Uses and methods for modulating bile acid homeostasis and treatment of bile acid disorders and diseases

Patent metadata

Field	Value
Publication number	US-2016168221-A1
Application number	US-201514985087-A
Country	US
Kind code	A1
Filing date	Dec 30, 2015
Priority date	Dec 27, 2012
Publication date	Jun 16, 2016
Grant date	—

Abstract

The invention relates to variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and/or FGF21, and variants or fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics), having one or more activities, such as bile acid homeostasis modulating activity, and methods for and uses in treatment of bile acid and other disorders.

First claim

1 - 71 . (canceled)

72 . A method of reducing bile acid synthesis in a subject having error of bile acid synthesis, 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]);
wherein the peptide (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 FGF 19 activates FGFR4; (iii) has at least one of reduced hepatocellular carcinoma (HCC) formation; 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 FGF 19, or as compared to an FGF 19 variant sequence having any of GQV, GDI, WGPI, WGDPV, WGDI, GDPI, GPI, WGQPI, WGAPI, AGDPI, WADPI, WGDAI, WGDPA, WDPI, WGDI, WGDP or FGDPI substituted for the WGDPI 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.

73 . The method of claim 72 , wherein the second C-terminal region sequence comprises from 1 to 5 amino acid substitutions, deletions or insertions.

74 . The method of claim 72 , wherein the peptide is less than about 250 amino acids in length.

75 . The method of claim 72 , wherein the N-terminal region comprises amino acid residues VHYG (SEQ ID NO:101), DASPHVHYG (SEQ ID NO:102), or DSSPLVHYG (SEQ ID NO:103).

76 . The method of claim 75 , wherein the G corresponds to the last position of the N-terminal region.

77 . The method of claim 72 , 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.

78 . The method of claim 76 , 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.

79 . The method of claim 77 , 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.

80 . The method of claim 72 , 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.

81 . The method of claim 72 , wherein amino acid residues HPIP (SEQ ID NO:107) are the first 4 amino acid residues of the N-terminal region.

82 . The method of claim 72 , 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.

83 . The method of claim 72 , 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); HPIPDSSPLLQWGDPIRLRHLYTSG (M47) (amino acids 1-25 of SEQ ID NO:47); RDSSPLLQWGDPIRLRHLYTSG (M52) (amino acids 1-22 of SEQ ID NO:52); DSSPLLQWGDPIRLRHLYTSG (M52-R) (amino acids 2-22 of SEQ ID NO:52); MDSSPLVHYGWGDPIRLRHLYTSG (M53) (amino acids 1-24 of SEQ ID NO:53); RDSSPLVHYGWGDPIRLRHLYTSG (M69) (amino acids 1-24 of SEQ ID NO:69); DSSPLVHYGWGDPIRLRHLYTSG (M69-R) (amino acids 2-24 of SEQ ID NO:69); MRDSSPLVHYGWGDPIRLRHLYTSG (M70) (amino acids 1-25 of SEQ ID NO:70); DSSPLVHYGWGDPIRLRHLYTSG (M141) (amino acids 1-23 of SEQ ID NO:141); or HPIPDSSPLLQFGWGDPIRLRHLYTSG (M163) (amino acids 1-27 of SEQ ID NO:163).

84 . The method of claim 72 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:1 (M1), SEQ ID NO:2 (M2), SEQ ID NO:8 (M8), SEQ ID NO:9 (M9), SEQ ID NO:26 (M26), SEQ ID NO:47 (M47), SEQ ID NO:52 (M52), SEQ ID NO:53 (M53), SEQ ID NO:69, (M69), SEQ ID NO:70 (M70); SEQ ID NO:141 or SEQ ID NO:163.

85 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:1.

86 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:2.

87 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:52.

88 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:53.

89 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:69.

90 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:8.

91 . The method of claim 84 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:9.

92 . The method of claim 84 , wherein the peptide

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Luo Jian

Classifications

• C07K14/50 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

• G01N33/68

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

• A61K38/1825 Primary

  Fibroblast growth factor [FGF] · CPC title

• G01N33/5067

  Liver cells · CPC title