公开(公告)号：US08512984B2

公开(公告)日：2013-08-20

申请号：US13212868

申请日：2011-08-18

申请人： Keith Foster ,  John Chaddock ,  Charles Penn ,  Kei Aoki ,  Joseph Francis ,  Lance Steward

发明人： Keith Foster ,  John Chaddock ,  Charles Penn ,  Kei Aoki ,  Joseph Francis ,  Lance Steward

IPC分类号： A61K38/16 ,  A61K38/48 ,  C12P21/04 ,  C12P21/06

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.

公开(公告)号：US20060211619A1

公开(公告)日：2006-09-21

申请号：US11376696

申请日：2006-03-15

申请人： Lance Steward ,  Fernandez-Salas Ester ,  Joseph Francis ,  Shengwin Li ,  Marcella Gilmore ,  Kei Aoki

发明人： Lance Steward ,  Fernandez-Salas Ester ,  Joseph Francis ,  Shengwin Li ,  Marcella Gilmore ,  Kei Aoki

IPC分类号： A61K38/17 ,  C07K14/715 ,  C07K16/28

CPC分类号： C07K14/33 ,  A61K38/4886 ,  C07K2319/00 ,  C07K2319/035 ,  C07K2319/06

摘要： The present invention is directed to multivalent Clostridial neurotoxin derivatives having more than one binding domain directed to a cell surface feature of a target cell. Such modified neurotoxins are useful as therapeutic compositions to prevent exocytosis and secretion by the target cell. Conditions in which such compositions man be useful include, without limitation, disorders of the sensory or motor nervous system, acute or chronic pain, cancer, pancreatitis, hyperhydrosis, glandular disorders, viral infections, cystic fibrosis and the like. The invention is also directed to methods of using and administering such a composition, and methods of treating a given condition using such a composition.

摘要翻译： 本发明涉及具有针对靶细胞的细胞表面特征的多于一个结合结构域的多价梭菌神经毒素衍生物。 这种修饰的神经毒素可用作预防目标细胞胞吐和分泌的治疗组合物。 这些组合物可用的条件包括但不限于感觉或运动神经系统的疾病，急性或慢性疼痛，癌症，胰腺炎，超氧化，腺体疾病，病毒感染，囊性纤维变性等。 本发明还涉及使用和施用这种组合物的方法，以及使用这种组合物治疗给定病症的方法。

公开(公告)号：US20080032931A1

公开(公告)日：2008-02-07

申请号：US11834068

申请日：2007-08-06

申请人： Lance Steward ,  Joseph Francis ,  Ester Fernandez-Salas ,  Marcella Gilmore ,  Shengwen Li ,  J. Dolly ,  Kei Aoki

发明人： Lance Steward ,  Joseph Francis ,  Ester Fernandez-Salas ,  Marcella Gilmore ,  Shengwen Li ,  J. Dolly ,  Kei Aoki

IPC分类号： A61K38/22 ,  A61P43/00 ,  C07H21/00 ,  C07K14/575 ,  C12P21/02

CPC分类号： C12N9/52 ,  C07K1/22 ,  C07K14/33 ,  C07K14/68 ,  C07K14/695 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/50

摘要： Compositions comprising activatable recombinant neurotoxins and polypeptides derived therefrom. The invention also comprises nucleic acids encoding such polypeptides, and methods of making such polypeptides and nucleic acids.

公开(公告)号：US20080032930A1

公开(公告)日：2008-02-07

申请号：US11832173

申请日：2007-08-01

申请人： Lance Steward ,  Joseph Francis ,  Ester Fernandez-Salas ,  Marcella Gilmore ,  Shengwen Li ,  J. Dolly ,  Kei Aoki

发明人： Lance Steward ,  Joseph Francis ,  Ester Fernandez-Salas ,  Marcella Gilmore ,  Shengwen Li ,  J. Dolly ,  Kei Aoki

IPC分类号： A61K38/02 ,  C07H21/00 ,  C07K1/14 ,  C07K14/00 ,  C12P21/00

CPC分类号： C07K1/22 ,  C07K14/33 ,  C07K14/68 ,  C07K14/695 ,  C12N9/52

摘要： Compositions comprising activatable recombinant neurotoxins and polypeptides derived therefrom. The invention also comprises nucleic acids encoding such polypeptides, and methods of making such polypeptides and nucleic acids.

摘要翻译： 包含可活化的重组神经毒素和由其衍生的多肽的组合物。 本发明还包括编码这种多肽的核酸，以及制备这种多肽和核酸的方法。

公开(公告)号：US20080025994A1

公开(公告)日：2008-01-31

申请号：US11845638

申请日：2007-08-27

申请人： Lance Steward ,  George Sachs ,  Kei Aoki

发明人： Lance Steward ,  George Sachs ,  Kei Aoki

IPC分类号： A61K39/395 ,  A61P1/18

CPC分类号： C07K14/33 ,  A61K47/6415 ,  C07K2317/53 ,  C07K2319/00 ,  C07K2319/33

摘要： Methods and compositions for the treatment of acute pancreatitis in a mammal. Particular compositions comprise a binding element, a translocation element, and a therapeutic element able to prevent accumulation of digestive enzymes within the pancreas.

摘要翻译： 用于治疗哺乳动物急性胰腺炎的方法和组合物。 特定的组合物包含结合元件，易位元件和能够防止胰脏内的消化酶积累的治疗元件。

公开(公告)号：US20060063222A1

公开(公告)日：2006-03-23

申请号：US10948097

申请日：2004-09-22

申请人： Dudley Williams ,  Marcella Gilmore ,  Lance Steward ,  Marc Verhagen ,  Kei Aoki

发明人： Dudley Williams ,  Marcella Gilmore ,  Lance Steward ,  Marc Verhagen ,  Kei Aoki

IPC分类号： C12Q1/37 ,  C12N11/16

CPC分类号： G01N33/542 ,  C12N9/52 ,  C12Q1/37 ,  G01N2333/33

摘要： The present invention provides a method of determining the presence or activity of a clostridial toxin by (a) treating with a sample, under conditions suitable for clostridial toxin protease activity, a clostridial toxin substrate which includes a fluorophore; a bulking group; and a clostridial toxin recognition sequence containing a cleavage site that intervenes between the fluorophore and the bulking group; (b) exciting the fluorophore with plane polarized light; and (c) determining fluorescence polarization of the treated substrate relative to a control substrate, where a change in fluorescence polarization of the treated substrate as compared to fluorescence polarization of the control substrate is indicative of the presence or activity of the clostridial toxin.

公开(公告)号：US20080057575A1

公开(公告)日：2008-03-06

申请号：US11570706

申请日：2005-08-03

申请人： Ester Fernandez-Salas ,  Lance Steward ,  Ronald Miller ,  Kei Aoki ,  Marcella Gilmore ,  Shengwen Li

发明人： Ester Fernandez-Salas ,  Lance Steward ,  Ronald Miller ,  Kei Aoki ,  Marcella Gilmore ,  Shengwen Li

IPC分类号： C12N15/31 ,  C12N1/19 ,  C12N5/10

CPC分类号： C07K14/33

摘要： Nucleic acid molecules that comprise modified open reading frames providing increased expression of the encoded active BoNT/A in a heterologous cell, expression constructs and cells comprising such nucleic acid molecules and methods useful for expressing the encoding active BoNT/A from such nucleic acid molecules, expression constructs and cells.

摘要翻译： 包含修饰的开放阅读框的核酸分子提供编码的活性BoNT / A在异源细胞中的表达增加，表达构建体和包含此类核酸分子的细胞以及用于从该核酸分子表达编码活性BoNT / A的方法， 表达构建体和细胞。

公开(公告)号：US20080032318A1

公开(公告)日：2008-02-07

申请号：US11780872

申请日：2007-07-20

申请人： Lance Steward ,  Ester Fernandez-Salas ,  Kei Aoki

发明人： Lance Steward ,  Ester Fernandez-Salas ,  Kei Aoki

IPC分类号： G01N33/569 ,  C07K14/33 ,  C12Q1/04

CPC分类号： C12Q1/37 ,  C07K14/001 ,  C07K14/435 ,  G01N33/56911 ,  G01N2333/33

摘要： The present invention provides clostridial toxin substrates useful in assaying for the protease activity of any clostridial toxin, including botulinum toxins of all serotypes as well as tetanus toxins. A clostridial toxin substrate of the invention contains a donor fluorophore; an acceptor having an absorbance spectrum overlapping the emission spectrum of the donor fluorophore; and a clostridial toxin recognition sequence that includes a cleavage site, where the cleavage site intervenes between the donor fluorophore and the acceptor and where, under the appropriate conditions, resonance energy transfer is exhibited between the donor fluorophore and the acceptor.

公开(公告)号：US20050276820A1

公开(公告)日：2005-12-15

申请号：US11039268

申请日：2005-01-19

申请人： Lance Steward ,  Todd Herrington ,  Kei Aoki

发明人： Lance Steward ,  Todd Herrington ,  Kei Aoki

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61P1/00 ,  A61P5/00 ,  A61P21/00 ,  A61P25/00 ,  A61P25/04 ,  A61P27/02 ,  A61P29/02 ,  A61P37/00 ,  C07K14/33 ,  A61K39/08

CPC分类号： C07K14/33 ,  A61K38/00 ,  Y10S530/825

摘要： Modified neurotoxin comprising neurotoxin including structural modification, wherein the structural modification alters the biological persistence, preferably the biological half-life, of the modified neurotoxin relative to an identical neurotoxin without the structural modification. The structural modification includes addition or deletion of a leucine-based motif or parts thereof. In one embodiment, methods of making the modified neurotoxin include using recombinant techniques. In another embodiment, methods of using the modified neurotoxin to treat biological disorders include treating autonomic disorders, neuromuscular disorders or pains.

摘要翻译： 包含神经毒素的改性神经毒素包括结构修饰，其中所述结构修饰改变了修饰神经毒素相对于相同神经毒素的生物学持续性，优选生物半衰期而没有结构修饰。 结构修饰包括加入或缺失基于亮氨酸的基序或其部分。 在一个实施方案中，制备修饰的神经毒素的方法包括使用重组技术。 在另一个实施方案中，使用经修饰的神经毒素治疗生物学障碍的方法包括治疗自主神经障碍，神经肌肉疾病或疼痛。

公开(公告)号：US20080038756A1

公开(公告)日：2008-02-14

申请号：US11780925

申请日：2007-07-20

申请人： Lance Steward ,  Ester Fernandez-Salas ,  Kei Aoki

发明人： Lance Steward ,  Ester Fernandez-Salas ,  Kei Aoki

IPC分类号： G01N33/569 ,  C07K14/33 ,  C12Q1/04

CPC分类号： C12Q1/37 ,  C07K14/001 ,  C07K14/435 ,  G01N33/56911 ,  G01N2333/33

摘要： The present invention provides clostridial toxin substrates useful in assaying for the protease activity of any clostridial toxin, including botulinum toxins of all serotypes as well as tetanus toxins. A clostridial toxin substrate of the invention contains a donor fluorophore; an acceptor having an absorbance spectrum overlapping the emission spectrum of the donor fluorophore; and a clostridial toxin recognition sequence that includes a cleavage site, where the cleavage site intervenes between the donor fluorophore and the acceptor and where, under the appropriate conditions, resonance energy transfer is exhibited between the donor fluorophore and the acceptor.

摘要翻译： 本发明提供了可用于测定任何梭菌毒素（包括所有血清型的肉毒毒素）以及破伤风毒素的蛋白酶活性的梭菌毒素底物。 本发明的梭菌毒素底物含有供体荧光团; 具有与供体荧光团的发射光谱重叠的吸收光谱的受体; 和梭菌毒素识别序列，其包括切割位点，其中切割位点插入供体荧光团和受体之间，并且在适当条件下，在供体荧光团和受体之间显示共振能量转移。