Suppression of cancer

Abstract

Polypeptides for use in suppressing cancer and cancer disorders and methods of treatment using such polypeptides.

1 . A polypeptide comprising:
 (i) a non-cytotoxic protease capable of cleaving a SNARE protein that is expressed in a cancer cell;   (ii) a targeting moiety capable of binding to a binding site located on the surface of the cancer cell wherein the binding site is capable of undergoing endocytosis to be incorporated into an endosome within the cancer cell; and   (iii) a translocation domain capable of translocating the protease from within an endosome, across the endosomal membrane and into the cytosol of the cancer cell;   
       wherein the cancer cell is not a neuroendocrine tumour cell and the polypeptide is not clostridial neurotoxin. 
     
     
         2 . (canceled) 
     
     
         3 . The polypeptide of  claim 1 , wherein the cancer cell is selected from the group consisting of: a lung cancer cell, a renal cancer cell, a brain cancer cell, a breast cancer cell, a pancreatic cancer cell, a colorectal cancer cell, an adrenal cancer cell, an oesophageal cancer cell, a lymphoma cancer cell, a leukaemia cancer cell, an acute leukaemia cancer cell, a bladder cancer cell, a bone cancer cell, a bowel cancer cell, a cervical cancer cell, a chronic lymphocytic leukaemia cell, a Hodgkin's lymphoma cell, a liver cancer cell, a melanoma skin cancer cell, an oropharyngeal cancer cell, a myeloma cell, a prostate cancer cell, a soft tissue sarcoma cell, a gastric cancer cell, a testicular cancer cell, a uterine cancer cell and, a Kaposi sarcoma cancer cell. 
     
     
         4 . The polypeptide of  claim 1 , wherein the targeting moiety binds to a receptor selected from the group consisting of: an ErbB receptor a growth hormone-releasing hormone (GHRH) receptor; an insulin-like growth factor receptor (IGFR); a gastrin-releasing peptide (GRP) receptor; a bombesin peptide (BB) receptor; a growth hormone (GH) receptor; a vascular endothelial growth factor (VEGF) receptor; an acetylcholine (ACH) receptor; a somatostatin (SST) receptor; a cortistatin (CST) receptor; a chemokine (C-X-C motif) receptor; a neuropilin receptor; a gonadotropin-releasing hormone (GnRH) receptor; a VIP-glucagon-GRF-secretin superfamily receptor; a FLT receptor; a CHRN receptor; an EPH receptor; an EFN receptor; a DLK1 receptor, a DLL3 receptor, a FGF receptor; a JAG receptor; a LIF receptor; a NMB receptor; a NOTCH receptor; a PDGF receptor; a c-kit receptor; a TGF receptor; an endothelin receptor; a chemokine receptor; and an angiopoietin receptor. 
     
     
         5 . The polypeptide of  claim 1 , wherein the targeting moiety is selected from the group consisting of: an ErbB peptide, an adrenomedullin (ADM) peptide, an AM peptide, an AMF peptide, an amphiregulin peptide, an APRIL peptide, an artemin peptide, a betacellulin peptide, a bombesin peptide, a CTR peptide, an endothelin peptide, an erythropoietin peptide, a FGF peptide, a FSH peptide, a gastrin peptide, a gastrin releasing peptide (GRP), a GDNF peptide, a ghrelin peptide, a GHRH peptide, a G-CSF peptide, a growth hormone peptide, a HB-EGF peptide, a hepatocyte growth factor (HGF) peptide, an IL peptide, a keratinocyte growth factor peptide, a leptin peptide, a LIF peptide, an alpha-melanotropin peptide, a MGSA/GRO peptide, a NRG peptide, an oxytocin peptide, an osteopontin (OPN) peptide, a neuregulin-1 peptide, a VIP peptide, a PACAP peptide, a PDGF peptide, a prolactin peptide, a SCF peptide, a somatostatin (SST) peptide, a cortistatin (CST) peptide, a TNF peptide, a TGF peptide, a VEGF peptide, a vasopressin peptide, an angiopoietin peptide, a B-CLL peptide, a BCGF-12KD peptide, a BAFF peptide, a galanin peptide, a GDNF peptide, a GnRH peptide, an IGF-II peptide, a LH peptide, a neurotrophin peptide, a substance P peptide, a TGF-alpha peptide, an IGF peptide, an angiopoietin peptide, a CXC peptide, and a CCL peptide. 
     
     
         6 . The polypeptide of  claim 1 , wherein the non-cytotoxic protease comprises a clostridial neurotoxin L-chain or an IgA protease. 
     
     
         7 . The polypeptide of  claim 1 , wherein the translocation domain comprises a clostridial neurotoxin translocation domain. 
     
     
         8 - 12 . (canceled) 
     
     
         13 . The polypeptide of  claim 1 , wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 7, 10, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44. 
     
     
         14 . A nucleic acid encoding the polypeptide of  claim 1 . 
     
     
         15 . A nucleic acid encoding the polypeptide of  claim 1 , wherein the nucleic acid comprises a nucleic acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 6 or 9. 
     
     
         16 . A method of suppressing a cancer in a patient, the method comprising administering to the patient an effective amount of the polypeptide of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from the group consisting of: lung cancer, renal cancer, brain cancer, breast cancer, pancreatic cancer, colorectal cancer, adrenal cancer, oesophageal cancer, lymphoma, leukaemia, acute leukaemia, bladder cancer, bone cancer, bowel cancer, cervical cancer, chronic lymphocytic leukaemia, Hodgkin's lymphoma, liver cancer, skin cancer, oropharyngeal cancer, myeloma, prostate cancer, gastric cancer, testicular cancer, uterine cancer, and Kaposi sarcoma. 
     
     
         18 . The method of  claim 16 , wherein the method comprises suppressing secretion from a cancer cell selected from the group consisting of: a lung cancer cell, a renal cancer cell, a brain cancer cell, a breast cancer cell, a pancreatic cancer cell, a colorectal cancer cell, an adrenal cancer cell, an oesophageal cancer cell, a lymphoma cancer cell, a leukaemia cancer cell, an acute leukaemia cancer cell, a bladder cancer cell, a bone cancer cell, a bowel cancer cell, a cervical cancer cell, a chronic lymphocytic leukaemia cell, a Hodgkin's lymphoma cell, a liver cancer cell, a skin cancer cell, an oropharyngeal cancer cell, a myeloma cell, a prostate cancer cell, a soft tissue sarcoma cell, a gastric cancer cell, a testicular cancer cell, a uterine cancer cell, and or a Kaposi sarcoma cell. 
     
     
         19 . The polypeptide of  claim 4 , wherein the targeting moiety is an antibody or antibody fragment. 
     
     
         20 . A method of suppressing a cancer in a patient, the method comprising administering to the patient an effective amount of the nucleic acid of  claim 14 . 
     
     
         21 . The polypeptide of  claim 1 , wherein the polypeptide comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 7, 10, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44. 
     
     
         22 . The polypeptide of  claim 1 , wherein the polypeptide comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 7, 10, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44. 
     
     
         23 . A nucleic acid encoding the polypeptide of  claim 1 , wherein the nucleic acid comprises a nucleic acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 6 or 9. 
     
     
         24 . A nucleic acid encoding the polypeptide of  claim 1 , wherein the said nucleic acid comprises a nucleic acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 6 or 9.