US2020140557A1PendingUtilityA1

Fgfr1 agonists and methods of use

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Assignee: GENENTECH INCPriority: May 16, 2011Filed: May 16, 2019Published: May 7, 2020
Est. expiryMay 16, 2031(~4.8 yrs left)· nominal 20-yr term from priority
Inventors:Junichiro SonodaYan Wu
A61P 5/50A61K 2039/505A61P 15/00A61K 39/3955C07K 2317/75A61K 45/06A61P 3/04C07K 2317/31C07K 2317/34A61P 1/16C07K 16/40C07K 16/28C07K 2317/92C07K 16/2863C07K 2317/35A61P 15/08A61P 43/00A61P 5/48A61P 3/06A61P 9/00A61P 3/10A61P 9/12C07K 2317/56A61P 3/00A61K 39/395
65
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Claims

Abstract

The invention provides FGFR1 agonists, including agonistic anti-FGFR1 antibodies, and methods of using the same.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating a metabolic disease or condition in an individual, comprising administering to the individual an effective amount of an anti-fibroblast growth factor receptor-1 (FGFR1) agonist, wherein the metabolic disease is selected from the group consisting of: polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, hypertension, type 2 diabetes, non-type 2 diabetes, type 1 diabetes, latent autoimmune diabetes (LAD), and maturity onset diabetes fo the young (MODY), wherein the FGFR1 agonist does not activate FGFR2 or FGFR3. 
     
     
         2 . The method of  claim 1 , wherein the FGFR1 agonist is an anti-FGFR1 antibody. 
     
     
         3 . The method of  claim 2 , wherein the anti-FGFR1 antibody binds to peptide #26 KLHAVPAAKTVKFKCP (SEQ ID NO: 28) or peptide #28 FKPDHRIGGYKVRY (SEQ ID NO: 29). 
     
     
         4 . The method of  claim 2 , wherein the anti-FGFR1 antibody binds to both FGFR1b and FGFR1c. 
     
     
         5 . The method of  claim 1 , wherein the antibody is a bispecific antibody. 
     
     
         6 . The method of  claim 5 , wherein the antibody also binds to beta-Klotho. 
     
     
         7 . An isolated antibody that binds to FGFR1, wherein the antibody is an agonist of FGFR1 activity. 
     
     
         8 . The isolated antibody of  claim 7 , wherein the antibody is not an agonist of FGFR2 or FGFR3. 
     
     
         9 . The antibody of  claim 7  or  8 , wherein the antibody is a monoclonal antibody. 
     
     
         10 . The antibody of any one of  claims 7 - 9 , wherein antibody binds to peptide #26 KLHAVPAAKTVKFKCP (SEQ ID NO: 28) or peptide #28 FKPDHRIGGYKVRY (SEQ ID NO: 29). 
     
     
         11 . The antibody of any one of  claims 7 - 10 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
         12 . An anti-FGFR1 antibody, wherein the antibody comprises (a) HVR-H3 comprising an amino acid sequence selected from the group consisting of SSGYGGSDYAMDY (SEQ ID NO: 16), SGYGGSDYAMDY (SEQ ID NO: 17), EHFDAWVHYYVMDY (SEQ ID NO: 18), TGTDVMDY (SEQ ID NO: 19), and GTDVMDY (SEQ ID NO: 20), (b) HVR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 23), and (c) HVR-H2 comprising an amino acid sequence selected from the group consisting of X 1 X 2 IX 3 PX 4 DGX 5 TX 6 YADSVKG, wherein X 1  is A or G, X 2  is D or E, X 3  is D or Y, X 4  is N or Y, X 5  is A or D, and X 6  is D or Y (SEQ ID NO: 24) and X 1 IX 2 PX 3 DGX 4 TX 5 YADSVKG, wherein X 1  is D or E, X 2  is D or Y, X 3  is N or Y, X 4  is A or D, and X 5  is D or Y (SEQ ID NO: 25). 
     
     
         13 . An anti-FGFR1 antibody, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFX 1 X 2 X 3 X 4 IX 5 , wherein X 1  is S or T, X 2  is N or S, X 3  is N or T, X 4  is W or Y, X 5  is H or S (SEQ ID NO: 26), (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of X 1 X 2 IX 3 PX 4 DGX 5 TX 6 YADSVKG, wherein X 1  is A or G, X 2  is D or E, X 3  is D or Y, X 4  is N or Y, X 5  is A or D, and X 6  is D or Y (SEQ ID NO: 24) and X 1 IX 2 PX 3 DGX 4 TX 5 YADSVKG, wherein X 1  is D or E, X 2  is D or Y, X 3  is N or Y, X 4  is A or D, and X 5  is D or Y (SEQ ID NO: 25), and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SSGYGGSDYAMDY (SEQ ID NO: 16), SGYGGSDYAMDY (SEQ ID NO: 17), EHFDAWVHYYVMDY (SEQ ID NO: 18), TGTDVMDY (SEQ ID NO: 19), and GTDVMDY (SEQ ID NO: 20). 
     
     
         14 . The antibody of  claim 13 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFTSTWIS (SEQ ID NO: 7), (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of GEIDPYDGDTYYADSVKG (SEQ ID NO: 10) and EIDPYDGDTYYADSVKG (SEQ ID NO: 11), and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SSGYGGSDYAMDY (SEQ ID NO: 16) and SGYGGSDYAMDY (SEQ ID NO: 17). 
     
     
         15 . The antibody of  claim 13 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSNNYIH (SEQ ID NO: 8), (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of ADIYPNDGDTDYADSVKG (SEQ ID NO: 12) and DIYPNDGDTDYADSVKG (SEQ ID NO: 13), and (c) HVR-H3 comprising the amino acid sequence EHFDAWVHYYVMDY (SEQ ID NO: 18). 
     
     
         16 . The antibody of  claim 13 , the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFTSNWIS (SEQ ID NO: 9), (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of AEIDPYDGATDYADSVKG (SEQ ID NO:
 14) and EIDPYDGATDYADSVKG (SEQ ID NO: 15), and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of TGTDVMDY (SEQ ID NO: 19) and GTDVMDY (SEQ ID NO: 20).   
     
     
         17 . The antibody of any one of  claims 12 - 16 , further comprising (a) HVR-L1 comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 21); (b) HVR-L2 comprising the amino acid sequence SASFLYS (SEQ ID NO: 22); and (c) HVR-L3 comprising the amino acid sequence QQSYTTPPT (SEQ ID NO: 23). 
     
     
         18 . The antibody of  claim 13 , comprising a VH sequence selected from the group consisting of SEQ ID NO: 2, 3 and 4. 
     
     
         19 . The antibody of  claim 18 , further comprising a VL sequence of SEQ ID NO: 6. 
     
     
         20 . The antibody of any one of  claims 7 - 19 , wherein the antibody is a multispecific antibody. 
     
     
         21 . The antibody of  claim 20 , wherein the antibody also binds to beta-Klotho. 
     
     
         22 . The antibody of any one of  claims 7 - 21 , which is an IgG1 antibody. 
     
     
         23 . Isolated nucleic acid encoding the antibody of any one of  claims 7 - 22 . 
     
     
         24 . A host cell comprising the nucleic acid of  claim 23 . 
     
     
         25 . A method of producing an antibody comprising culturing the host cell of  claim 24  so that the antibody is produced. 
     
     
         26 . The method of  claim 25 , further comprising recovering the antibody from the host cell. 
     
     
         27 . A pharmaceutical formulation comprising an antibody of any one of  claims 7 - 22  and a pharmaceutically acceptable carrier. 
     
     
         28 . The antibody of any one of  claims 7 - 22  for use as a medicament. 
     
     
         29 . The antibody of any one of  claims 7 - 22  for use in treating a metabolic disease or condition selected from the group consisting of: polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, hypertension, type 2 diabetes, non-type 2 diabetes, type 1 diabetes, latent autoimmune diabetes (LAD), and maturity onset diabetes fo the young (MODY). 
     
     
         30 . The antibody of any one of  claims 7 - 22  for use in sensitizing an individual to insulin. 
     
     
         31 . Use of the antibody of any one of  claims 7 - 22  in the manufacture of a medicament. 
     
     
         32 . The use of  claim 31 , wherein the medicament is for treatment of a metabolic disease or condition selected from the group consisting of: polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, hypertension, type 2 diabetes, non-type 2 diabetes, type 1 diabetes, latent autoimmune diabetes (LAD), and maturity onset diabetes fo the young (MODY). 
     
     
         33 . The use of  claim 31 , wherein the medicament is for sensitizing an individual to insulin. 
     
     
         34 . A method of treating diabetes in an individual, comprising administering to the individual an effective amount of the antibody according to any one of  claims 7 - 22 . 
     
     
         35 . The method of  claim 34 , further comprising administering to the individual another agent to treat diabetes provided that the other agent is not insulin. 
     
     
         36 . The method of  claim 34 , further comprising administering to the individual an agent to treat cardiovascular disease.

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