Methods of using compositions comprising variants of FGF19 polypeptides for reducing bile acid synthesis in a subject having cirrhosis

Patent metadata

Field	Value
Publication number	US-11103554-B2
Application number	US-201916282058-A
Country	US
Kind code	B2
Filing date	Feb 21, 2019
Priority date	Dec 27, 2012
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

The invention relates to methods of using variants of fibroblast growth factor 19 (FGF19) for reducing bile acid synthesis in a subject having cirrhosis.

First claim

What is claimed is:

1. A method of reducing bile acid synthesis in a subject having cirrhosis, comprising administering to the subject an effective amount of a peptide, wherein the peptide comprises:
a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises DSSPL (SEQ ID NO:121) or DASPH (SEQ ID NO:122); and
b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises
(i) a first C-terminal region sequence comprising WGDPIRLRHLYTSG (amino acids 16 to 29 of SEQ ID NO:99 [FGF19]), wherein the W residue corresponds to the first amino acid position of the C-terminal region; and
(ii) a second C-terminal region sequence comprising PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHS VRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRL PVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESD MFSSPLETDSMDPFGLVTGLEAVRSPSFEK (amino acid residues 30 to 194 of SEQ ID NO:99 [FGF19]); or a sequence comprising from 1 to 5 amino acid substitutions, deletions or insertions thereof;

wherein the peptide
(A) has reduced hepatocellular carcinoma (HCC) formation as compared to FGF19, or as compared to an FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184), substituted for the WGDPI (SEQ ID NO:170) sequence at amino acids 16-20 of FGF19 (SEQ ID NO:99); and
(B)(i) binds to fibroblast growth factor receptor 4 (FGFR4) with an affinity equal to or greater than FGF19 binding affinity for FGFR4;
(ii) activates FGFR4 to an extent or amount equal to or greater than FGF19 activates FGFR4;
(iii) has at least one of greater glucose lowering activity, less lipid increasing activity, less triglyceride activity, less cholesterol activity, less non-HDL activity or less HDL increasing activity, as compared to FGF19, or as compared to an FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184), substituted for the WGDPI (SEQ ID NO:170) sequence at amino acids 16-20 of FGF19 (SEQ ID NO:99); and/or
(iv) has less lean mass reducing activity as compared to FGF21;
thereby reducing bile acid synthesis in said subject without inducing HCC formation.

2. The method of claim 1 , wherein the second C-terminal region sequence comprises from 1 to 5 amino acid substitutions, deletions or insertions.

3. The method of claim 1 , wherein the peptide is less than about 250 amino acids in length.

4. The method of claim 1 , wherein the N-terminal region comprises amino acid residues DASPHVHYG (SEQ ID NO:102), or DSSPLVHYG (SEQ ID NO:103).

5. The method of claim 4 , wherein the G corresponds to the last position of the N-terminal region.

6. The method of claim 5 , wherein the N-terminal region further comprises:
RHPIP (SEQ ID NO:106), wherein R is the first amino acid position of the N-terminal region;
HPIP (SEQ ID NO:107), wherein H is the first amino acid position of the N-terminal region;
RPLAF (SEQ ID NO:108), wherein R is the first amino acid position of the N-terminal region;
PLAF (SEQ ID NO:109), wherein P is the first amino acid position of the N-terminal region; or
R, wherein R is the first amino acid position of the N-terminal region.

7. The method of claim 1 , wherein the N-terminal region comprises amino acid residues DSSPLLQ (SEQ ID NO:104), and wherein the Q residue is the last amino acid position of the N-terminal region.

8. The method of claim 7 , wherein the N-terminal region further comprises:
RHPIP (SEQ ID NO:106), wherein R is the first amino acid position of the N-terminal region;
HPIP (SEQ ID NO:107), wherein H is the first amino acid position of the N-terminal region;
RPLAF (SEQ ID NO:108), wherein R is the first amino acid position of the N-terminal region;
PLAF (SEQ ID NO:109), wherein P is the first amino acid position of the N-terminal region; or
R, wherein R is the first amino acid position of the N-terminal region.

9. The method of claim 1 , wherein the N-terminal region comprises amino acid residues DSSPLLQFGGQV (SEQ ID NO:105), and wherein the V residue corresponds to the last position of the N-terminal region.

10. The method of claim 1 , wherein amino acid residues HPIP (SEQ ID NO:107) are the first 4 amino acid residues of the N-terminal region.

11. The method of claim 1 , wherein
the first position of the N-terminal region is a R or M residue;
the first and second positions of the N-terminal region is a MR, RM, RD, DS, MD or MS sequence;
the first through third positions of the N-terminal region is a MDS, RDS, MSD, MSS, or DSS sequence;
the first through fourth positions of the N-terminal region is a RDSS (SEQ ID NO:115) or MDSS (SEQ ID NO:116) sequence;
the first through fifth positions of the N-terminal region is an MRDSS (SEQ ID NO:117) sequence;
the first through sixth positions of the N-terminal region is an MDSSPL (SEQ ID NO:119) sequence; or
the first through seventh positions of the N-terminal region is an MSDSSPL (SEQ ID NO:120) sequence.

12. The method of claim 1 , wherein the N-terminal region and the first C-terminal region of the peptide has an amino acid sequence comprising or consisting of any of:

RPLAFSDASPHVHYGWGDPIRLRHLYTSG (M1)(amino acids 1-

29 of SEQ ID NO: 1);

PLAFSDASPHVHYGWGDPIRLRHLYTSG (M1-R)(amino acids 2-

29 of SEQ ID NO: 1);

RPLAFSDSSPLVHYGWGDPIRLRHLYTSG (M2)(amino acids 1-

29 of SEQ ID NO: 2);

PLAFSDSSPLVHYGWGDPIRLRHLYTSG (M2-R)(amino acids 2-

29 of SEQ ID NO: 2);

RHPIPDSSPLLQWGDPIRLRHLYTSG (M8)(amino acids 1-26

of SEQ ID NO: 8);

RHPIPDSSPLLQFGWGDPIRLRHLYTSG (M9)(amino acids 1-28

of SEQ ID NO: 9);

RPLAFSDSSPLVHWGDPIRLRHLYTSG (M26)(amino acids 1-27

of SEQ ID NO: 26);

PLAFSDSSPLVHWGDPIRLRHLYTSG (M26-R)(amino acids 2-

27 of SEQ ID NO: 26);

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Luo Jian

Classifications

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title

• G01N33/5067

  Liver cells · CPC title

• C07K14/50

  Fibroblast growth factor [FGF] · CPC title

• A61K38/1825 Primary

  Fibroblast growth factor [FGF] · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title