INHIBITION OF SECRETION FROM NON-NEURONAL CELLS

• US 20140348828A1
• Filed: 08/14/2014
• Published: 11/27/2014
• Est. Priority Date: 09/23/1999
• Status: Abandoned Application

• Current Assignee: Ipsen Bioinnovation Limited (Ipsen Sa)
• Original Assignee: Syntaxin Limited
• Inventors: FOSTER, Keith Alan, CHADDOCK, John Andrew, QUINN, Conrad Padraig, PURKISS, John Robert
• Application Number:
  US14/459,955
• Publication Number:
  US 20140348828A1
• Time in Patent Office: Days
• US Class Current: 424/134.1
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 16/1282 from Clostridium (G)
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 9/52 derived from bacteria or Archaea
• CPC Class Codes: C12Y 304/24069 Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin

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.

Claims

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.

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.

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).

3. (canceled)

12-20. -20. (canceled)