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。

公开(公告)号：US09006395B2

公开(公告)日：2015-04-14

申请号：US12900214

申请日：2010-10-07

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

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

IPC分类号： A61K38/00 ,  A61K39/08 ,  A61K47/48 ,  C07K14/33 ,  C07K16/12 ,  C12N9/52 ,  C12N15/62 ,  A61K39/00

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

摘要： A single polypeptide is provided which comprises first and second domains. The first domain enables the polypeptide to cleave one or more vesicle or plasma-membrane associated proteins essential to exocytosis, and the second domain enables the polypeptide to be translocated into a target cell or increases the solubility of the polypeptide, or both. The polypeptide thus combines useful properties of a clostridial toxin, such as a botulinum or tetanus toxin, without the toxicity associated with the natural molecule. The polypeptide can also contain a third domain that targets it to a specific cell, rendering the polypeptide useful in inhibition of exocytosis in target cells. Fusion proteins comprising the polypeptide, nucleic acids encoding the polypeptide and methods of making the polypeptide are also provided. Controlled activation of the polypeptide, is possible and the polypeptide can be incorporated into vaccines and toxin assays.

摘要翻译： 提供了包含第一和第二结构域的单个多肽。 第一结构域使多肽能够切割一种或多种与胞吐作用相关的囊泡或质膜相关的蛋白质，而第二结构域使多肽易位于靶细胞或增加多肽或两者的溶解度。 因此，该多肽结合梭菌毒素如肉毒杆菌或破伤风毒素的有用性质，而不与天然分子相关的毒性。 多肽还可以含有将其靶向特定细胞的第三结构域，使得多肽可用于抑制靶细胞中的胞吐作用。 还提供了包含多肽的融合蛋白，编码多肽的核酸和制备多肽的方法。 多肽的受控活化是可能的，并且多肽可以并入疫苗和毒素测定中。

公开(公告)号：US08790897B2

公开(公告)日：2014-07-29

申请号：US11806496

申请日：2007-05-31

申请人： Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock

发明人： Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock

IPC分类号： C07K14/00 ,  A61K38/00 ,  C12P21/00 ,  C07H21/04

CPC分类号： C07K14/33 ,  A61K38/4886 ,  A61K47/62 ,  C07K2319/33

摘要： The present invention relates to treatment of mucus hypersecretion, to compositions therefore and manufacture of those compositions. The present invention relates particularly, though not exclusively, to the treatment of chronic bronchitis in chronic obstructive pulmonary disease (COPD), asthma and other clinical conditions involving COPD.

摘要翻译： 本发明涉及治疗粘液分泌过多，因此涉及组合物和这些组合物的制造。 本发明特别涉及治疗慢性阻塞性肺疾病（COPD），哮喘和涉及COPD的其它临床病症中的慢性支气管炎。

公开(公告)号：US20110027256A1

公开(公告)日：2011-02-03

申请号：US12862948

申请日：2010-08-25

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 ,  C12N15/63

CPC分类号： C12N9/96 ,  A61K38/00 ,  A61K47/64 ,  C07K2319/01 ,  C07K2319/33 ,  C07K2319/50 ,  C12N9/50

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 dynorphin 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 dynorphin 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.

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。

公开(公告)号：US20070184048A1

公开(公告)日：2007-08-09

申请号：US10571515

申请日：2004-09-13

申请人： Keith Foster ,  John Chaddock ,  Charles Penn

发明人： Keith Foster ,  John Chaddock ,  Charles Penn

IPC分类号： A61K39/00 ,  G01N33/567 ,  A61K39/395

CPC分类号： C12N9/52 ,  A61K47/64 ,  A61K47/642

摘要： The present invention provides a method for designing a re-targeted toxin conjugate for use in treating a medical condition or disease. Also provided, is the use of said conjugates in the manufacture of a medicament for treating medical conditions or diseases. The conjugates include a Targeting Moiety, which directs the conjugate to a desired target cell, and are characterised by a Targeting Moiety that increases exocytic fusion in the target cell. The present invention also provides methods for identifying agonists suitable for use as Targeting Moieties, and methods for preparing conjugates comprising said Targeting Moieties, to re-target a toxin to a cell of therapeutic interest. In particular, the present invention describes a method for designing a toxin conjugate, and describes therapeutic applications of said conjugates to inhibit or reduce cellular processes. Even more particularly, the present invention describes a method for designing toxin conjugates based upon non-cytotoxic toxins able to inhibit exocytosis, such as clostridial neurotoxins, and describes therapeutic applications of said conjugates to inhibit or reduce exocytosis (for example secretion, or the delivery of proteins such as receptors, transporters, and membrane channels to the plasma membrane of a cell).

摘要翻译： 本发明提供了一种用于设计用于治疗医学病症或疾病的再靶向毒素缀合物的方法。 还提供了所述缀合物在制备用于治疗医学病症或疾病的药物中的用途。 缀合物包括将缀合物引导至期望的靶细胞的靶向部位，其特征在于靶细胞增加靶细胞中的胞外融合。 本发明还提供了用于鉴定适合用作靶向部分的激动剂的方法，以及用于制备包含所述靶向部分的缀合物的方法，以将毒素重新靶向治疗感兴趣的细胞。 特别地，本发明描述了一种用于设计毒素缀合物的方法，并且描述了所述缀合物抑制或减少细胞过程的治疗应用。 甚至更具体地，本发明描述了一种基于能够抑制胞吐作用的非细胞毒素毒素（例如梭菌神经毒素）设计毒素缀合物的方法，并且描述了所述缀合物抑制或减少胞吐作用（例如分泌或递送）的治疗应用 的蛋白质，如受体，转运蛋白和膜通道的细胞质膜）。

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。

公开(公告)号：US08778634B2

公开(公告)日：2014-07-15

申请号：US13418453

申请日：2012-03-13

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： A61K39/08 ,  C12P21/04 ,  C07K14/00

CPC分类号： C12N9/6432 ,  A61K38/00 ,  A61K38/22 ,  A61K38/48 ,  A61K47/48246 ,  A61K47/48338 ,  A61K47/48361 ,  A61K47/64 ,  A61K47/65 ,  A61K47/67 ,  C07K14/665 ,  C07K2319/00 ,  C07K2319/01 ,  C07K2319/21 ,  C07K2319/55 ,  C12N9/96 ,  C12N15/62 ,  C12Y304/00 ,  C12Y304/21006

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 wherein the Targeting Moiety is selected from the group consisting of BAM, β-endorphin, bradykinin, substance P, dynorphin and/or nociceptin.

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，其中易位域将内体内的蛋白酶或蛋白酶片段转移穿过内体膜，并转移到伤害性感觉传入细胞的胞质溶胶中，其中靶向部分选自BAM ，内啡肽，缓激肽，物质P，强啡肽和/或伤害感受肽。

公开(公告)号：US20120207735A1

公开(公告)日：2012-08-16

申请号：US13418453

申请日：2012-03-13

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 ,  A61P29/00 ,  C12N9/96 ,  C12N15/62

CPC分类号： C12N9/6432 ,  A61K38/00 ,  A61K38/22 ,  A61K38/48 ,  A61K47/48246 ,  A61K47/48338 ,  A61K47/48361 ,  A61K47/64 ,  A61K47/65 ,  A61K47/67 ,  C07K14/665 ,  C07K2319/00 ,  C07K2319/01 ,  C07K2319/21 ,  C07K2319/55 ,  C12N9/96 ,  C12N15/62 ,  C12Y304/00 ,  C12Y304/21006

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 to 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 wherein the Targeting Moiety is selected from the group consisting of BAM, β-endorphin, bradykinin, substance P, dynorphin and/or nociceptin.

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将伤感融合蛋白质切割成伤害性感觉传入细胞的装置; 易位结构域，其中易位域将内体内的蛋白酶或蛋白酶片段转移穿过内体膜，并转移到伤害性感觉传入细胞的胞质溶胶中，其中靶向部分选自BAM ，内啡肽，缓激肽，物质P，强啡肽和/或伤害感受肽。

公开(公告)号：US08187834B2

公开(公告)日：2012-05-29

申请号：US11791979

申请日：2005-12-01

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： A61K39/08 ,  C07K14/00 ,  C07H21/04

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。