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    Conjugates of galactose-binding lectins and clostridial neurotoxins as analgesics
    1.
    发明申请
    Conjugates of galactose-binding lectins and clostridial neurotoxins as analgesics 失效
    与半乳糖结合的凝集素和梭菌神经毒素作为镇痛药的结合物

    公开(公告)号：US20060121056A1

    公开(公告)日：2006-06-08

    申请号：US11257500

    申请日：2005-10-25

    申请人： John Chaddock ,  Philip Marks ,  Michael Duggan

    发明人： John Chaddock ,  Philip Marks ,  Michael Duggan

    IPC分类号： A61K39/08 ,  C07K14/415

    CPC分类号： A61K47/6415 ,  A61K38/00

    摘要： A class of novel agents that are able to modify nociceptive afferent function is provided. The agents may inhibit the release of neurotransmitters from discrete populations of neurones and thereby reduce or preferably prevent the transmission of afferent pain signals from peripheral to central pain fibres. They comprise a galactose-binding lectin linked to a derivative of a clostridial neurotoxin. The derivative of the clostridial neurotoxin comprises the L-chain, or a fragment thereof, which includes the active proteolytic enzyme domain of the light (L) chain, linked to a molecule or domain with membrane translocating activity. The agents may be used in or as pharmaceuticals for the treatment of pain, particular chronic pain.

    摘要翻译： 提供了一类能够修改伤害感受传入功能的新型药剂。 这些试剂可以抑制神经递质从离散的神经元群中的释放，从而减少或优选地防止传入的疼痛信号从周围的中枢疼痛纤维的传播。 它们包含与梭菌神经毒素衍生物连接的半乳​​糖结合凝集素。 梭菌神经毒素的衍生物包括L链或其片段，其包括与具有膜易位活性的分子或结构域连接的轻链（L）链的活性蛋白水解酶结构域。 这些药剂可以用于或作为药物用于治疗疼痛，特别是慢性疼痛。

    Fusion proteins
    2.
    发明授权
    Fusion proteins 有权
    融合蛋白

    公开(公告)号：US09243301B2

    公开(公告)日：2016-01-26

    申请号：US13419381

    申请日：2012-03-13

    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： A61K38/00 ,  C12N9/52 ,  C12N15/62 ,  C07K14/665

    CPC分类号： C12Y304/24069 ,  A61K38/00 ,  A61K38/1709 ,  A61K38/482 ,  A61K38/4886 ,  A61K38/4893 ,  A61K47/6415 ,  A61K47/65 ,  C07K14/665 ,  C07K2319/055 ,  C07K2319/06 ,  C07K2319/50 ,  C12N9/52 ,  C12N15/62

    摘要： A single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, or a fragment thereof, which protease or protease fragment can cleave a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a Targeting Moiety that can bind to a Binding Site on the nociceptive sensory afferent, which Binding Site can undergo 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, which is located between the non-cytotoxic protease and the Targeting Moiety; and a translocation domain that can translocate the protease or protease fragment from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent; wherein the Targeting Moiety is BAM, β-endorphin, bradykinin, substance P, dynorphin and/or nociceptin. Nucleic acid sequences encoding the 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可以切割伤害性感觉传入的胞外融合装置的蛋白质; 可以结合伤害性感觉传入物上的结合位点的靶向物质，其结合位点可以进行内吞作用以掺入伤害性感觉传入体内的内体; 蛋白酶切割位点，位于融合蛋白可被位于非细胞毒性蛋白酶和靶向部位之间的蛋白酶切割; 以及易位区域，其可以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; 其中靶向部分是BAM，β-内啡肽，缓激肽，物质P，强啡肽和/或伤害感受肽。 还描述了编码融合蛋白的核酸序列，其制备方法及其用途。

    Fusion Proteins
    4.
    发明申请
    Fusion Proteins 有权
    融合蛋白

    公开(公告)号：US20100247509A1

    公开(公告)日：2010-09-30

    申请号：US11792210

    申请日：2005-12-01

    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： A61K38/48 ,  C07H21/04 ,  A61P29/00 ,  C12N9/48 ,  C12N15/74 ,  C12P21/00 ,  C12P21/02

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

    公开(公告)号：US08124405B2

    公开(公告)日：2012-02-28

    申请号：US11853517

    申请日：2007-09-11

    申请人： Keith Alan Foster ,  John Chaddock ,  Philip Marks ,  Patrick Stancombe ,  Lyndsey Durose

    发明人： Keith Alan Foster ,  John Chaddock ,  Philip Marks ,  Patrick Stancombe ,  Lyndsey Durose

    IPC分类号： C07K14/00 ,  C12N15/62 ,  C12N15/63

    CPC分类号： C12N9/50 ,  A61K38/00 ,  C07K14/33 ,  C07K2319/06 ,  C07K2319/50 ,  C12N15/62

    摘要： The invention provides 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 target cell; a Targeting Moiety that is capable of binding to a Binding Site on the target cell, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the target cell; 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 target cell.

    摘要翻译： 本发明提供了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靶细胞的胞外融合装置的蛋白质; 能够结合目标细胞上的结合位点的靶向物质，所述结合位点能够经历内吞作用以掺入靶细胞内的内体; 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; 以及能够将位于内体内的蛋白酶或蛋白酶片段穿过体内膜并进入靶细胞的胞质溶胶的易位结构域。

    Recombinant toxin fragments
    6.
    发明授权
    Recombinant toxin fragments 有权
    重组毒素片段

    公开(公告)号：US08012479B2

    公开(公告)日：2011-09-06

    申请号：US12399542

    申请日：2009-03-06

    申请人： Clifford Charles Shone ,  Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock ,  Philip Marks ,  J. Mark Sutton ,  Patrick Stancombe ,  Jonathan Wayne

    发明人： Clifford Charles Shone ,  Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock ,  Philip Marks ,  J. Mark Sutton ,  Patrick Stancombe ,  Jonathan Wayne

    IPC分类号： A61K39/00 ,  A61K39/38 ,  A61K39/08

    CPC分类号： C12N15/62 ,  A61K38/00 ,  A61K39/00 ,  A61K39/08 ,  A61K47/6415 ,  A61K47/646 ,  A61K2039/505 ,  A61K2039/53 ,  A61K2039/627 ,  C07K14/33 ,  C07K14/475 ,  C07K14/65 ,  C07K2319/00 ,  C07K2319/20 ,  C07K2319/23 ,  C07K2319/50 ,  C07K2319/55 ,  C07K2319/705 ,  C07K2319/75 ,  C12N9/52 ,  Y02A50/469 ,  Y10S530/825

    摘要： Antigenic compositions are provided comprising a single chain polypeptide comprising first and second domains, wherein said first domain is a clostridial neurotoxin light chain or a fragment or a variant thereof and is capable of cleaving one or more vesicle or plasma membrane associated proteins essential to exocytosis; and said second domain is a clostridial neurotoxin heavy chain HN portion or a fragment or a variant thereof, wherein said second domain is capable of (i) translocating the polypeptide into a cell or (ii) increasing the solubility of the polypeptide compared to the solubility of the first domain on its own or (iii) both translocating the polypeptide into a cell and increasing the solubility of the polypeptide compared to the solubility of the first domain on its own; and wherein the second domain lacks a functional C-terminal part of a clostridial neurotoxin heavy chain designated HC thereby rendering the polypeptide incapable of binding to cell surface receptors that are the natural cell surface receptors to which native clostridial neurotoxin binds. Antibodies that bind to the polypeptides, and compositions comprising these antibodies, are also provided, as are DNA vaccines comprising polynucleotides that encode these polypeptides.The antigenic and antibody compositions, and the DNA vaccine compositions, can be used in methods of immunising against, or treating, clostridial neurotoxin poisoning in a subject by administering to that subject a therapeutically effective amount of the composition.

    摘要翻译： 提供抗原组合物，其包含包含第一和第二结构域的单链多肽，其中所述第一结构域是梭菌神经毒素轻链或其片段或变体，并且能够切割一种或多种与胞吐作用必需的相关蛋白或质膜相关蛋白; 并且所述第二结构域是梭菌神经毒素重链HN部分或其片段或变体，其中所述第二结构域能够（i）将多肽转位到细胞中，或（ii）与溶解度相比增加多肽的溶解度 或（iii）将多肽转移到细胞中并且与第一结构域本身的溶解度相比增加多肽的溶解度; 并且其中所述第二结构域缺少称为HC的梭菌神经毒素重链的功能性C-末端部分，从而使所述多肽不能结合作为天然梭菌神经毒素结合的天然细胞表面受体的细胞表面受体。 还提供了结合多肽的抗体和包含这些抗体的组合物，DNA疫苗也包括编码这些多肽的多核苷酸。 抗原和抗体组合物和DNA疫苗组合物可用于通过向该受试者施用治疗有效量的组合物来免疫或治疗受试者的梭菌神经毒素中毒的方法。

    Fusion proteins
    9.
    发明授权
    Fusion proteins 有权
    融合蛋白

    公开(公告)号：US08399401B2

    公开(公告)日：2013-03-19

    申请号：US13239573

    申请日：2011-09-22

    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： C07K14/00 ,  C07H21/02

    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： 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; 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 acids encoding the 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; 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的易位结构域。 还描述了编码融合蛋白的核酸，其制备方法及其用途。

    FUSION PROTEINS
    10.
    发明申请
    FUSION PROTEINS 有权
    融合蛋白

    公开(公告)号：US20120230975A1

    公开(公告)日：2012-09-13

    申请号：US13419381

    申请日：2012-03-13

    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： A61K38/48 ,  C12N9/52 ,  A61P25/00 ,  C12N15/63 ,  A61P29/00 ,  C12N9/50 ,  C12N15/62

    CPC分类号： C12Y304/24069 ,  A61K38/00 ,  A61K38/1709 ,  A61K38/482 ,  A61K38/4886 ,  A61K38/4893 ,  A61K47/6415 ,  A61K47/65 ,  C07K14/665 ,  C07K2319/055 ,  C07K2319/06 ,  C07K2319/50 ,  C12N9/52 ,  C12N15/62

    摘要： A single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, or a fragment thereof, which protease or protease fragment can cleave a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a Targeting Moiety that can bind to a Binding Site on the nociceptive sensory afferent, which Binding Site can undergo 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, which is located between the non-cytotoxic protease and the Targeting Moiety; and a translocation domain that can translocate the protease or protease fragment from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent; wherein the Targeting Moiety is BAM, β-endorphin, bradykinin, substance P, dynorphin and/or nociceptin. Nucleic acid sequences encoding the 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可以切割伤害性感觉传入的胞外融合装置的蛋白质; 可以结合伤害性感觉传入物上的结合位点的靶向物质，该结合位点可以进行内吞作用以掺入伤害性感觉传入体内的内体; 蛋白酶切割位点，位于融合蛋白可被位于非细胞毒性蛋白酶和靶向部位之间的蛋白酶切割; 以及易位区域，其可以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; 其中靶向部分是BAM，β-内啡肽，缓激肽，物质P，强啡肽和/或伤害感受肽。 还描述了编码融合蛋白的核酸序列，其制备方法及其用途。