 ,  A61K31/711 ,  A61K38/4893 ,  A61K47/64 ,  A61K47/6415 ,  C07K14/33 ,  C07K2319/00 ,  C07K2319/01 ,  C07K2319/33 ,  C12N9/6489 ,  C12N15/62 ,  C12Y304/24069

    摘要： The present invention is directed to non-cytotoxic protein conjugates for inhibition or reduction of exocytic fusion in a nociceptive sensory afferent cell. The protein conjugates comprise: (i) a Targeting Moiety (TM), wherein the TM is an agonist of a receptor present on a nociceptive sensory afferent cell, and wherein the receptor undergoes endocytosis to be incorporated into an endosome within the nociceptive sensory afferent cell; (ii) a non-cytotoxic protease or a fragment thereof, wherein the protease or protease fragment is capable of cleaving a protein of the exocytic fusion apparatus of the nociceptive sensory afferent cell; and (iii) a Translocation Domain, wherein the Translocation Domain translocates the protease or protease fragment from within the endosome, across the endosomal membrane, and into the cytosol of the nociceptive sensory afferent cell. Nucleic acid sequences encoding the protein conjugates, methods of preparing same and uses thereof are also described.

    摘要翻译： 本发明涉及用于抑制或减少伤害性感觉传入细胞中的胞外融合的非细胞毒性蛋白质缀合物。 所述蛋白质缀合物包含：（i）靶向部分（TM），其中所述TM是存在于伤害性感觉传入细胞上的受体的激动剂，并且其中所述受体经受内吞作用以掺入伤害性感觉传入细胞内的内体 ; （ii）非细胞毒性蛋白酶或其片段，其中所述蛋白酶或蛋白酶片段能够切割伤害性感觉传入细胞的胞外融合装置的蛋白质; 易位结构域（Translocation Domain），其中易位域将位于内体内的蛋白酶或蛋白酶片段穿过内体膜并转移到伤害性感觉传入细胞的胞质溶胶中。 还描述了编码蛋白质缀合物的核酸序列，其制备方法及其用途。

    FUSION PROTEINS
    2.
    发明申请
    FUSION PROTEINS 审中-公开
    融合蛋白

    公开(公告)号：US20140056870A1

    公开(公告)日：2014-02-27

    申请号：US13595927

    申请日：2012-08-27

    申请人： Peter James ,  Keith Foster ,  John Chaddock ,  Kei Roger Aoki ,  Lance Steward ,  Joseph Francis

    发明人： Peter James ,  Keith Foster ,  John Chaddock ,  Kei Roger Aoki ,  Lance Steward ,  Joseph Francis

    IPC分类号： C12N9/48 ,  A61P29/00 ,  A61K38/48 ,  C12N15/57 ,  C12N15/63

    摘要： A single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, which cleaves a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a galanin Targeting Moiety that binds a Binding Site on the nociceptive sensory afferent, which can undergo endocytosis to be incorporated into an endosome; a protease cleavage site where the fusion protein is cleavable by a protease located between the non-cytotoxic protease and the galanin Targeting Moiety; a translocation domain that translocates the protease from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent; a first spacer from 4 to 25 amino acids between the non-cytotoxic protease and protease cleavage site; and a second spacer comprising from 4 to 35 residues between the galanin Targeting Moiety and translocation domain. Nucleic acid sequences encoding the polypeptide fusion proteins, methods of preparing same and uses thereof are also described.

    摘要翻译： 一种单链多肽融合蛋白，其包含：非细胞毒性蛋白酶，其切割伤害性感觉传入的胞外融合装置的蛋白质; 将甘露聚糖靶向部位结合到伤害性感觉传入物上的结合位点，其可能经历内吞作用以掺入内体; 蛋白酶切割位点，其中融合蛋白可被位于非细胞毒性蛋白酶和甘丙肽靶向部位之间的蛋白酶切割; 一个易位结构域，其从内体内转移蛋白酶，穿过内体膜并进入伤害性感觉传入体的细胞溶质; 非细胞毒性蛋白酶和蛋白酶切割位点之间的4至25个氨基酸的第一个间隔区; 以及在甘露糖靶向部位和易位结构域之间包含4至35个残基的第二间隔物。 还描述了编码多肽融合蛋白的核酸序列，其制备方法及其用途。

    Non-cytotoxic protein conjugates
    3.
    发明授权
    Non-cytotoxic protein conjugates 有权
    非细胞毒性蛋白偶联物

    公开(公告)号：US08603779B2

    公开(公告)日：2013-12-10

    申请号：US13343892

    申请日：2012-01-05

    申请人： Keith Foster ,  John Chaddock ,  Charles Penn ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    发明人： Keith Foster ,  John Chaddock ,  Charles Penn ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    IPC分类号： C07K14/00 ,  A61K38/16 ,  C12P21/04 ,  C12P21/06

    CPC分类号： A61K38/4893 ,  A61K38/4886 ,  C07K14/575 ,  C07K2319/00 ,  C07K2319/01 ,  C12N9/52 ,  C12Y304/21072

    摘要： The present invention is directed to non-cytotoxic protein conjugates for inhibition or reduction of exocytic fusion in a nociceptive sensory afferent cell. The protein conjugates comprise: (i) a galanin Targeting Moiety (TM), wherein the TM is an agonist of a receptor present on a nociceptive sensory afferent cell, and wherein the receptor undergoes endocytosis to be incorporated into an endosome within the nociceptive sensory afferent cell; (ii) a non-cytotoxic protease or a fragment thereof, wherein the protease or protease fragment is capable of cleaving a protein of the exocytic fusion apparatus of the nociceptive sensory afferent cell; and (iii) a Translocation Domain, wherein the Translocation Domain translocates the protease or protease fragment from within the endosome, across the endosomal membrane, and into the cytosol of the nociceptive sensory afferent cell. Nucleic acid sequences encoding the protein conjugates, methods of preparing same and uses thereof are is also described.

    摘要翻译： 本发明涉及用于抑制或减少伤害性感觉传入细胞中的胞外融合的非细胞毒性蛋白质缀合物。 所述蛋白质缀合物包括：（i）甘丙肽靶向部分（TM），其中所述TM是存在于伤害性感觉传入细胞上的受体的激动剂，并且其中所述受体经受内吞作用以掺入伤害性感觉传入物内的内体 细胞; （ii）非细胞毒性蛋白酶或其片段，其中所述蛋白酶或蛋白酶片段能够切割伤害性感觉传入细胞的胞外融合装置的蛋白质; 易位结构域（Translocation Domain），其中易位域将位于内体内的蛋白酶或蛋白酶片段穿过内体膜并转移到伤害性感觉传入细胞的胞质溶胶中。 还描述了编码蛋白质缀合物的核酸序列，其制备方法及其用途。

    Fusion proteins
    5.
    发明授权
    Fusion proteins 有权
    融合蛋白

    公开(公告)号：US07659092B2

    公开(公告)日：2010-02-09

    申请号：US11834311

    申请日：2007-08-06

    申请人： Keith Foster ,  John Chaddock ,  Philip Marks ,  Patrick Stancombe ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    发明人： Keith Foster ,  John Chaddock ,  Philip Marks ,  Patrick Stancombe ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    IPC分类号： C12P21/06 ,  C07K14/00

    CPC分类号： C12N15/62 ,  C07K14/575 ,  C07K2319/06 ,  G01N33/6848

    摘要： A single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, or a fragment thereof, which protease or protease fragment is capable of cleaving a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a Targeting Moiety that is capable of binding to a Binding Site on the nociceptive sensory afferent, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the nociceptive sensory afferent; a protease cleavage site at which site the fusion protein is cleavable by a protease, wherein the protease cleavage site is located between the non-cytotoxic protease or fragment thereof and the Targeting Moiety; and a translocation domain that is capable of translocating the protease or protease fragment from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent. Nucleic acid sequences encoding the polypeptide fusion proteins, methods of preparing same and uses thereof are also described.

    摘要翻译： 一种单链多肽融合蛋白，其包含：非细胞毒性蛋白酶或其片段，所述蛋白酶或蛋白酶片段能够切割伤害性感觉传入的胞外融合装置的蛋白质; 能够结合伤害性感觉传入的结合位点的靶向部位，该结合位点能够经历内吞作用以掺入伤害性感觉传入内的内体; 蛋白酶切割位点，其中融合蛋白可被蛋白酶切割，其中蛋白酶切割位点位于非细胞毒性蛋白酶或其片段与靶向部位之间; 以及易位区域，其能够将位于内体内的蛋白酶或蛋白酶片段穿过内体膜并转移到伤害性感觉传入物的胞质溶胶中。 还描述了编码多肽融合蛋白的核酸序列，其制备方法及其用途。

    Fusion Proteins
    6.
    发明申请
    Fusion Proteins 有权
    融合蛋白

    公开(公告)号：US20090035822A1

    公开(公告)日：2009-02-05

    申请号：US11834311

    申请日：2007-08-06

    申请人： Keith Foster ,  John Chaddock ,  Philip Marks ,  Patrick Stancombe ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    发明人： Keith Foster ,  John Chaddock ,  Philip Marks ,  Patrick Stancombe ,  Kei Roger Aoki ,  Joseph Francis ,  Lance Steward

    IPC分类号： C12P21/04 ,  C07K14/00 ,  C12N15/11 ,  C12N15/00

    CPC分类号： C12N15/62 ,  C07K14/575 ,  C07K2319/06 ,  G01N33/6848

    摘要： A single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, or a fragment thereof, which protease or protease fragment is capable of cleaving a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a Targeting Moiety that is capable of binding to a Binding Site on the nociceptive sensory afferent, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the nociceptive sensory afferent; a protease cleavage site at which site the fusion protein is cleavable by a protease, wherein the protease cleavage site is located between the non-cytotoxic protease or fragment thereof and the Targeting Moiety; and a translocation domain that is capable of translocating the protease or protease fragment from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent. Nucleic acid sequences encoding the polypeptide fusion proteins, methods of preparing same and uses thereof are also described.

    摘要翻译： 一种单链多肽融合蛋白，其包含：非细胞毒性蛋白酶或其片段，所述蛋白酶或蛋白酶片段能够切割伤害性感觉传入的胞外融合装置的蛋白质; 能够结合伤害性感觉传入的结合位点的靶向部位，该结合位点能够经历内吞作用以掺入伤害性感觉传入内的内体; 蛋白酶切割位点，其中融合蛋白可被蛋白酶切割，其中蛋白酶切割位点位于非细胞毒性蛋白酶或其片段与靶向部位之间; 以及易位区域，其能够将位于内体内的蛋白酶或蛋白酶片段穿过内体膜并转移到伤害性感觉传入物的胞质溶胶中。 还描述了编码多肽融合蛋白的核酸序列，其制备方法及其用途。

    FLUORESCENCE POLARIZATION ASSAYS FOR DETERMINING CLOSTRIDIAL TOXIN ACTIVITY
    9.
    发明申请
    FLUORESCENCE POLARIZATION ASSAYS FOR DETERMINING CLOSTRIDIAL TOXIN ACTIVITY 有权
    用于测定离子毒素活性的荧光偏振测定

    公开(公告)号：US20080293084A1

    公开(公告)日：2008-11-27

    申请号：US12125235

    申请日：2008-05-22

    申请人： Dudley J. Williams ,  Marcella Gilmore ,  Lance Steward ,  Marc Verhagen ,  Kei Roger Aoki

    发明人： Dudley J. Williams ,  Marcella Gilmore ,  Lance Steward ,  Marc Verhagen ,  Kei Roger Aoki

    IPC分类号： C12Q1/37

    CPC分类号： G01N33/542 ,  C12N9/52 ,  C12Q1/37 ,  G01N2333/33

    摘要： The present invention provides a method of determining the presence or activity of a clostridial toxin by (a) treating with a sample, under conditions suitable for clostridial toxin protease activity, a clostridial toxin substrate which includes a fluorophore; a bulking group; and a clostridial toxin recognition sequence containing a cleavage site that intervenes between the fluorophore and the bulking group; (b) exciting the fluorophore with plane polarized light; and (c) determining fluorescence polarization of the treated substrate relative to a control substrate, where a change in fluorescence polarization of the treated substrate as compared to fluorescence polarization of the control substrate is indicative of the presence or activity of the clostridial toxin.

    摘要翻译： 本发明提供一种通过（a）在适合于梭菌毒素蛋白酶活性的条件下用样品处理包括荧光团的梭菌毒素底物来确定梭菌毒素的存在或活性的方法; 一个胖胖的小组 和含有插入在荧光团和膨化基团之间的切割位点的梭菌毒素识别序列; （b）用平面偏振光激发荧光团; 和（c）确定经处理的底物相对于对照底物的荧光偏振，其中与对照底物的荧光偏振相比，经处理的底物的荧光偏振的变化指示梭菌毒素的存在或活性。