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Last Updated: October 19, 2019

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Claims for Patent: 9,636,420

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Summary for Patent: 9,636,420
Title:Polypeptide complex comprising non-peptidyl polymer having three functional ends
Abstract: Disclosed is a protein complex, comprising a physiologically active polypeptide, a dimeric protein and a non-peptidyl polymer having three functional ends (3-arm), with the linkage of both the physiologically active polypeptide and the dimeric protein to the 3-arm non-peptidyl polymer via respective covalent bonds. The protein complex guarantees the long acting activity and biostability of a physiologically active polypeptide. Having the ability to maintain the bioactivity of physiologically active polypeptides or peptides highly and to significantly improve the serum half life of the polypeptides or peptides, the protein complex can be applied to the development of sustained release formulations of various physiologically active polypeptide drugs. Also, it utilizes raw materials including the physiologically active polypeptides without significant loss, thereby increasing the production yield. Further, it can be easily purified.
Inventor(s): Song; Dae Hae (Seoul, KR), Shin; Jae Hee (Suwon-si, KR), Lee; Mi Ji (Incheon, KR), Hong; Sung Hee (Suwon-si, KR), Kwon; Se Chang (Seoul, KR), Lee; Gwan Sun (Seoul, KR)
Assignee: HANMI SCIENCE CO., LTD. (Hwaseong-si, KR)
Application Number:13/055,406
Patent Claims:1. A protein complex, comprising a physiologically active polypeptide, a dimeric protein, and a non-peptidyl polymer linker, said non-peptidyl polymer linker having three functional ends, wherein the physiologically active polypeptide and the dimeric protein are linked to the functional ends of the non-peptidyl polymer via respective covalent bonds, wherein two of the three functional ends of the non-peptidyl polymer are covalently linked to two N-terminal amino groups of the dimeric protein, respectively, and remaining one of the three functional ends of the non-peptidyl polymer is covalently linked to the physiologically active polypeptide, wherein the dimeric protein is an immunoglobulin Fc domain, and wherein the non-peptidyl polymer has three functional aldehyde groups at respective termini thereof.

2. The protein complex as defined in claim 1, wherein the immunoglobulin Fc domain is aglycosylated.

3. The protein complex as defined in claim 1, wherein the immunoglobulin Fc domain is composed of one to four different domains selected from the group consisting of C.sub.H1, C.sub.H2, C.sub.H3 and C.sub.H4.

4. The protein complex as defined in claim 3, wherein the immunoglobulin Fc domain further comprises a hinge region.

5. The protein complex as defined in claim 1, wherein the immunoglobulin Fc domain is selected from the group consisting of IgG Fc domain, IgA Fc domain, IgD Fc domain, IgE Fc domain, IgM Fc domain, a combination thereof, and a hybrid thereof.

6. The protein complex as defined in claim 5, wherein the immunoglobulin Fc domain is selected from the group consisting of IgG1 Fc domain, IgG2 Fc domain, IgG3 Fc domain, IgG4 Fc domain, a combination thereof, and a hybrid thereof.

7. The protein complex as defined in claim 5, wherein the immunoglobulin Fc domain is in a form of dimers or multimers (combinations of immunoglobulin Fc), each comprising glycosylated immunoglobulins composed of domains of the same origin.

8. The protein complex as defined in claim 5, wherein the immunoglobulin Fc domain is an IgG4 Fc domain.

9. The protein complex as defined in claim 8, wherein the immunoglobulin Fc domain is a human aglycosylated IgG4 Fc domain.

10. The protein complex as defined in claim 1, wherein the non-peptidyl polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, a copolymer of ethylene glycol and propylene glycol, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, a biodegradable polymer, lipopolymer, chitin, hyaluronic acid and a combination thereof.

11. The protein complex as defined in claim 10, wherein the non-peptidyl polymer is a polyethylene glycol.

12. The protein complex as defined in claim 1, wherein the three functional ends of the non-peptidyl polymer bind to N-terminal, functional groups of the immunoglobulin Fc domain and the physiologically active polypeptide, said N-terminal, functional groups being selected from the group consisting of lysine, histidine, cysteine residues and a combination thereof.

13. The protein complex as defined in claim 1, wherein the physiologically active polypeptide is selected from the group consisting of hormone, cytokine, interleukin, interleukin-binding protein, enzyme, antibody, growth factor, transcription factor, blood factor, ligand protein, receptor, and cell surface antigen.

14. The protein complex as defined in claim 13, wherein the physiologically active polypeptide is selected from the group consisting of human growth hormone, growth hormone releasing hormone, growth hormone releasing peptide, interferon-alpha, interferon-beta, interferon receptor, granulocyte colony-stimulating factor, glucagon-like peptide, exendin-4 peptide, imidazole acetyl exendin-4 peptide (exendin-4 agonist), calcitonin, A-type natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), D-type natriuretic peptide (DNP), G protein-coupled receptor, interleukin and interleukin receptor, enzyme, interleukin-binding protein, cytokine-binding protein, macrophage activating factor, macrophage peptide, B-cell factor, T-cell factor, Protein A, cell necrosis glycoprotein, immunotoxin, lymphotoxin, tumor necrosis factor, tumor suppressor, transforming growth factor, alpha-1 anti-trypsin, albumin, .alpha.-lactalbumin, apolipoprotein-E, erythropoietin, highly glycosylated erythropoietin, angiopoeitin, hemoglobin, thrombin, thrombin receptor activating peptide, thrombomodulin, blood factor VII, VIIa, VIII, IX and XIII, plasminogen activator, fibrin-binding peptide, urokinase, streptokinase, hirudin, Protein C, C-reactive protein, superoxide dismutase, leptin, platelet-derived growth factor, epithelial growth factor, epidermal growth factor, angiostatin, angiotensin, bone growth factor, bone stimulating protein, calcitonin, insulin, somatostatin, octreotide (somatostatin agonist), atriopeptin, cartilage inducing factor, elcatonin, connective tissue activating factor, follicle stimulating hormone, luteinizing hormone, luteinizing hormone releasing hormone, nerve growth factors, parathyroid hormone, relaxin, secretin, somatomedin, insulin-like growth factor, adrenocortical hormone, glucagon, cholecystokinin, gastrin releasing peptide, corticotropin releasing factor, thyroid stimulating hormone, autotaxin, lactoferrin, myostatin, cell surface antigen, virus derived vaccine antigen, monoclonal antibody, polyclonal antibody, and an antibody fragment.

15. The protein complex as defined in claim 1, wherein the physiologically active polypeptide is selected from the group consisting of human growth harmone, interferon-alpha, interferon-beta, granulocyte colony stimulating factor, erythropoietin, exendin-4 peptide, imidazole acetyl exendin-4 peptide (exendin-4 agonist), calcitonin, octreotide (somatostatin agonist), B-type natriuretic peptide (BNP), and an antibody fragment, said antibody fragment being an Fab' fragment.

16. A method for preparing a protein complex composed of a physiologically active polypeptide, a dimeric protein and a non-peptidyl polymer having three functional ends, wherein the physiologically active polypeptide and the dimeric protein are linked to the functional ends of the non-peptidyl polymer via respective covalent bonds, wherein two of the three functional ends of the non-peptidyl polymer are covalently linked to two N-terminal amino groups of the dimeric protein, respectively, and remaining one of the three functional ends of the non-peptidyl polymer is covalently linked to the physiologically active polypeptide, said method comprising: (1) covalently linking two of the three functional ends of the non-peptidyl polymer to N-terminal amino groups of the dimeric protein to form a conjugate (2) isolating from the reaction mixture of step (1) the conjugate in which the dimeric protein is covalently linked at N-termini thereof with the non-peptidyl polymer and (3) covalently linking the physiologically active polypeptide to one free functional end of the non-peptidyl polymer of the isolated conjugate, wherein the dimeric protein is an immunoglobulin Fc domain, and wherein the non-peptidyl polymer has three functional aldehyde groups at respective termini thereof.

17. The method as defined in claim 16, wherein the dimeric protein is reacted at a molar ratio of from 1:2 to 1:5 with the non-peptidyl polymer in step (1).

18. The method as defined in claim 16, wherein the conjugate is reacted at a molar ratio of from 1:0.5 to 1:0.05 with the physiologically active polypeptide in step (3).

19. The method as defined in claim 16, wherein the reactions in both steps (1) and (3) are conducted in the presence of a reducing agent.

20. The method as defined in claim 19, wherein the reducing agent is selected from a group consisting of sodium cyanoborohydride, sodium borohydride, dimethylamine borate and pyridine borate.

21. A composition, comprising the protein complex of claim 1 and optionally a pharmaceutically acceptable vehicle.

22. The protein complex as defined in claim 1, wherein the protein complex is prepared by the method comprising: (1) covalently linking two functional ends of the non-peptidyl polymer to the N-terminal amino groups of the dimeric protein to form a conjugate; (2) isolating from the reaction mixture of step (1) the conjugate in which the dimeric protein is covalently linked at N-termini thereof with the non-peptidyl polymer and (3) covalently linking the physiologically active polypeptide to one of free functional end of the non-peptidyl polymer of the isolated conjugate.

23. A pharmaceutical composition, comprising the protein complex of claim 13 and optionally a pharmaceutically acceptable vehicle.

24. A pharmaceutical composition, comprising the protein complex of claim 14 and optionally a pharmaceutically acceptable vehicle.

Summary for Patent:   Start Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
South Korea10-2008-0071766Jul 23, 2008
PCT Information
PCT FiledJuly 23, 2009PCT Application Number:PCT/KR2009/004114
PCT Publication Date:January 28, 2010PCT Publication Number:WO2010/011096

Details for Patent 9,636,420

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   Start Trial HANMI SCIENCE CO., LTD. (Hwaseong-si, KR) 2028-07-23 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23   Start Trial HANMI SCIENCE CO., LTD. (Hwaseong-si, KR) 2028-07-23 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23   Start Trial HANMI SCIENCE CO., LTD. (Hwaseong-si, KR) 2028-07-23 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 004 2015-01-23   Start Trial HANMI SCIENCE CO., LTD. (Hwaseong-si, KR) 2028-07-23 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

International Patent Family for US Patent 9,636,420

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