Claims for Patent: 9,969,786

Summary for Patent: 9,969,786

Title:	Trophic hormone fusion protein, preparation method and application thereof
Abstract:	Disclosed herein is a gonadotropin fusion protein or a thyroid stimulating hormone fusion protein, a method for preparing the same and use thereof. .beta.-subunit of the gonadotropin or thyroid stimulating hormone is fused to an Fc fragment directly or indirectly through a linker, and .alpha.-subunit binds to the .beta.-subunit via an affinity between the .alpha.-subunit and the .beta.-subunit. The fusion protein has a prolonged half-life and less fluctuating activity.
Inventor(s):	Xu; Ting (Jiangsu, CN), Guo; Kangping (Jiangsu, CN), Yun; Lihong (Jiangsu, CN)
Assignee:	Suzhou Alphamab Co, Ltd. (Suzhou Jiangsu, CN)
Application Number:	14/646,926
Patent Claims:	1. A fusion protein comprising a trophic hormone protein having an .alpha.-subunit, a .beta.-subunit and an Fc fragment of an antibody, wherein the .beta.-subunit of the trophic hormone protein is linked to the Fc fragment directly or indirectly via a linker, and the .alpha.-subunit of the trophic hormone protein binds to the .beta.-subunit via intermolecular interactions between the .alpha.-subunit and the .beta.-subunit, wherein the .alpha.-subunit of the trophic hormone is not directly or indirectly linked to an Fc fragment, and wherein the trophic hormone is selected from the group consisting of luteotropic hormone, follicle stimulating hormone, chorionic gonadotropin, and thyroid stimulating hormone. 2. A heterodimeric protein comprising one fusion protein according to claim 1 and an Fc chain, wherein the Fc chain is associated with the Fc fragment in the fusion protein via chemical association. 3. The heterodimeric protein according to claim 2, wherein the heterodimeric protein has the formula: .alpha.FSH@.beta.FSH-L-Fc:Fc, wherein "FSH" refers to follicle stimulating hormone protein, ".alpha." refers to the .alpha.-subunit of the follicle stimulating hormone protein, ".beta." refers to the .beta.-subunit of the follicle stimulating hormone protein, "@" is the intermolecular interaction between the .alpha.-subunit and .beta.-subunit of the follicle stimulating hormone protein, "L" represents direct linking between the .beta.-subunit and Fc fragment or indirect linking via a linker, "Fc" refers to the Fc fragment of an immunoglobulin, and ":" refers to the chemical association between .beta.FSH-L-Fc and Fc. 4. The heterodimeric protein according to claim 2, wherein the heterodimeric protein has the formula: Ta-.alpha.XXX@.beta.XXX-L-Fc:Fc or Ta-Fc:Fc-L-.beta.XXX@.alpha.XXX wherein "XXX" refers to follicle stimulating hormone, ".alpha." refers to the .alpha.-subunit of the follicle stimulating hormone, ".beta." refers to the .beta.-subunit of the follicle stimulating hormone, "@" is the intermolecular interaction between the .alpha.-subunit and .beta.-subunit of the trophic hormone protein, "L" represents direct linking between the .beta.-subunit and Fc fragment or indirect linking via a linker, "Fc" refers to the Fc fragment of an immunoglobulin, ":" refers to the chemical association between .beta.XXX-L-Fc and Fc, and "Ta" refers to a protein purification tag. 5. A pharmaceutical composition comprising the fusion protein according to claim 1, and a pharmaceutically acceptable carrier or excipient. 6. A recombinant expression vector comprising a nucleotide sequence encoding an .alpha.-subunit of a trophic hormone protein, a nucleotide sequence encoding a fusion protein comprising a .beta.-subunit of the trophic hormone protein and an Fc fragment of an antibody, and a nucleotide sequence encoding an Fc fragment of an antibody, wherein each of the proteins is transcribed and translated independently, and the trophic hormone is selected from the group consisting of luteotropic hormone, follicle stimulating hormone, chorionic gonadotropin and thyroid stimulating hormone. 7. A recombinant cell comprising the recombinant expression vector according to claim 6. 8. A method for preparing a heterodimeric protein comprising a fusion protein that comprises a trophic hormone protein having an .alpha.-subunit and a .beta.-subunit and an Fc fragment of an antibody, wherein the .beta.-subunit of the trophic hormone protein is linked to the Fc fragment directly or indirectly via a linker, and the .alpha.-subunit of the trophic hormone protein binds to the .beta.-subunit via intermolecular interactions between the .alpha.-subunit and the .beta.-subunit, wherein the .alpha.-subunit of the trophic hormone is not directly or indirectly linked to an Fc fragment, and wherein the trophic hormone is selected from the group consisting of luteotropic hormone, follicle stimulating hormone, chorionic gonadotropin and thyroid stimulating hormone, and an Fc chain, wherein the Fc chain is associated with the Fc fragment in the fusion protein via chemical association, comprising the step of isolating and purifying a mixture of heterodimeric proteins and homodimeric proteins, wherein the homodimeric proteins comprise two fusion proteins, wherein each fusion protein comprises a trophic hormone protein having an .alpha.-subunit and a .beta.-subunit and an Fc fragment of an antibody, wherein the .beta.-subunit of the trophic hormone protein is linked to the Fc fragment directly or indirectly via a linker, and the .alpha.-subunit of the trophic hormone protein binds to the .beta.-subunit via intermolecular interactions between the .alpha.-subunit and the .beta.-subunit, wherein the .alpha.-subunit of the trophic hormone is not directly or indirectly linked to an Fc fragment, and wherein the trophic hormone is selected from the group consisting of luteotropic hormone, follicle stimulating hormone, chorionic gonadotropin and thyroid stimulating hormone, and wherein the Fc fragments in the two fusion proteins are associated with each other via chemical association to obtain the heterdimeric protein. 9. The fusion protein according to claim 1, wherein the trophic hormone is follicle stimulating hormone. 10. The fusion protein according to claim 9, wherein the follicle stimulating hormone .alpha.-subunit comprises a sequence according to SEQ ID NO: 1. 11. The fusion protein according to claim 9, wherein the follicle stimulating hormone .beta.-subunit linked to the Fc fragment comprises a sequence according to SEQ ID NO:4. 12. The fusion protein according to claim 9, wherein the follicle stimulating hormone .alpha.-subunit comprises a sequence according to SEQ ID NO:1 and the follicle stimulating hormone .beta.-subunit linked to the Fc fragment comprises a sequence according to SEQ ID NO:4. 13. The fusion protein according to claim 1, wherein the Fc fragment comprises a hinge region, a CH2 domain, and a CH3 domain of an immunoglobulin. 14. The fusion protein according to claim 1, wherein the Fc fragment comprises an IgG1 Fc.a.

Details for Patent 9,969,786

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	01/15/1974		2032-11-22
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	12/27/1984		2032-11-22
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/15/1985		2032-11-22
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/16/1990		2032-11-22