Inhibition of secretion from non-neuronal cells

Abstract

The present invention relates to treatment of disease by inhibition of cellular secretory processes, to agents and compositions therefor, and to manufacture of those agents and compositions. The present invention relates particularly, to treatment of disease 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.

1 . A method of suppressing hypersecretion from an endocrine cell in a patient in need thereof, said method comprising:
 administering an effective amount of a modified clostridial neurotoxin to said patient;   wherein the modified clostridial neurotoxin comprises a clostridial toxin light chain and a clostridial toxin translocation domain in which the neuronal targeting activity of the clostridial neurotoxin has been removed; and   wherein said modified clostridial neurotoxin is covalently linked to a ligand that binds to a receptor present on said endocrine cell;   wherein upon binding of the ligand to the receptor, the light chain is translocated into the cytosol of the cell by the translocation domain and cleaves one or more SNARE proteins essential to exocytosis in the cell.   
     
     
         2 . The method according to  claim 1 , wherein the modified clostridial neurotoxin comprises a clostridial neurotoxin in which the H C  binding ability of the clostridial neurotoxin has been removed. 
     
     
         3 . (canceled) 
     
     
         4 . The method according to  claim 1 , wherein said clostridial toxin translocation domain is provided by a clostridial neurotoxin H-chain having a carboxy-terminal half and an amino-terminal half, wherein the neuronal targeting activity of the carboxy-terminal half of the H-chain has been removed. 
     
     
         5 . The method according to  claim 1 , wherein said clostridial toxin translocation domain comprises the amino-terminal half of a clostridial neurotoxin H-chain. 
     
     
         6 . The method according to  claim 1 , wherein said clostridial neurotoxin L-chain and said clostridial toxin translocation domain are present in the form of a di-chain in which the clostridial neurotoxin L-chain is covalently bonded to the clostridial toxin translocation domain. 
     
     
         7 . The method according to  claim 1 , wherein the endocrine cell is a pituitary cell, and wherein the modified clostridial neurotoxin binds to said pituitary cell. 
     
     
         8 . The method according to  claim 1 , wherein the patient suffers from acromegaly. 
     
     
         9 . The method according to  claim 1 , wherein the patient suffers from Cushings disease. 
     
     
         10 . The method according to  claim 1 , wherein the patient suffers from endocrine neoplasia. 
     
     
         11 . The method according to  claim 1 , wherein the patient suffers from hyperprolactinaemia. 
     
     
         12 - 20 . (canceled) 
     
     
         21 . The method according to  claim 1 , wherein the endocrine cell is a cell of the anterior pituitary, posterior pituitary, thyroid, parathyroid, adrenal cortex, adrenal medulla, pancreas, ovary or testes. 
     
     
         22 . The method according to  claim 1 , wherein the ligand is selected from the group consisting of: iodine; thyroid stimulating hormone (TSH); TSH receptor antibodies; antibodies to the islet-specific monosialo-ganglioside GM2-1; insulin, insulin-like growth factor; antibodies to the receptors of insulin; antibodies to the receptors of insulin-like growth factor; TSH releasing hormone (protirelin); antibodies to the TSH releasing hormone receptor; FSH/LH releasing hormone (gonadorelin); antibodies to the FSH/LH releasing hormone receptor; corticotrophin releasing hormone (CRH); antibodies to the corticotrophin releasing hormone (CRH) receptor; ACTH; and antibodies to the ACTH receptor. 
     
     
         23 . The method according to  claim 10 , wherein the patient suffers from multiple endocrine neoplasia (MEN). 
     
     
         24 . The method according to  claim 23 , wherein the patient suffers from type 1 multiple endocrine neoplasia (MEN) or type 2 multiple endocrine neoplasia (MEN).