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Claims for Patent: 10,081,803

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Summary for Patent: 10,081,803
Title:Therapeutic fusion proteins
Abstract: The present invention relates to the construction of a new class of Targeted Secretion Inhibitors (TSIs), which comprise a non-cytotoxic protease, translocation peptide and a targeting moiety peptide, wherein the targeting moiety peptide has a free N-terminal domain and a free C-terminal domain; to a single-chain fusion protein precursor thereof, and to a method of activating said single-chain fusion protein precursor.
Inventor(s): Chaddock; John (Abingdon, GB), Harper; Elaine (Abingdon, GB)
Assignee: Ipsen Bioinnovation Limited (Abingdon, Oxfordshire, GB)
Application Number:14/117,286
Patent Claims:1. A single-chain, polypeptide fusion protein, comprising: (a) a non-cytotoxic protease capable of cleaving a protein of the exocytic fusion apparatus of a target cell; (b) a targeting moiety that is capable of binding to a binding site on the target cell, which binding site is capable of undergoing endocytosis to be incorporated into an endosome within the target cell; (c) a translocation domain that is capable of translocating the protease from within an endosome, across the endosomal membrane and into the cytosol of the target cell; (d) a first protease cleavage site at which site the fusion protein is cleavable by a first protease, wherein the first protease cleavage site is located between the non-cytotoxic protease and the translocation domain; (e) a second protease cleavage site at which site the fusion protein is cleavable by a second protease, wherein the second protease cleavage site is located between the translocation domain and the targeting moiety; and (f) a covalent linkage between the targeting moiety and the translocation domain; wherein: following proteolytic cleavage at the second protease cleavage site, the targeting moiety remains linked to the translocation domain by the covalent linkage; and following cleavage at the first and second cleavage sites, the targeting moiety is capable of interacting with the binding site on the target cell via an interaction between an N-terminal domain of the targeting moiety and a domain of the binding site and simultaneously via an interaction between a C-terminal domain of the targeting moiety and a domain of the binding site.

2. The fusion protein of claim 1, wherein the translocation domain is located between the non-cytotoxic protease and the targeting moiety.

3. The fusion protein of claim 1, wherein the targeting moiety is located between the non-cytotoxic protease and the translocation domain and the first protease cleavage site is located between the noncytotoxic protease and the targeting moiety.

4. The fusion protein of claim 1, wherein the non-cytotoxic protease is located at the N-terminus of the protein.

5. The fusion protein of claim 1, wherein the covalent linkage is a disulphide linkage.

6. The fusion protein of claim 1, wherein a short polypeptide that provides a secondary polypeptide structure is located between the translocation domain and the targeting moiety and the secondary polypeptide structure acts to bring part of the targeting moiety into close proximity to the translocation domain, thereby making formation of the covalent linkage energetically more favorable.

7. The fusion protein of claim 1 wherein the targeting moiety comprises first and second domains, wherein the first and second domains are separated by at most 10 amino acid residues.

8. The fusion protein of claim 7, wherein the first and second domains are derived from ligands to different receptors.

9. The fusion protein of claim 1, wherein the targeting moiety comprises a peptide selected from the group consisting of: a gonadotropin-releasing hormone (GnRH) peptide, an opioid peptide, a beta-endorphin peptide, a bradykinin peptide, a BAM peptide, a nociceptin peptide, a dynorphin peptide, a galanin peptide, an enkephalin peptide, a substance P peptide, a corticotropin-releasing factor (CRF) peptide, a gastrin-releasing peptide (GRP), a Neuromedin B peptide, a bombesin peptide, a gastrin peptide, a CCK peptide, a somatostatin (SST) peptide, a cortistatin (CST) peptide, a growth hormone releasing hormone (GHRH) peptide, a PAR peptide, a parathyroid hormone (PTH) peptide, a vasointestinal peptide (VIP), a beta2 adrenoreceptor agonist peptide, a gastrin-releasing peptide, a calcitonin gene related peptide, a thyroid stimulating hormone (TSH) peptide, an insulin peptide, an insulin-like growth factor peptide, a gonadorelin peptide, a corticotrophin releasing hormone (CRH) peptide, an adrenocorticotropic hormone (ACTH) peptide, and a pituitary adenyl cyclase activating peptide (PACAP).

10. The fusion protein of claim 1, wherein the non-cytotoxic protease and the first protease cleavage site are separated by at most 10 amino acid residues.

11. The fusion protein of claim 1, wherein the translocation domain and the first protease cleavage site are separated by at most 10 amino acid residues.

12. The fusion protein of claim 1, wherein the translocation domain and the second protease cleavage site are separated by at most 10 amino acid residues.

13. The fusion protein of claim 1, wherein the targeting moiety and the second protease cleavage site are separated by at most 10 amino acid residues.

14. The fusion protein of claim 1, wherein the first protease and the second protease are the same.

15. The fusion protein of claim 1, wherein the non-cytotoxic protease is a clostridial neurotoxin L-chain or a fragment thereof.

16. The fusion protein of claim 1, wherein the translocation domain is a clostridial neurotoxin H.sub.N domain or a fragment thereof.

17. The fusion protein of claim 1, wherein the fusion protein comprises a purification tag.

18. A method for preparing a single-chain polypeptide fusion protein, comprising expressing a nucleic acid sequence encoding the fusion protein of claim 1 in a host cell.

19. A method of preparing a non-cytotoxic agent, comprising: providing a solution containing the fusion protein of claim 1; adding to the solution a first protease capable of cleaving the first protease cleavage site and a second protease capable of cleaving the second protease cleavage site; and cleaving the first protease cleavage site and the second protease cleavage site, thereby forming a tri-chain polypeptide.

20. A non-cytotoxic polypeptide, wherein the polypeptide is a tri-chain polypeptide prepared using the method of claim 19 and wherein: the first chain comprises the non-cytotoxic protease capable of cleaving a protein of the exocytic fusion apparatus of a target cell; the second chain comprises a translocation domain capable of translocating the non-cytotoxic protease from within an endosome, across the endosomal membrane and into the cytosol of the target cell; the third chain comprises a targeting moiety capable of binding to a binding site on the target cell, which binding site is capable of undergoing endocytosis to be incorporated into an endosome within the target cell; and the first and second chains are linked by a disulphide linkage and the second and third domains are linked by a covalent linkage.

21. A method of treating a medical condition comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising the fusion protein of claim 1, wherein the medical condition is selected from the group consisting of: pain, neurogenic inflammation, a urogenital-neurological condition, over active bladder, prostate cancer, lung cancer, breast cancer, and colorectal cancer.

22. A method of treating a medical condition comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising the non-cytotoxic polypeptide of claim 20, wherein the medical condition is selected from the group consisting of: pain, neurogenic inflammation, a urogenital-neurological condition, over active bladder, prostate cancer, lung cancer, breast cancer, and colorectal cancer.

23. The fusion protein of claim 1, wherein the targeting moiety comprises a gonadotropin-releasing hormone (GnRH) peptide.

24. The fusion protein of claim 23, wherein the GnRH peptide is a ten amino acid GnRH peptide that has a cysteine residue at position 6 from the N-terminus of the peptide.

25. The fusion protein of claim 1, wherein the targeting moiety comprises GnRH.

Summary for Patent: ⤷  Free Forever Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
United Kingdom1108108.0May 16, 2011
PCT Information
PCT FiledMay 16, 2012PCT Application Number:PCT/GB2012/051104
PCT Publication Date:November 22, 2012PCT Publication Number:WO2012/156743

Details for Patent 10,081,803

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 001 2015-01-23 ⤷  Free Forever Trial Ipsen Bioinnovation Limited (Abingdon, Oxfordshire, GB) 2031-05-16 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23 ⤷  Free Forever Trial Ipsen Bioinnovation Limited (Abingdon, Oxfordshire, GB) 2031-05-16 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23 ⤷  Free Forever Trial Ipsen Bioinnovation Limited (Abingdon, Oxfordshire, GB) 2031-05-16 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 004 2015-01-23 ⤷  Free Forever Trial Ipsen Bioinnovation Limited (Abingdon, Oxfordshire, GB) 2031-05-16 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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