公开(公告)号：US07887810B2

公开(公告)日：2011-02-15

申请号：US11819650

申请日：2007-06-28

Applicant: Keith Alan Foster ,  Michael John Duggan ,  Clifford Charles Shone

Inventor： Keith Alan Foster ,  Michael John Duggan ,  Clifford Charles Shone

IPC: A61K38/16 ,  C07K19/00 ,  C07K14/33 ,  C07K16/46

CPC classification number: C07K14/48 ,  A61K38/4886 ,  A61K38/4893 ,  A61K47/62 ,  C07K14/33 ,  C07K2319/00 ,  Y10S424/832

Abstract: This invention describes a novel agent for the targeted control of a mammalian cell activity, in particular the agent is used to control the interaction of particular cell types with their external environment. The agent has applications as a pharmaceutical for the treatment of a variety of disorders. An agent according to the invention comprises three Domains B, T and E linked together in the following manner: Domain B-Domain T-Domain E where Domain B is the Binding Domain which binds the agent to a Binding Site on the cell which undergoes endocytosis to produce an endosome, Domain T is the Translocation Domain which translocates the agent (with or without the Binding Site) from within the endosome across the endosomal membrane into the cytosol of the cell, Domain E is the Effector Domain which inhibits the ability of the Recyclable Membrane Vesicles to transport the Integral Membrane Proteins to the surface of the cell.

公开(公告)号：US07658933B2

公开(公告)日：2010-02-09

申请号：US11829118

申请日：2007-07-27

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

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

IPC: A61K39/08 ,  C07K14/00 ,  C07H21/04

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

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US09139635B2

公开(公告)日：2015-09-22

申请号：US13072865

申请日：2011-03-28

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

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

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

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

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US08940870B2

公开(公告)日：2015-01-27

申请号：US13774587

申请日：2013-02-22

Applicant: Syntaxin Ltd. ,  Allergan Inc.

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

IPC: C07K14/00 ,  C12N9/96 ,  A61K47/48 ,  C12N9/50 ,  A61K38/00

CPC classification number: C12N9/96 ,  A61K38/00 ,  A61K47/64 ,  C07K2319/01 ,  C07K2319/33 ,  C07K2319/50 ,  C12N9/50

Abstract: 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.

Abstract translation: 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强啡肽靶向部位，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; 蛋白酶切割位点位于融合蛋白可被蛋白酶切割的蛋白酶切割位点，其中蛋白酶切割位点位于非细胞毒性蛋白酶或其片段与强啡肽靶向部位之间; 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：US08603779B2

公开(公告)日：2013-12-10

申请号：US13343892

申请日：2012-01-05

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

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

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

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

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US08399400B2

公开(公告)日：2013-03-19

申请号：US12862948

申请日：2010-08-25

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

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

IPC: C07K14/00 ,  C07H21/02

CPC classification number: C12N9/96 ,  A61K38/00 ,  A61K47/64 ,  C07K2319/01 ,  C07K2319/33 ,  C07K2319/50 ,  C12N9/50

Abstract: 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：US07727538B2

公开(公告)日：2010-06-01

申请号：US11518213

申请日：2006-09-11

Applicant: Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock

Inventor： Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock

IPC: A61K39/68 ,  A61K39/00 ,  C07K14/00

CPC classification number: A61K38/4886 ,  A61K47/62 ,  C07K14/33 ,  C07K2319/33

Abstract: A method of treating mucus hypersecretion, the causative factor in chronic obstructive pulmonary disease (COPD), asthma and other clinical conditions involving COPD, comprises administering a compound that inhibits exocytosis in mucus secreting cells or neurones that control or direct mucus secretion. Also described is a compound, for use in the treatment of hypersecretion of mucus, which inhibits mucus secretion by inhibiting mucus secretion by mucus secreting cells, and/or inhibiting neurotransmitter release from neuronal cells controlling or directing mucus secretion.

Abstract translation: 一种治疗粘液分泌过多症的方法，慢性阻塞性肺疾病（COPD），哮喘和其它涉及COPD的临床病症的因素包括给予抑制或分泌粘液分泌细胞或神经元中的胞吐作用的化合物。 还描述了一种用于治疗粘液分泌过高的化合物，其通过抑制由分泌分泌细菌的粘液分泌而抑制粘液分泌，和/或抑制神经递质从控制或引导粘液分泌的神经元细胞释放。

公开(公告)号：US07659092B2

公开(公告)日：2010-02-09

申请号：US11834311

申请日：2007-08-06

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

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

IPC: C12P21/06 ,  C07K14/00

CPC classification number: C12N15/62 ,  C07K14/575 ,  C07K2319/06 ,  G01N33/6848

Abstract: 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.

Abstract translation: 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：US07452543B2

公开(公告)日：2008-11-18

申请号：US11257500

申请日：2005-10-25

Applicant: John Andrew Chaddock ,  Philip Marks ,  Michael John Duggan

Inventor： John Andrew Chaddock ,  Philip Marks ,  Michael John Duggan

IPC: A61K39/68 ,  C07K14/00

CPC classification number: A61K47/6415 ,  A61K38/00

Abstract: 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 fibers. 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.

Abstract translation: 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。