Suppression of neuroendocrine diseases
View Patent ↗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 tumor 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 internalized and inhibits secretion from said tumor cell. The present invention also relates to polypeptides and nucleic acids for use in said methods.
1. A polypeptide comprising the amino acid sequence of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 or 111.
2. A nucleic acid sequence encoding a polypeptide according to claim 1 .
3. A nucleic acid sequence according to claim 2 , wherein said sequence comprises the nucleic acid sequence of SEQ ID NO: 112.
4. A method for activating a polypeptide comprising:
(i) providing a polypeptide according to claim 1 , said polypeptide comprising an amino acid sequence having an N-terminus and a C-terminus, wherein said amino acid sequence comprises in an N-terminus to C-terminus direction:
a) a clostridial neurotoxin L-chain amino acid sequence
b) a site for cleavage by a proteolytic enzyme;
c) a GHRH amino acid sequence; and
d) a clostridial neurotoxin H N translocation domain amino acid sequence;
(ii) contacting said polypeptide with a proteolytic enzyme that cleaves said cleavage site;
(iii) cleaving said polypeptide at said cleavage site, and thereby providing a di-chain polypeptide wherein the clostridial neurotoxin L-chain amino acid sequence and the clostridial neurotoxin H N translocation domain amino acid sequence are linked together by a disulphide bond.
5. A method according to claim 4 , wherein the proteolytic enzyme is a factor Xa proteolytic enzyme.
6. A method for suppressing secretion from a neuroendocrine tumour cell, said method comprising administering to a patient a therapeutically effective amount of a polypeptide, wherein said polypeptide is a polypeptide according to claim 1 .
7. A method according to claim 6 , wherein said method suppresses Cushing's disease.
8. A method according to claim 6 , wherein said method suppresses acromegaly.