Methods of using compositions comprising variants of FGF19 polypeptides for treating primary biliary cirrhosis in a subject

Patent metadata

Field	Value
Publication number	US-11564972-B2
Application number	US-201815895812-A
Country	US
Kind code	B2
Filing date	Feb 13, 2018
Priority date	Dec 27, 2012
Publication date	Jan 31, 2023
Grant date	Jan 31, 2023

Abstract

The invention relates to methods of using variants of fibroblast growth factor 19 (FGF19) for treating primary biliary cirrhosis.

First claim

What is claimed is:

1. A method of treating a subject having primary biliary cirrhosis (PBC) with reduced hepatocellular carcinoma (HCC) formation, comprising administering to the subject an effective amount of a peptide, wherein said 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 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 a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

wherein the peptide
(A) has reduced 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.

2. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:193.

3. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:194.

4. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:195.

5. The method of claim 1 , further comprising monitoring bilirubin levels in the subject.

6. The method of claim 1 , further comprising monitoring alkaline phosphatase (ALP) levels in the subject.

7. A method of treating a subject having PBC, comprising administering to the subject an effective amount of a peptide, wherein said peptide has an amino acid sequence comprising or consisting of MRDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSA HSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEI RPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPE DLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK (SEQ ID NO:70), or a sequence comprising a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD (amino acids 99-103 of SEQ ID NO:70) sequence thereof,
thereby treating the subject.

8. The method of claim 7 , wherein the peptide has an amino acid sequence comprising SEQ ID NO:70.

9. The method of claim 7 , wherein the peptide has an amino acid sequence consisting of SEQ ID NO:70.

10. The method of claim 7 , wherein the amino acid sequence comprises EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD (amino acids 99-103 of SEQ ID NO:70) sequence of SEQ ID NO:70.

11. The method of claim 7 , wherein said peptide is fused with an immunoglobulin Fc region.

12. The method of claim 7 , wherein the peptide is formulated as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

13. The method of claim 7 , further comprising administration of a supplemental therapy.

14. The method of claim 7 , further comprising monitoring bilirubin levels in the subject.

15. The method of claim 7 , further comprising monitoring ALP levels in the subject.

16. A method of treating a subject having PBC, comprising administering to the subject an effective amount of a peptide, wherein said peptide has an amino acid sequence comprising a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD (amino acids 98-102 of SEQ ID NO:69) sequence of SEQ ID NO:69.

17. The method of claim 16 , further comprising monitoring bilirubin levels in the subject.

18. The method of claim 16 , further comprising monitoring ALP levels in the subject.

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Luo Jian

Classifications

• C12Q2600/136

  Screening for pharmacological compounds · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• A61K38/1825 Primary

  Fibroblast growth factor [FGF] · CPC title

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title

• G01N33/92

  involving lipids, e.g. cholesterol {, lipoproteins, or their receptors (steroid hormones G01N33/743)} · CPC title