Antibodies targeting bone morphogenetic protein 9 (bmp9) and methods therefor

Abstract

The present invention relates to isolated antibodies and antigen-binding fragments thereof which bind human BMP9 and compositions and methods of use thereof.

1 .- 22 . (canceled) 
     
     
         23 . A method of reducing the activity of bone morphogenetic protein 9 (BMP9) in a cell, comprising contacting the cell with an isolated BMP9 antibody or antigen-binding fragment thereof of, wherein the isolated BMP9 antibody or antigen-binding fragment thereof comprises:
 (a) heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) sequences of SEQ ID NOs: 1, 2 and 3, respectively, and light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 1 (LCDR3) sequences of SEQ ID NOs: 11, 12 and 13, respectively; or   (b) HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 4, 5 and 6, respectively, and LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 14, 15 and 16, respectively.   
     
     
         24 . A method of inhibiting BMP9 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an isolated BMP9 antibody or antigen-binding fragment thereof of, wherein the isolated BMP9 antibody or antigen-binding fragment thereof comprises:
 (a) heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) sequences of SEQ ID NOs: 1, 2 and 3, respectively, and light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 1 (LCDR3) sequences of SEQ ID NOs: 11, 12 and 13, respectively; or   (b) HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 4, 5 and 6, respectively, and LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NOs: 14, 15 and 16, respectively.   
     
     
         25 . The method of  claim 24 , wherein the patient has liver disease. 
     
     
         26 . The method of  claim 25 , wherein the liver disease is or is associated with one or more of: hepatitis C virus (“HCV”) infection; hepatitis B virus (“HBV”) infection; autoimmune hepatitis; alcohol exposure; toxin exposure; drug exposure; liver trauma; biliary obstruction; primary biliary cirrhosis; alagille syndrome; chronic hepatic congestion; nonalcoholic steatohepatitis (NASH); primary sclerosing cholangitis; hemochromatosis; alpha 1-antitrypsin deficiency; and Wilson disease. 
     
     
         27 . The method of  claim 25 , wherein the liver disease is selected from the group consisting of liver fibrosis, portal vein hypertension, nonalcoholic steatohepatitis (NASH), fatty liver disease, and cirrhosis. 
     
     
         28 . The method of  claim 24 , further comprising administering an additional therapeutic agent. 
     
     
         29 . The method of  claim 28 , wherein the additional therapeutic agent reduces the activity of BMP9. 
     
     
         30 . The method of  claim 28 , wherein the additional therapeutic agent is a siRNA, an antibody or antigen-binding fragment thereof, a soluble receptor, a protein, or a small molecule. 
     
     
         31 . The method of  claim 28 , wherein the additional therapeutic agent is selected from the group consisting of: an antiviral agent, an anti-inflammatory agent, an anti-fibrotic agent, an anti-steatotic agent, an anti-apoptotic, a hepatoprotective agent, and combinations thereof. 
     
     
         32 . The method of  claim 31 , wherein the additional therapeutic agent is selected from the group consisting of: tenofovir, entecavir, lamivudine, telbuvudine, adefovir, pegylated interferon, sofusbuvir, telaprevir, daclatsivir, simeprevir, ledasprevir, corticosteroid, GFT-505, cenicriviroc, vitamin E, pioglitazone, metformin, obeticholic acid, GR-MD-02, and combinations thereof. 
     
     
         33 . The method of  claim 28 , wherein (a) the isolated BMP9 antibody or antigen-binding fragment thereof and the additional therapeutic agent are administered simultaneously or sequentially, and/or (b) the isolated BMP9 antibody or antigen-binding fragment thereof is administered adjunctively to administration of the additional therapeutic agent. 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen-binding fragment thereof is encoded by an isolated polynucleotide comprising a nucleic acid sequence encoding a VH or a VL sequence. 
     
     
         36 . The method of  claim 35 , wherein the nucleic acid sequence encodes a VH sequence comprising SEQ ID NO: 7. 
     
     
         37 . The method of  claim 35 , wherein the nucleic acid sequence encodes a VL sequence comprising SEQ ID NO: 17. 
     
     
         38 . The method of  claim 35 ,
 wherein the polynucleotide comprises a nucleic acid sequence encoding a VH sequence and a nucleic acid sequence encoding a VL sequence, wherein the VH sequence comprising SEQ ID NO: 7 and the VL sequence comprising SEQ ID NO: 17.   
     
     
         39 . The method of  claim 35 , wherein the polynucleotide comprises a nucleic acid sequence encoding a heavy chain sequence of SEQ ID NO: 9. 
     
     
         40 . The method of  claim 35 , wherein the polynucleotide comprises a nucleic acid sequence encoding a light chain sequence of SEQ ID NO: 19. 
     
     
         41 . The method of  claim 35 , wherein the isolated BMP9 antibody or antigen-binding fragment thereof comprises:
 a heavy chain sequence of SEQ ID NO: 9; and a light chain sequence of SEQ ID NO: 19.   
     
     
         42 . The method of  claim 35 , wherein the polynucleotide comprising:
 (a) a VH sequence of SEQ ID NO: 8;   (b) a heavy chain sequence of SEQ ID NO: 10;   (c) a VL sequence of SEQ ID NO: 18; or   (d) a light chain sequence of SEQ ID NO: 20.   
     
     
         43 . The method of  claim 35 , wherein the polynucleotide comprising the VH sequence of SEQ ID NO: 8 and the VL sequence of SEQ ID NO: 18. 
     
     
         44 . The method of  claim 35 , wherein the polynucleotide is disposed on a single continuous polynucleotide. 
     
     
         45 . The method of  claim 35 , wherein the polynucleotide is disposed on two or more continuous polynucleotides. 
     
     
         46 .- 58 . (canceled) 
     
     
         59 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 7. 
     
     
         60 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises a light chain variable region (VL) sequence of SEQ ID NO: 17. 
     
     
         61 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 17. 
     
     
         62 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises:
 (a) a VH sequence having 95%-99% sequence identity to SEQ ID NO: 7; or   (b) a VH sequence having one, two, three, four or five amino acid mutations relative to SEQ ID NO: 7.   
     
     
         63 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises:
 (a) a VL sequence having 95%-99% sequence identity to SEQ ID NO: 17; or   (b) a VL sequence having one, two, three, four or five amino acid mutations relative to SEQ ID NO: 17.   
     
     
         64 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises a heavy chain sequence of SEQ ID NO: 9. 
     
     
         65 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises a light chain sequence of SEQ ID NO: 19. 
     
     
         66 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises a heavy chain sequence of SEQ ID NO: 9; and a light chain sequence of SEQ ID NO: 19. 
     
     
         67 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof comprises:
 (a) a heavy chain amino acid sequence having 95%-99% sequence identity to SEQ ID NO: 9;   (b) a light chain amino acid sequence having 95%-99% sequence identity to SEQ ID NO: 19; or   (c) a heavy chain amino acid sequence having 95%-99% sequence identity to SEQ ID NO: 9 and a light chain amino acid sequence having 95%-99% sequence identity to SEQ ID NO: 19.   
     
     
         68 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof is an IgG. 
     
     
         69 . The method of  claim 68 , wherein the IgG is selected from the group consisting of an IgG1, an IgG2, an IgG3 and an IgG4. 
     
     
         70 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof has altered effector function through mutation of amino acids within a Fc region. 
     
     
         71 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof is a monoclonal antibody, a chimeric antibody, a single chain antibody, a Fab or a scFv. 
     
     
         72 . The method of  claim 24 , wherein the isolated BMP9 antibody a chimeric, humanized or fully human antibody. 
     
     
         73 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen binding fragment thereof binds to human BMP9 and inhibits the binding of human BMP9 to a BMP Type II receptor. 
     
     
         74 . The method of  claim 73 , wherein the inhibition of the binding of human BMP9 to said BMP Type II receptor is at an IC 50  of less than or equal to about 1 nM. 
     
     
         75 . The method of  claim 24 , wherein the isolated BMP9 antibody or antigen-binding fragment thereof is a component of an immunoconjugate.