Growth differentiation factor 15 (gdf-15) constructs

Patent metadata

Field	Value
Publication number	US-2016168213-A1
Application number	US-201414908459-A
Country	US
Kind code	A1
Filing date	Jul 31, 2014
Priority date	Jul 31, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

Constructs comprising GDF15, and mutants thereof are provided. In various embodiments the constructs comprising GDF15, and mutants thereof, can be of use in the treatment or ameliorating a metabolic disorder. In various embodiments the metabolic disease or disorder is type 2 diabetes, obesity, dyslipidemia, elevated glucose levels, elevated insulin levels and diabetic nephropathy.

First claim

What is claimed is:

1 . A fusion protein comprising a GDF15 region and an Fc domain.

2 . The fusion protein of claim 1 , wherein the Fc domain comprises a sequence selected from the group consisting of SEQ ID NOs:16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

3 . The fusion protein of claim 2 , wherein the GDF15 region comprises a sequence selected from the group consisting of SEQ ID NOs:4, 8, 12, 25, 52 and 55.

4 . The fusion protein of claim 2 , wherein the GDF15 region and the Fc domain are joined by a polypeptide linker.

5 . The fusion protein of claim 4 , wherein the polypeptide linker is selected from the group consisting of SEQ ID NOs:18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125, 128.

6 . The fusion protein of claim 1 , wherein the fusion protein comprises a sequence selected from the group consisting of SEQ ID NOs: 46, 24, 27, 32, 37, 20, 42, 50, 54, 57, 60, 63, 66, 68, 71, 74, 77, 82, 84, 88, 93, 96, 98, 100, 102, 104, 108, 134, 137, 139, 143, 146, 150, 153, 269, 272, 276, 279, 157, 160, 164, 167, 171, 174, 178, 181, 185, 188, 194, 197, 201, 204, 208, 211, 215, 218, 222, 225, 229, 232, 233, 238 and 240.

7 . The fusion protein of claim 1 , wherein the fusion protein comprises two or more Fc domains.

8 . A dimer comprising (i) a first polypeptide chain comprising a GDF15 region and a first Fc domain, and (ii) a second polypeptide chain comprising a second Fc domain.

9 . The dimer of claim 8 , wherein first Fc domain comprises a sequence selected from the group consisting of SEQ ID NOs:16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

10 . The dimer of claim 9 , wherein second Fc domain comprises a sequence selected from the group consisting of SEQ ID NOs:16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

11 . The dimer of claim 9 , wherein the GDF15 region comprises a sequence selected from the group consisting of SEQ ID NOs:4, 8, 12, 25, 52 and 55.

12 . The dimer of claim 9 , wherein the GDF15 region and the Fc domain are joined by a polypeptide linker.

13 . The dimer of 12 , wherein the polypeptide linker is selected from the group consisting of SEQ ID NOs:18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125, 128.

14 . The dimer of claim 8 , wherein the fusion protein comprises a sequence selected from the group consisting of SEQ ID NOs: 46, 24, 27, 32, 37, 20, 42, 50, 54, 57, 60, 63, 66, 68, 71, 74, 77, 82, 84, 88, 93, 96, 98, 100, 102, 104, 108, 134, 137, 139, 143, 146, 150, 153, 269, 272, 276, 279, 157, 160, 164, 167, 171, 174, 178, 181, 185, 188, 194, 197, 201, 204, 208, 211, 215, 218, 222, 225, 229, 232, 233, 238 and 240.

15 . The dimer of claim 8 , wherein the first and second polypeptide chains are non-covalently associated.

16 . The dimer of claim 8 , wherein the first and second polypeptide chains are covalently associated.

17 . The dimer of claim 16 , wherein the first and second polypeptide chains are covalently associated via disulfide bonds between their respective Fc domains.

18 . A tetramer comprising (i) a first dimer and (ii) a second dimer, wherein the first and second dimer independently comprise a dimer of claim 1 and wherein the first polypeptide chain of the first dimer is linked to the first polypeptide chain of the second dimer via an interchain disulfide bond between their respective GDF15 regions.

19 . The tetramer of claim 18 , wherein the Fc domain of the first polypeptide of the first dimer comprises a sequence selected from the group consisting of SEQ ID NOs:16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

20 . The tetramer of claim 19 , wherein the GDF15 region of the first polypeptide chain of the first dimer comprises a sequence selected from the group consisting of SEQ ID NOs:4, 8, 12, 25, 52 and 55.

21 . The tetramer of claim 20 , wherein the GDF15 region and the Fc domain are joined by a polypeptide linker.

22 . The tetramer of claim 21 , wherein the polypeptide linker is selected from the group consisting of SEQ ID NOs:18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125, 128.

23 . The tetramer of claim 18 , wherein the Fc domain of the first polypeptide of the first dimer comprises a sequence selected from the group consisting of SEQ ID NOs: 46, 24, 27, 32, 37, 20, 42, 50, 54, 57, 60, 63, 66, 68, 71, 74, 77, 82, 84, 88, 93, 96, 98, 100, 102, 104, 108, 134, 137, 139, 143, 146, 150, 153, 269, 272, 276, 279, 157, 160, 164, 167, 171, 174, 178, 181, 185, 188, 194, 197, 201, 204, 208, 211, 215, 218, 222, 225, 229, 232, 233, 238 and 240.

24 . The tetramer of claim 19 , wherein the Fc domain of the first polypeptide of the second dimer comprises a sequence selected from the group consisting of SEQ ID NOs:16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

25 . The tetramer of claim 24 , wherein the Fc domain of the first polypeptide of the second dimer comprises a sequence selected from the group consisting of SEQ ID NOs: 46, 24, 27, 32, 37, 20, 42, 50, 54, 57, 60, 63, 66, 68, 71, 74, 77, 82, 84, 88, 93, 96, 98, 100, 102, 104, 108, 134, 137, 139, 143, 146, 150, 153, 269, 272, 276, 279, 157, 160, 164, 167, 171, 174, 178, 181, 185, 188, 194, 197, 201, 204, 208, 211, 215, 218, 222, 225, 229, 232, 233, 238 and 240.

Assignees

• Amgen Inc

Inventors

• Xiong Yumei
• Zhang Yi
• Sheng Jackie Z
• Hamburger Agnes Eva
• Veniant-Ellison Murielle
• Shimamoto Grant
• Min Xiaoshan
• Wang Zhulun
• Tang Jie
• Kannan Gunasekaran
• Mock Marissa
• Walker Kenneth

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title