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1. 发明申请

US20130295643A1 NON-CYTOTOXIC PROTEIN CONJUGATES 有权
标题翻译：非细胞毒素蛋白结合
公开(公告)号：US20130295643A1
公开(公告)日：2013-11-07
申请号：US13944427
申请日：2013-07-17
申请人： Allergan Inc. , Syntaxin Ltd.
发明人： Keith FOSTER , John CHADDOCK , Charles PENN , Kei Roger AOKI , Joseph FRANCIS , Lance STEWARD
IPC分类号： C12N9/96
CPC分类号： C12N9/96 , A61K38/482 , A61K38/4893 , A61K47/48246 , A61K47/64 , C07K14/665 , C07K2319/00
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 dynorphin 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）强啡肽靶向剂量（TM），其中所述TM是感受伤害感觉传入细胞上存在的受体的激动剂，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。

2. 发明申请

US20140294797A1 NON-CYTOTOXIC PROTEIN CONJUGATES 有权
标题翻译：非细胞毒素蛋白结合
公开(公告)号：US20140294797A1
公开(公告)日：2014-10-02
申请号：US14300746
申请日：2014-06-10
申请人： Syntaxin Ltd. , Allergan Inc.
发明人： Keith FOSTER , John CHADDOCK , Charles PENN , Kei Roger AOKI , Joseph FRANCIS , Lance STEWARD
IPC分类号： A61K47/48 , A61K38/22 , A61K38/48
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。

3. 发明申请

US20130189238A1 FUSION PROTEINS 有权
标题翻译：融合蛋白
公开(公告)号：US20130189238A1
公开(公告)日：2013-07-25
申请号：US13774587
申请日：2013-02-22
申请人： Syntaxin Ltd. , Allergan Inc.
发明人： Keith FOSTER , John CHADDOCK , Philip MARKS , Patrick STANCOMBE , Kei Roger AOKI , Joseph FRANCIS , Lance STEWARD
IPC分类号： C12N9/96
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.
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。

4. 发明申请

US20190309277A1 FUSION PROTEINS AND METHODS FOR TREATING, PREVENTING OR AMELIORATING PAIN 审中-公开
公开(公告)号：US20190309277A1
公开(公告)日：2019-10-10
申请号：US16416435
申请日：2019-05-20
申请人： IPSEN BIOINNOVATION LIMITED , ALLERGAN, INC.
发明人： Peter JAMES , Keith FOSTER , John CHADDOCK , Roger AOKI , Lance STEWARD
IPC分类号： C12N9/52 , C12N15/62 , A61K47/65 , A61K47/64 , C07K14/575
摘要： A single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, which protease is capable of cleaving a protein of the exocytic fusion apparatus of a nociceptive sensory afferent (eg clostridial neurotoxin L-chain or IgA protease); a galanin 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 (eg GALR1, GALR2, or GALR3 receptor); 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 and the galanin Targeting Moiety; a translocation domain that is capable of translocating the protease from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent (eg HN domain of clostridial neurotoxin); a first spacer located between the non-cytotoxic protease and the protease cleavage site, wherein said first spacer comprises an amino acid sequence of from 4 to 25 amino acid residues; and a second spacer located between the galanin Targeting Moiety and the translocation domain, wherein said second spacer comprises an amino acid sequence of from 4 to 35 amino acid residues. Nucleic acid sequences encoding the polypeptide fusion proteins, methods of preparing same and uses thereof are also described (eg of treating, preventing or ameliorating pain).

5. 发明申请

US20170327810A1 FUSION PROTEINS AND METHODS FOR TREATING, PREVENTING OR AMELIORATING PAIN 审中-公开
公开(公告)号：US20170327810A1
公开(公告)日：2017-11-16
申请号：US15661433
申请日：2017-07-27
申请人： IPSEN BIOINNOVATION LIMITED , Allergan, Inc.
发明人： Peter JAMES , Keith FOSTER , John CHADDOCK , Roger Kei AOKI , Lance STEWARD , Joseph FRANCIS
IPC分类号： C12N9/52 , C07K14/575
CPC分类号： C12N9/52 , A61K38/00 , A61K47/64 , A61K47/65 , C07K14/575 , C07K2319/01 , C07K2319/50 , C07K2319/55 , C07K2319/74 , C12N15/625 , C12Y304/21072 , C12Y304/24013 , C12Y304/24068 , C12Y304/24069
摘要： A single chain polypeptide fusion protein, comprising: a non-cytotoxic protease capable of cleaving a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a galanin targeting moiety; a protease cleavage site at which site the fusion protein is cleavable by a protease; a translocation domain capable of translocating the protease from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent; a first spacer located between the non-cytotoxic protease and the protease cleavage site; and a second spacer located between the galanin targeting moiety and the translocation domain.

6. 发明申请

US20160369257A1 NON-CYTOTOXIC PROTEIN CONJUGATES 审中-公开
标题翻译：非细胞毒素蛋白结合
公开(公告)号：US20160369257A1
公开(公告)日：2016-12-22
申请号：US15258282
申请日：2016-09-07
申请人： Ipsen Bioinnovation Ltd. , Allergan Inc.
发明人： Keith FOSTER , John CHADDOCK , Charles PENN , Kei Roger AOKI , Joseph FRANCIS , Lance STEWARD
IPC分类号： C12N9/64 , C12N9/96 , C07K14/665 , A61K47/48 , A61K38/48
CPC分类号： C12N9/6432 , A61K38/00 , A61K38/22 , A61K38/48 , 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 ，β-内啡肽，缓激肽，物质P，强啡肽和/或伤害感受肽。

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