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1. 发明申请

WO2013068476A1 NEUROTOXINS EXHIBITING SHORTENED BIOLOGICAL ACTIVITY 审中-公开
标题翻译：神经毒素展示生物活性
公开(公告)号：WO2013068476A1
公开(公告)日：2013-05-16
申请号：PCT/EP2012/072158
申请日：2012-11-08
申请人： MERZ PHARMA GMBH & CO. KGAA , SCHMIDT, Michael , FREVERT, Jürgen , HOFMANN, Fred , GROER, Gerhard
发明人： SCHMIDT, Michael , FREVERT, Jürgen , HOFMANN, Fred , GROER, Gerhard
IPC分类号： C07K14/47 , C07K14/435 , C07K14/33 , C12N5/00 , A61K38/00
CPC分类号： C12N9/52 , A61K38/4893 , C07K14/4746 , C12Y304/24069
摘要： The present invention relates to the pharmaceutical field. Specifically, it contemplates a polynucleotide encoding a neurotoxin polypeptide exhibiting a reduced duration of the biological effect in a subject, wherein said polypeptide comprises at least one E3 ligase recognition motif in the light chain, wherein said E3 ligase recognition motif is preferably abinding motif for the E3 ligase MDM2. The invention further pertains to polypeptides encoded by the polynucleotide of the invention as well as polypeptides comprising one or more amino acid substitutions. Further encompassed by the present invention are vectors and host cells comprising the said polynucleotide, polypeptides encoded thereby and antibodies specifically binding to the polypeptides. Moreover, the invention relates to medicaments comprising said polynucleotides and polypeptides, as well as specific therapeutic applications thereof. Furthermore, the present invention contemplates methods for the manufacture of the polypeptides and medicaments.
摘要翻译：本发明涉及制药领域。具体地，其考虑了编码神经毒素多肽的多核苷酸，其在受试者中显示生物效应的持续时间减少，其中所述多肽在轻链中包含至少一个E3连接酶识别基序，其中所述E3连接酶识别基序优选为 E3连接酶MDM2。本发明还涉及由本发明的多核苷酸编码的多肽以及包含一个或多个氨基酸取代的多肽。本发明还包括载体和宿主细胞，其包含所述多核苷酸，由其编码的多肽和与多肽特异性结合的抗体。此外，本发明涉及包含所述多核苷酸和多肽的药物，以及其具体的治疗应用。此外，本发明考虑了制备多肽和药物的方法。

2. 发明申请

WO2014086494A1 NOVEL RECOMBINANT CLOSTRIDIAL NEUROTOXINS WITH ENHANCED MEMBRANE LOCALIZATION 审中-公开
标题翻译：具有增强膜局部化的新型重组离子神经毒素
公开(公告)号：WO2014086494A1
公开(公告)日：2014-06-12
申请号：PCT/EP2013/003680
申请日：2013-12-05
申请人： MERZ PHARMA GMBH & CO. KGAA
发明人： GROER, Gerhard , FREVERT, Juergen , HOFMANN, Fred , SCHMIDT, Michael
IPC分类号： C07K14/33
CPC分类号： C07K14/33 , A61K38/00 , C07K14/4728 , C07K2319/00 , C07K2319/01 , C07K2319/033 , C07K2319/31
摘要： This invention relates to novel recombinant clostridial neurotoxins exhibiting increased membrane localization and to methods for the manufacture of such recombinant clostridial neurotoxins. These methods comprise the steps of inserting a nucleic acid sequence coding for a C2 domain into a nucleic acid sequence coding for a parental clostridial neurotoxin and expression of the recombinant nucleic acid sequence comprising the C2 domain in a host cell. The invention further relates to novel recombinant single-chain precursor clostridial neurotoxins used in such methods, nucleic acid sequences encoding such recombinant single-chain precursor clostridial neurotoxins, and pharmaceutical compositions comprising the recombinant clostridial neurotoxin with increased membrane localization.
摘要翻译：本发明涉及显示增加的膜定位的新型重组梭菌神经毒素和用于制备这种重组梭菌神经毒素的方法。这些方法包括以下步骤：将编码C2结构域的核酸序列插入到编码亲本梭菌神经毒素的核酸序列中，并在宿主细胞中表达包含C2结构域的重组核酸序列。本发明还涉及用于这些方法的新型重组单链前体梭菌神经毒素，编码这种重组单链前体梭菌神经毒素的核酸序列，以及包含具有增加的膜定位的重组梭菌神经毒素的药物组合物。

3. 发明申请

WO2014029497A1 NOVEL METHOD FOR THE MANUFACTURING OF RECOMBINANT PROTEINS HARBOURING AN N-TERMINAL LYSINE 审中-公开
标题翻译：用于制造结合N末端蛋白的重组蛋白的新方法
公开(公告)号：WO2014029497A1
公开(公告)日：2014-02-27
申请号：PCT/EP2013/002506
申请日：2013-08-20
申请人： MERZ PHARMA GMBH & CO. KGAA
发明人： FREVERT, Juergen , SCHMIDT, Michael , HOFMANN, Fred , GROER, Gerhard
IPC分类号： C07K14/33 , C12N9/58
CPC分类号： C07K14/33 , C07K2319/50 , C12N15/70 , C12P21/02 , C12Y304/2402
摘要： This invention relates to a novel method for manufacturing and obtaining recombinant proteins, such as clostridial neurotoxins, harbouring an N-terminal lysine from precursor proteins. The method comprises the step of expressing a nucleic acid sequence encoding a precursor protein comprising an N-terminal motif, which can be recognised by an endoprotease specific for a lysine in Ρ'1 position, and the step of cleaving the precursor protein with said endoprotease. The invention further relates to novel precursor proteins used in such methods, nucleic acid sequences encoding such precursor proteins and novel recombinant proteins, such as clostridial neurotoxins, harbouring an N-terminal lysine.
摘要翻译：本发明涉及一种制备和获得重组蛋白质的新方法，所述重组蛋白质如来自前体蛋白质的携带N-末端赖氨酸的梭菌神经毒素。该方法包括表达编码包含N末端基序的前体蛋白的核酸序列的步骤，其可被Rho'1位置的赖氨酸特异的内切蛋白酶识别，以及用所述内切蛋白酶切割前体蛋白的步骤。本发明还涉及用于这些方法的新型前体蛋白，编码这些前体蛋白的核酸序列和含有N-末端赖氨酸的新型重组蛋白，如梭菌神经毒素。

4. 发明公开

EP2928912A1 NOVEL RECOMBINANT CLOSTRIDIAL NEUROTOXINS WITH ENHANCED MEMBRANE LOCALIZATION 无效
标题翻译：中性粒细胞重组蛋白胆固醇氧化酶麻醉剂VERBESSERTER MEMBRANLOKALISIERUNG
公开(公告)号：EP2928912A1
公开(公告)日：2015-10-14
申请号：EP13814432.4
申请日：2013-12-05
申请人： Merz Pharma GmbH & Co. KGaA
发明人： GROER, Gerhard , FREVERT, Juergen , HOFMANN, Fred , SCHMIDT, Michael
IPC分类号： C07K14/33
CPC分类号： C07K14/33 , A61K38/00 , C07K14/4728 , C07K2319/00 , C07K2319/01 , C07K2319/033 , C07K2319/31
摘要： This invention relates to novel recombinant clostridial neurotoxins exhibiting increased membrane localization and to methods for the manufacture of such recombinant clostridial neurotoxins. These methods comprise the steps of inserting a nucleic acid sequence coding for a C2 domain into a nucleic acid sequence coding for a parental clostridial neurotoxin and expression of the recombinant nucleic acid sequence comprising the C2 domain in a host cell. The invention further relates to novel recombinant single-chain precursor clostridial neurotoxins used in such methods, nucleic acid sequences encoding such recombinant single-chain precursor clostridial neurotoxins, and pharmaceutical compositions comprising the recombinant clostridial neurotoxin with increased membrane localization.
摘要翻译：本发明涉及显示增加的膜定位的新型重组梭菌神经毒素和用于制备这种重组梭菌神经毒素的方法。这些方法包括以下步骤：将编码C2结构域的核酸序列插入到编码亲本梭菌神经毒素的核酸序列中，并在宿主细胞中表达包含C2结构域的重组核酸序列。本发明还涉及用于这些方法的新型重组单链前体梭菌神经毒素，编码这种重组单链前体梭菌神经毒素的核酸序列，以及包含具有增加的膜定位的重组梭菌神经毒素的药物组合物。

5. 发明授权

EP2776457B1 NEUROTOXINS EXHIBITING SHORTENED BIOLOGICAL ACTIVITY 有权
标题翻译：神经毒素表现出生物活性的缩短
公开(公告)号：EP2776457B1
公开(公告)日：2017-08-02
申请号：EP12783603.9
申请日：2012-11-08
申请人： Merz Pharma GmbH & Co. KGaA
发明人： SCHMIDT, Michael , FREVERT, Jürgen , HOFMANN, Fred , GROER, Gerhard
IPC分类号： C07K14/47 , C07K14/435 , C07K14/33 , C12N5/00 , A61K38/00
CPC分类号： C12N9/52 , A61K38/4893 , C07K14/4746 , C12Y304/24069

6. 发明公开

EP2885316A1 NOVEL METHOD FOR THE MANUFACTURING OF RECOMBINANT PROTEINS HARBOURING AN N-TERMINAL LYSINE 无效
标题翻译：维生素VERFAHREN ZUR HERSTELLUNG REKOMBINANTER蛋白质麻醉剂EINEM N-TERMINALEN LYSIN
公开(公告)号：EP2885316A1
公开(公告)日：2015-06-24
申请号：EP13755959.7
申请日：2013-08-20
申请人： Merz Pharma GmbH & Co. KGaA
发明人： FREVERT, Juergen , SCHMIDT, Michael , HOFMANN, Fred , GROER, Gerhard
IPC分类号： C07K14/33 , C12N9/58
CPC分类号： C07K14/33 , C07K2319/50 , C12N15/70 , C12P21/02 , C12Y304/2402
摘要： This invention relates to a novel method for manufacturing and obtaining recombinant proteins, such as clostridial neurotoxins, harbouring an N-terminal lysine from precursor proteins. The method comprises the step of expressing a nucleic acid sequence encoding a precursor protein comprising an N-terminal motif, which can be recognised by an endoprotease specific for a lysine in Ρ'1 position, and the step of cleaving the precursor protein with said endoprotease. The invention further relates to novel precursor proteins used in such methods, nucleic acid sequences encoding such precursor proteins and novel recombinant proteins, such as clostridial neurotoxins, harbouring an N-terminal lysine.
摘要翻译：本发明涉及一种用于制造和获得重组蛋白质的新方法，所述重组蛋白质如来自前体蛋白质的携带N-末端赖氨酸的梭菌神经毒素。该方法包括表达编码包含N末端基序的前体蛋白的核酸序列的步骤，其可以被P'1位置的赖氨酸特异的内切蛋白酶识别，以及用内切蛋白酶切割前体蛋白质的步骤。本发明还涉及用于这些方法的新型前体蛋白，编码这种前体蛋白的核酸序列和含有N-末端赖氨酸的新型重组蛋白，如梭菌神经毒素。

7. 发明公开

EP2776457A1 NEUROTOXINS EXHIBITING SHORTENED BIOLOGICAL ACTIVITY 有权
标题翻译：神经毒素麻醉科植物生物学家AKTIVITÄT
公开(公告)号：EP2776457A1
公开(公告)日：2014-09-17
申请号：EP12783603.9
申请日：2012-11-08
申请人： Merz Pharma GmbH & Co. KGaA
发明人： SCHMIDT, Michael , FREVERT, Jürgen , HOFMANN, Fred , GROER, Gerhard
IPC分类号： C07K14/47 , C07K14/435 , C07K14/33 , C12N5/00 , A61K38/00
CPC分类号： C12N9/52 , A61K38/4893 , C07K14/4746 , C12Y304/24069
摘要： The present invention relates to the pharmaceutical field. Specifically, it contemplates a polynucleotide encoding a neurotoxin polypeptide exhibiting a reduced duration of the biological effect in a subject, wherein said polypeptide comprises at least one E3 ligase recognition motif in the light chain, wherein said E3 ligase recognition motif is preferably abinding motif for the E3 ligase MDM2. The invention further pertains to polypeptides encoded by the polynucleotide of the invention as well as polypeptides comprising one or more amino acid substitutions. Further encompassed by the present invention are vectors and host cells comprising the said polynucleotide, polypeptides encoded thereby and antibodies specifically binding to the polypeptides. Moreover, the invention relates to medicaments comprising said polynucleotides and polypeptides, as well as specific therapeutic applications thereof. Furthermore, the present invention contemplates methods for the manufacture of the polypeptides and medicaments.
摘要翻译：本发明涉及药物领域。具体地，本发明涉及一种编码神经毒素多肽的多核苷酸，其在受试者中表现出生物学作用的持续时间减少，其中所述多肽在轻链中包含至少一个E3连接酶识别基序，其中所述E3连接酶识别基序优选为 E3连接酶MDM2。本发明还涉及由本发明的多核苷酸编码的多肽以及包含一个或多个氨基酸取代的多肽。本发明还包括载体和宿主细胞，其包含所述多核苷酸，由其编码的多肽和与多肽特异性结合的抗体。此外，本发明涉及包含所述多核苷酸和多肽的药物，以及其具体的治疗应用。此外，本发明考虑了制备多肽和药物的方法。

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