公开(公告)号：US07192596B2

公开(公告)日：2007-03-20

申请号：US10241596

申请日：2002-09-12

Applicant: Clifford Charles Shone ,  Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock ,  Philip Marks ,  J. Mark Sutton ,  Patrick Stancombe ,  Jonathan Wayne

Inventor： Clifford Charles Shone ,  Conrad Padraig Quinn ,  Keith Alan Foster ,  John Chaddock ,  Philip Marks ,  J. Mark Sutton ,  Patrick Stancombe ,  Jonathan Wayne

IPC: A61K39/08 ,  A61K39/085 ,  A61K39/40 ,  A61K39/02 ,  A61K38/00 ,  C07K14/00 ,  C07K17/00

CPC classification number: 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

Abstract: 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.

公开(公告)号：US20060216283A1

公开(公告)日：2006-09-28

申请号：US11327855

申请日：2006-01-09

Applicant: Keith Foster ,  John Chaddock ,  Conrad Quinn ,  John Purkiss

Inventor： Keith Foster ,  John Chaddock ,  Conrad Quinn ,  John Purkiss

IPC: A61K48/00 ,  A61K39/35 ,  A61K39/00

CPC classification number: A61K38/4886 ,  A61K47/64

Abstract: A method of treatment of disease by inhibition of cellular secretory processes is provided. The method has particular application in the treatment of diseases dependent upon the exocytotic activity of endocrine cells, exocrine cells, inflammatory cells, cells of the immune system, cells of the cardiovascular system, and bone cells. Agents and compositions therefor, as well as methods for manufacturing these agents and compositions, are provided. In a preferred embodiment a clostridial neurotoxin, substantially devoid of holotoxin binding affinity for neuronal cells of the presynaptic muscular junction, is associated with a targeting moiety. The targeting moiety is selected such that the clostridial toxin conjugate so formed may be directed to a non-neuronal target cell to which the conjugate may bind. Following binding, a neurotoxin component of the conjugate, which is capable of inhibition of cellular secretion, passes into the cytosol of the target cell by cellular internalisation mechanisms. Thereafter, inhibition of secretion from the target cell is effected.

公开(公告)号：US20060110410A1

公开(公告)日：2006-05-25

申请号：US10527411

申请日：2003-09-12

Applicant: Clifford Shone ,  Keith Foster ,  John Chaddock ,  Philip Marks ,  J. Mark Sutton ,  Patrick Stancombe ,  Jonathan Wayne

Inventor： Clifford Shone ,  Keith Foster ,  John Chaddock ,  Philip Marks ,  J. Mark Sutton ,  Patrick Stancombe ,  Jonathan Wayne

IPC: A61K39/08 ,  C07K14/33

CPC classification number: 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

Abstract: 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.

公开(公告)号：US20050244435A1

公开(公告)日：2005-11-03

申请号：US11077550

申请日：2005-03-11

Applicant: Charles Shone ,  Conrad Quinn ,  Keith Foster ,  John Chaddock ,  Philip Marks ,  J. Sutton ,  Patrick Stancombe ,  Jonathan Wayne

Inventor： Charles Shone ,  Conrad Quinn ,  Keith Foster ,  John Chaddock ,  Philip Marks ,  J. Sutton ,  Patrick Stancombe ,  Jonathan Wayne

IPC: C12N15/09 ,  A61K20060101 ,  A61K38/00 ,  A61K38/16 ,  A61K39/00 ,  A61K39/08 ,  A61K47/48 ,  A61K48/00 ,  A61P31/04 ,  C07K14/33 ,  C07K14/65 ,  C07K19/00 ,  C12N1/19 ,  C12N1/21 ,  C12N5/10 ,  C12N9/52 ,  C12N15/31 ,  C12N15/62 ,  C12P21/02 ,  C12P21/04 ,  C12R1/145 ,  C12R1/19

CPC classification number: C12N15/62 ,  A61K38/00 ,  A61K39/00 ,  A61K39/08 ,  A61K47/6415 ,  A61K47/646 ,  A61K2039/505 ,  A61K2039/53 ,  A61K2039/627 ,  C07K14/33 ,  C07K14/475 ,  C07K14/65 ,  C07K2319/00 ,  C07K2319/20 ,  C07K2319/23 ,  C07K2319/50 ,  C07K2319/55 ,  C07K2319/705 ,  C07K2319/75 ,  C12N9/52 ,  Y02A50/469 ,  Y10S530/825

Abstract: Antigenic compositions are provided comprising a single chain polypeptide comprising first and second domains, wherein said first domain is a clostridial neurotoxin light chain or a fragment or a variant thereof and is capable of cleaving one or more vesicle or plasma membrane associated proteins essential to exocytosis; and said second domain is a clostridial neurotoxin heavy chain HN portion or a fragment or a variant thereof, wherein said second domain is capable of (i) translocating the polypeptide into a cell or (ii) increasing the solubility of the polypeptide compared to the solubility of the first domain on its own or (iii) both translocating the polypeptide into a cell and increasing the solubility of the polypeptide compared to the solubility of the first domain on its own; and wherein the second domain lacks a functional C-terminal part of a clostridial neurotoxin heavy chain designated HC thereby rendering the polypeptide incapable of binding to cell surface receptors that are the natural cell surface receptors to which native clostridial neurotoxin binds. Antibodies that bind to the polypeptides, and compositions comprising these antibodies, are also provided, as are DNA vaccines comprising polynucleotides that encode these polypeptides. The antigenic and antibody compositions, and the DNA vaccine compositions, can be used in methods of immunising against, or treating, clostridial neurotoxin poisoning in a subject by administering to that subject a therapeutically effective amount of the composition.

Abstract translation: 提供抗原组合物，其包含包含第一和第二结构域的单链多肽，其中所述第一结构域是梭菌神经毒素轻链或其片段或变体，并且能够切割一种或多种与胞吐作用相关的蛋白质或质膜相关蛋白; 并且所述第二结构域是梭菌神经毒素重链H N N部分或其片段或变体，其中所述第二结构域能够（i）将所述多肽转位至细胞中，或（ii）增加 与第一结构域本身的溶解度相比，多肽的溶解度或（iii）两者都将多肽转移到细胞中，并且与第一结构域本身的溶解度相比增加多肽的溶解度; 并且其中所述第二结构域缺少指定为HCC的梭菌神经毒素重链的功能性C-末端部分，从而使所述多肽不能结合作为天然梭菌的天然细胞表面受体的细胞表面受体 神经毒素结合。 还提供了结合多肽的抗体和包含这些抗体的组合物，DNA疫苗也包括编码这些多肽的多核苷酸。 抗原和抗体组合物和DNA疫苗组合物可用于通过向该受试者施用治疗有效量的组合物来免疫或治疗受试者的梭菌神经毒素中毒的方法。