Anti-lrp5 antibodies and methods of use

Abstract

The invention provides anti-LRP5 antibodies and methods of making and using the same.

What is claimed is: 
     
         1 . An isolated antibody that binds to Low-density lipoprotein receptor-related protein 5 (LRP5), wherein the antibody potentiates Norrin activity and/or Norrin/Fzd4 signaling. 
     
     
         2 . The antibody of  claim 1 , which is a monoclonal antibody. 
     
     
         3 . The antibody of  claim 1 , which is a human, humanized, or chimeric antibody. 
     
     
         4 . The antibody of  claim 1 , which is an antibody fragment that binds LRP5. 
     
     
         5 . The antibody of  claim 1 , wherein the antibody comprises (a) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23) or WIPQSYPFX 1 SYKSGFDY, wherein X 1  is A or R (SEQ ID NO: 24), (b) HVR-L3 comprising the amino acid sequence QQYYX 1 YPFT, wherein X 1  is L or S (SEQ ID NO: 25), and (c) HVR-H2 comprising the amino acid sequence GX 1 ISX 2 X 3 GX 4 STYYADSVKG, wherein X 1  is A or G, X 2  is A or S, X 3  is P or S, X 4  is S or W (SEQ ID NO: 26), or SRISSNGGSTYYADSVKG (SEQ ID NO: 27). 
     
     
         6 . The antibody of  claim 1 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMX 1 , wherein X 1  is H or S (SEQ ID NO: 28), (b) HVR-H2 comprising the amino acid sequence GX 1 ISX 2 X 3 GX 4 STYYADSVKG, wherein X 1  is A or G, X 2  is A or S, X 3  is P or S, X 4  is S or W (SEQ ID NO: 26), or SRISSNGGSTYYADSVKG (SEQ ID NO: 27) and (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23) or WIPQSYPFX 1 SYKSGFDY, wherein X 1  is A or R (SEQ ID NO: 24). 
     
     
         7 . The antibody of  claim 6 , further comprising (a) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29) or RASQX 1 X 2 X 3 X 4 YLA, wherein X 1  is A, G, S or V, X 2  is I or M, X 3  is F, G, S or Y, and X 4  is G, S or Y (SEQ ID NO: 30); (b) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31) or DASX 1 X 2 ES, wherein X 1  is S or T and X 2  is L or R (SEQ ID NO: 32); and (c) HVR-L3 comprising the amino acid sequence QQYYX 1 YPFT, wherein X 1  is L or S (SEQ ID NO: 33). 
     
     
         8 . The antibody of  claim 1 , comprising (a) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29) or RASQX 1 X 2 X 3 X 4 YLA, wherein X 1  is A, G, S or V, X 2  is I or M, X 3  is G, F, Y or S, and X 4  is G, Y or S (SEQ ID NO: 30); (b) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31) or DASX 1 X 2 ES, wherein X 1  is S or T and X 2  is L or R (SEQ ID NO: 32); and (c) HVR-L3 comprising the amino acid sequence QQYYX 1 YPFT, wherein X 1  is L or S (SEQ ID NO: 33). 
     
     
         9 . The antibody of  claim 6 , further comprising one or more heavy chain variable domain framework sequences selected from the group consisting of SEQ ID NO: 34-37. 
     
     
         10 . The antibody of  claim 1 , comprising (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of one of SEQ ID NOs: 1 to 11; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of one of SEQ ID NOs: 12 to 22; or (c) a VH sequence as in (a) and a VL sequence as in (b). 
     
     
         11 . The antibody of  claim 10 , comprising a VH sequence of one of SEQ ID NOs: 1 to 11. 
     
     
         12 . The antibody of  claim 10 , comprising a VL sequence of one of SEQ ID NOs: 12 to 22. 
     
     
         13 . An antibody comprising a VH sequence of one of SEQ ID NOs: 1 to 11 and a VL sequence of one of SEQ ID NOs: 12 to 22. 
     
     
         14 . The antibody of  claim 1 , which is a full length IgG1 antibody. 
     
     
         15 . Isolated nucleic acid encoding the antibody of  claim 1 . 
     
     
         16 . A host cell comprising the nucleic acid of  claim 15 . 
     
     
         17 . A method of producing an antibody comprising culturing the host cell of  claim 16  so that the antibody is produced. 
     
     
         18 . An immunoconjugate comprising the antibody of  claim 1  and a cytotoxic agent. 
     
     
         19 . A pharmaceutical formulation comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . The antibody of  claim 1  for use as a medicament. 
     
     
         21 . The antibody of  claim 1  for use in treating a retinopathy including proliferative diabetic retinopathy, CNV, AMD, diabetic and other ischemia-related retinopathies, DME, pathological myopia, von Hippel-Lindau disease, histoplasmosis of the eye, CRVO, BRVO, corneal neovascularization, retinal neovascularization, ROP, FEVR, Coats' disease, Norrie Disease, OPPG (Osteporosis-Pseudoglioma Syndrome), subconjunctival hemorrhage, or hypertensive retinopathy. 
     
     
         22 . The antibody of  claim 1  for use in potentiating Norrin activity and/or Norrin/Fzd4 signaling. 
     
     
         23 . Use of the antibody of  claim 1  in the manufacture of a medicament. 
     
     
         24 . The use of  claim 23 , wherein the medicament is for treatment of a retinopathy including proliferative diabetic retinopathy, CNV, AMD, diabetic and other ischemia-related retinopathies, DME, pathological myopia, von Hippel-Lindau disease, histoplasmosis of the eye, CRVO, BRVO, corneal neovascularization, retinal neovascularization, ROP, FEVR, Coats' disease, Norrie Disease, OPPG (Osteporosis-Pseudoglioma Syndrome), subconjunctival hemorrhage, or hypertensive retinopathy. 
     
     
         25 . The use of  claim 23 , wherein the medicament is for potentiating Norrin activity and/or Norrin/Fzd4 signaling. 
     
     
         26 . A method of treating an individual having a retinopathy including proliferative diabetic retinopathy, CNV, AMD, diabetic and other ischemia-related retinopathies, DME, pathological myopia, von Hippel-Lindau disease, histoplasmosis of the eye, CRVO, BRVO, corneal neovascularization, retinal neovascularization, ROP, FEVR, Coats' disease, Norrie Disease, OPPG (Osteporosis-Pseudoglioma Syndrome), subconjunctival hemorrhage, or hypertensive retinopathy comprising administering to the individual an effective amount of the antibody of  claim 1 . 
     
     
         27 . A method of potentiating Norrin activity and/or Norrin/Fzd4 signaling in an individual comprising administering to the individual an effective amount of the antibody of  claim 1  to potentiate Norrin activity and/or Norrin/Fzd4 signaling. 
     
     
         28 . A method of rescuing a signaling defect in an individual caused by mutation in Norrin and/or Fzd4 comprising administering the antibody of  claim 1 .