Anti-rankl antibodies and methods of use

Abstract

The present invention provides anti-RANKL monoclonal antibodies and related compositions, which may be used in any of a variety of therapeutic methods for the treatment of rheumatoid arthritis and other diseases.

1 . An isolated antibody, or an antigen-binding fragment thereof, that binds to RANKL, comprising (i) a heavy chain variable region comprising the VHCDR1 region set forth in SEQ ID NO:3, the VHCDR2 region set forth in SEQ ID NO:4, and the VHCDR3 region set forth SEQ ID NO:5; and (ii) a light chain variable region comprising: the VLCDR1 region set forth in SEQ ID NO:6 or 15, the VLCDR2 region set forth in SEQ ID NO:7, and the VLCDR3 region set forth in SEQ ID NO: 8; or a variant of said antibody, or an antigen-binding fragment thereof, comprising heavy and light chain variable regions identical to the heavy and light chain variable regions of (i) and (ii) except for up to 8 amino acid substitutions in said CDR regions. 
     
     
         2 . The isolated antibody, or antigen-binding fragment thereof, of  claim 1  wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:1. 
     
     
         3 . The isolated antibody, or antigen-binding fragment thereof, of  claim 1  wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:2. 
     
     
         4 . (canceled) 
     
     
         5 . The isolated antibody, or antigen-binding fragment thereof, of  claim 1  comprising a light chain variable region which comprises an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:2. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The isolated antibody, or antigen binding fragment thereof, of  claim 1  comprising a heavy chain variable region which comprises an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         9 . The isolated antibody of  claim 1 , wherein the antibody is humanized. 
     
     
         10 . The isolated antibody of  claim 9 , wherein (a) the VH region comprises the amino acid sequence set forth in SEQ ID NO:9 and the VL region comprises the amino acid sequence set forth in SEQ ID NO: 10 or 11; or (b) the VH region comprises the amino acid sequence set forth in SEQ ID NO:226 and the VL region comprises the amino acid sequence set forth in SEQ ID NO:227. 
     
     
         11 . The isolated antibody of  claim 1  wherein the antibody is selected from the group consisting of a single chain antibody, a ScFv, a univalent antibody lacking a hinge region, a minibody, a Fab or a Fab′ fragment, a F(ab′) 2  fragment, and a whole antibody. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . The isolated antibody of  claim 1  comprising a human IgG constant domain. 
     
     
         16 . The isolated antibody of  claim 15  wherein the IgG constant domain comprises an IgG2 CH1 domain or an IgG2 Fc region. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . An isolated antibody, or antigen-binding fragment thereof, that binds RANKL with a KD of about 0.16 nM or lower. 
     
     
         20 . An isolated antibody, or antigen-binding fragment thereof, wherein the isolated antibody, or antigen-binding fragment thereof:
 a. blocks binding of RANKL to RANK;   b. inhibits RANKL-induced osteoclast differentiation;   c. inhibits osteoclast cell activity;   d. inhibits bone loss and increase bone density;   e. Binds and inhibits human, rodent and monkey RANKL; or   f. a combination of any one or more of a.-e.   
     
     
         21 . An isolated polynucleotide encoding the isolated antibody, or antigen-binding fragment thereof, according to  claim 1 , an expression vector comprising the isolated polynucleotide, or an isolated host cell comprising the vector. 
     
     
         22 - 23 . (canceled) 
     
     
         24 . A composition comprising a physiologically acceptable carrier and a therapeutically effective amount of the isolated antibody or antigen-binding fragment thereof according to  claim 1 . 
     
     
         25 . A method for treating a patient having an osteopenic disorder, comprising administering to the patient the composition of  claim 24 , thereby treating the osteopenic disorder. 
     
     
         26 . The method of  claim 25  wherein the osteopenic disorder is selected from the group consisting of osteoporosis, periodontitis, cancer associated bone metastasis, multiple myeloma, rheumatoid arthritis, psoriatic arthritis, familial expansile osteolysis, Paget's disease, juvenile Paget's disease, osteoclastoma, bone loss associated with chronic viral infection and adult and child leukemias, and periprosthetic bone loss. 
     
     
         27 . An isolated antibody, or an antigen-binding fragment thereof, that binds to RANKL, comprising (i) a heavy chain variable region comprising the VHCDR1, VHCDR2, and VHCDR3 of any one of the VH regions shown in  FIG. 1 ; and (ii) a light chain variable region comprising the VLCDR1, the VLCDR2, and the VLCDR3 region of the corresponding VL region of any one of the antibodies shown in  FIG. 1 ; or a variant of said antibody, or an antigen-binding fragment thereof, comprising heavy and light chain variable regions identical to the heavy and light chain variable regions of (i) and (ii) except for up to 8 amino acid substitutions in said CDR regions. 
     
     
         28 . The isolated antibody, or an antigen-binding fragment thereof, of  claim 27 , that binds to RANKL, comprising a heavy chain variable region comprising any one of the VH regions shown in  FIG. 1  or an amino acid sequence having at least 90% identity to the corresponding VH region as shown in  FIG. 1 , and a light chain variable region comprising any one of the VL regions shown in  FIG. 1  or a light chain variable region comprising an amino acid sequence having at least 90% identity to the corresponding VL region as shown in  FIG. 1 . 
     
     
         29 - 33 . (canceled)