Claims for Patent: 8,163,889

Summary for Patent: 8,163,889

Title:	Physiologically active polypeptide conjugate having prolonged in vivo half-life
Abstract:	A protein conjugate having a prolonged in vivo half-life of a physiological activity, comprising i) a physiologically active polypeptide, ii) a non-peptidic polymer, and iii) an immunoglobulin, is useful for the development of a polypeptide drug due to the enhanced in vivo stability and prolonged half-life in blood, while reducing the possibility of inducing an immune response.
Inventor(s):	Kim; Young-Min (Yongin-si, KR), Kim; Dae-Jin (Seoul, KR), Bae; Sung-Min (Seoul, KR), Lim; Chang-Ki (Seongnam-si, KR), Kwon; Se-Chang (Seoul, KR), Lee; Gwan-Sun (Seoul, KR)
Assignee:	Hanmi Holdings Co., Ltd. (Seoul, KR)
Application Number:	12/603,757
Patent Claims:	1. A protein conjugate of (A) a physiologically active polypeptide, (B) a non-peptidic polymer, and (C) immunoglobulin G, wherein the physiologically active polypeptide (A) is selected from the group consisting of human growth hormone, interferon alpha, interferon beta, granulocyte colony stimulating factor, and erythropoietin, wherein the non-peptidic polymer (B) is poly(ethylene glycol), wherein the physiologically active polypeptide (A) and the immunoglobulin G (C) are covalently linked through the non-peptidic polymer (B); and wherein the conjugate shows a prolonged in vivo half-life of the physiologically active polypeptide (A). 2. The protein conjugate according to claim 1, wherein the non-peptidic polymer (B) has reactive groups at both ends, the reactive group at one end being covalently linked to the physiologically active polypeptide (A) and the reactive group at the other end being covalently linked to the immunoglobulin G (C). 3. The protein conjugate according to claim 2, wherein the reactive group of the non-peptidic polymer (B) is selected from the group consisting of aldehyde, propion aldehyde, butyl aldehyde, maleimide and succinimide derivative. 4. The protein conjugate according to claim 3, wherein the succinimide derivative is succinimidyl propionate, succinimidyl carboxymethyl, hydroxy succinimidyl or succinimidyl carbonate. 5. The protein conjugate according to claim 3, wherein the non-peptidic polymer (B) has aldehyde groups at both ends. 6. The protein conjugate according to claim 1, wherein the immunoglobulin G (C) is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 7. The protein conjugate according to claim 1, wherein the immunoglobulin G (C) is a human immunoglobulin. 8. The protein conjugate according to claim 1, wherein the immunoglobulin G (C) is selected from the group consisting of an immunoglobulin having an increased or decreased degree of glycosylation, and an aglycosylated immunoglobulin. 9. The protein conjugate according to claim 8, wherein the increase or decrease of the degree of glycosylation or aglycosylation of an immunoglobulin is conducted by a method selected from the group consisting of a chemical method, enzymatic method, biotechnological method and a combination thereof. 10. The protein conjugate according to claim 1, wherein the non-peptidic polymer (B) is covalently linked at the ends thereof to the amino terminal, lysine residue, histidine residue or cysteine residue of the immunoglobulin and the amino terminal, lysine residue, histidine residue or cysteine residue of the physiologically active polypeptide, respectively. 11. A method for preparing the protein conjugate of claim 1, comprising: (a) covalently linking a physiologically active polypeptide and immunoglobulin G with a non-peptidic polymer, said non-peptidic polymer having reactive groups at both ends; and (b) isolating a protein conjugate of the active polypeptide, the immunoglobulin and the non-peptidic polymer, wherein the physiologically active polypeptide and the immunoglobulin are covalently linked through the non-peptidic polymer, wherein the physiologically active polypeptide is selected from the group consisting of human growth hormone, interferon alpha, interferon beta, granulocyte colony stimulating factor, and erythropoietin; and wherein the non-peptidic polymer is a poly(ethylene glycol). 12. The method according to claim 11, wherein step (a) comprises: (a1) covalently coupling one end of the non-peptidic polymer with either the immunoglobulin or the physiologically active polypeptide; (a2) isolating from the resulting reaction mixture a complex comprising the non-peptidic polymer coupled with the immunoglobulin or the physiologically active polypeptide; and (a3) covalently coupling the free end of the non-peptidic polymer of the complex with the immunoglobulin or physiologically active polypeptide, to produce a protein conjugate comprising the physiologically active polypeptide, the non-peptidic polymer and the immunoglobulin, which are covalently interlinked. 13. The method according to claim 12, wherein the molar ratio of the physiologically active polypeptide to the non-peptidic polymer in step (a1) ranges from 1:2.5 to 1: 5. 14. The method according to claim 12, wherein the molar ratio of the immunoglobulin to the non-peptidic polymer in step (a1) ranges from 1:5 to 1:10. 15. The method according to claim 12, wherein steps (a1) and (a3) are performed in the presence of a reducing agent. 16. The method according to claim 15, wherein the reducing agent is sodium cyanoborohydride, sodium borohydride, dimethylamine borate or pyridine borate. 17. The protein conjugate according to claim 1, wherein the immunoglobulin G has the wild-type glycosylation.

Details for Patent 8,163,889

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Octapharma Pharmazeutika Produktionsges.m.b.h.	CUTAQUIG	immune globulin subcutaneous (human)-hipp	Solution	125668	12/12/2018		2023-03-13