Suppression of neuroendocrine diseases

Abstract

The present invention relates to a method for suppressing neuroendocrine disease. The therapy employs use of a non-cytotoxic protease, which is targeted to a neuroendocrine tumour cell, preferably via a somatostatin or cortistatin receptor, a GHRH receptor, a ghrelin receptor, a bombesin receptor, a urotensin receptor a melanin-concentrating hormone receptor 1; a KiSS-1 receptor or a prolactin-releasing peptide receptor. When so delivered, the protease is internalised and inhibits secretion from said tumour cell. The present invention also relates to polypeptides and nucleic acids for use in said methods.

1 - 13 . (canceled) 
     
     
         14 . A method of treating acromegaly or Cushing's disease in a patient, comprising administering to the patient a therapeutically effective amount of a polypeptide comprising:
 (a) a non-cytotoxic protease, which protease is capable of cleaving a protein of the exocytic fusion apparatus in a pituitary tumour cell;   (b) a Targeting Moiety (TM) that binds to a Binding Site on a pituitary tumour cell, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the pituitary tumour cell; and   (c) a translocation domain that translocates the protease from within the endosome, across the endosomal membrane and into the cytosol of said pituitary tumour cell.   
     
     
         15 . The method according to  claim 14 , wherein the pituitary tumour cell is a cell derived from or contributing to somatotrophinomas or corticotrophinomas. 
     
     
         16 . The method according to  claim 14 , wherein the TM binds to a receptor selected from the group consisting of: a growth hormone-releasing hormone (GHRH) receptor; a somatostatin (SST) receptor, a cortistatin (CST) receptor, a ghrelin receptor; a bombesin receptor; a urotensin receptor, a melanin-concentrating hormone receptor 1; a KiSS-1 receptor; a gonadotropin-releasing hormone (GnRH) receptor, and a prolactin-releasing peptide receptor. 
     
     
         17 . The method according to  claim 14 , wherein the TM comprises a growth hormone releasing hormone (GHRH) peptide, a somatostatin peptide, a cortistatin peptide, a ghrelin peptide, a bombesin peptide, a urotensin peptide, melanin-concentrating hormone peptide, a KISS-1 peptide, a gonadotropin-releasing hormone (GnRH) peptide, or a prolactin-releasing peptide. 
     
     
         18 . The method according to  claim 14 , wherein the non-cytotoxic protease comprises a clostridial neurotoxin L-chain or an IgA protease. 
     
     
         19 . The method according to  claim 14 , wherein the translocation domain comprises a clostridial neurotoxin translocation domain. 
     
     
         20 . A polypeptide comprising:
 (a) a non-cytotoxic protease, which protease is capable of cleaving a protein of the exocytic fusion apparatus in a pituitary tumour cell;   (b) a Targeting Moiety (TM) that binds to a Binding Site on a pituitary tumour cell, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the pituitary tumour cell; and   (c) a translocation domain that translocates the protease from within the endosome, across the endosomal membrane and into the cytosol of said pituitary tumour cell.   
     
     
         21 . The polypeptide according to  claim 20 , wherein the pituitary tumour cell is a cell derived from or contributing to somatotrophinomas or corticotrophinomas. 
     
     
         22 . The polypeptide according to  claim 20 , wherein the TM binds to a receptor selected from the group comprising: a growth hormone-releasing hormone (GHRH) receptor; a somatostatin (SST) receptor, a cortistatin (CST) receptor, a ghrelin receptor, a bombesin receptor, a urotensin receptor, a melanin-concentrating hormone receptor 1; a KiSS-1 receptor; a gonadotropin-releasing hormone (GnRH) receptor, and a prolactin-releasing peptide receptor. 
     
     
         23 . The polypeptide according to  claim 20 , wherein the TM comprises a growth hormone releasing hormone (GHRH) peptide, a somatostatin peptide, a cortistatin peptide, a ghrelin peptide, a bombesin peptide, a urotensin peptide, melanin-concentrating hormone peptide, a KISS-1 peptide, a gonadotropin-releasing hormone (GnRH) peptide, or a prolactin-releasing peptide. 
     
     
         24 . The polypeptide according to  claim 20 , wherein the translocation domain comprises a clostridial neurotoxin translocation domain; and/or wherein the non-cytotoxic protease comprises a clostridial neurotoxin protease or an IgA protease. 
     
     
         25 . The polypeptide according to  claim 20 , wherein said polypeptide comprises an amino acid sequence having at least 90-92%, or at least 95-97%, or at least 98-99% sequence identity to any one of SEQ ID NOs: 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 or 94. 
     
     
         26 . A nucleic acid encoding a polypeptide according to  claim 20 . 
     
     
         27 . A nucleic acid encoding a polypeptide according to  claim 20 , wherein said nucleic acid comprises a nucleic acid sequence having at least 90-94%, or at least 95-97%, or at least 98-99% sequence identity to any one of SEQ ID NOs: 17 or 25. 
     
     
         28 . The polypeptide according to  claim 22 , wherein:
 the bombesin receptor is selected from the group consisting of BRS-1, BRS-2 and BRS-3; and/or   the urotensin receptor is a urotensin II receptor.   
     
     
         29 . The method according to  claim 18 , wherein the translocation domain comprises a clostridial neurotoxin translocation domain. 
     
     
         30 . The method according to  claim 17 , wherein:
 the translocation domain comprises a clostridial neurotoxin translocation domain; and   the non-cytotoxic protease comprises a clostridial neurotoxin protease or an IgA protease.   
     
     
         31 . The polypeptide according to  claim 23 , wherein:
 the translocation domain comprises a clostridial neurotoxin translocation domain; and   the non-cytotoxic protease comprises a clostridial neurotoxin protease or an IgA protease.   
     
     
         32 . The method according to  claim 16 , wherein:
 the bombesin receptor is selected from the group consisting of BRS-1, BRS-2 and BRS-3; and/or   the urotensin receptor is a urotensin II receptor.