Human Anti-OPGL Neutralizing Antibodies as Selective OPGL Pathway Inhibitors

Abstract

Monoclonal antibodies and hybridomas producing them that interact with osteoprotegerin ligand (OPGL) are provided. Methods of treating osteopenic disorders by administering a pharmaceutically effective amount of antibodies to OPGL are also provided. Methods of detecting the amount of OPGL in a sample using antibodies to OPGL are further provided.

We claim: 
     
         1 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence as set forth in any of SEQ ID NO: 6, SEQ ID NO: 14, SEQ ID NO: 22, or SEQ ID NO: 26, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         2 . The antibody of  claim 1 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         3 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10 or SEQ ID NO: 18, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         4 . The antibody of  claim 3 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.   
     
     
         5 . The antibody of  claim 4 , wherein the antibody specifically binds to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region, wherein binding is consecutive or simultaneous. 
     
     
         6 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence as set forth in any of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 24, or SEQ ID NO: 28, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         7 . The antibody of  claim 6 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         8 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 12 or SEQ ID NO: 20, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         9 . The antibody of  claim 8 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.   
     
     
         10 . The antibody of  claim 9 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         11 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as set forth in any of SEQ ID NO: 30, SEQ ID NO: 38, SEQ ID NO: 46, or SEQ ID NO: 50, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         12 . The antibody of  claim 11 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         13 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 34 or SEQ ID NO: 42, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         14 . The antibody of  claim 13 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.   
     
     
         15 . The antibody of  claim 14 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         16 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence as set forth in any of SEQ ID NO: 32, SEQ ID NO: 40, SEQ ID NO: 48, or SEQ ID NO: 52, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         17 . The antibody of  claim 16 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         18 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 36 or SEQ ID NO: 44, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         19 . The antibody of  claim 18 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.   
     
     
         20 . The antibody of  claim 19 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         21 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), wherein the antibody comprises:
 a. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 6, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 8, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   b. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 14, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 16, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   c. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 22, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 24, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   d. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 26, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 28, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   e. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 30, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 32, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   f. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 38, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 40, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   g. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 46, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 48, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof; or   h. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 50, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 52, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof.   
     
     
         22 . The antibody of  claim 21 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         23 . The antibody of  claim 21 , wherein the heavy chain comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 6, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 8, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         24 . The antibody of  claim 23 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 6, and wherein the light chain variable region comprises an amino acid sequence that has as least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 8, and wherein the antibody specifically binds to an osteoprotegerin ligand (OPGL). 
     
     
         25 . The antibody of  claim 21 , wherein the heavy chain comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 14, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 16, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         26 . The antibody of  claim 25 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 14, and wherein the light chain variable region comprises an amino acid sequence that has as least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 16, wherein the antibody specifically binds to an osteoprotegerin ligand (OPGL). 
     
     
         27 . The antibody of  claim 21 , wherein the heavy chain comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 22, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 24, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         28 . The antibody of  claim 27 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 22, and wherein the light chain variable region comprises an amino acid sequence that has as least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 24, wherein the antibody specifically binds to an osteoprotegerin ligand (OPGL). 
     
     
         29 . The antibody of  claim 21 , wherein the heavy chain comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 26, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 28, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         30 . The antibody of  claim 29 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 26, and wherein the light chain variable region comprises an amino acid sequence that has as least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 28, wherein the antibody in specifically binds to an osteoprotegerin ligand (OPGL). 
     
     
         31 . The antibody of  claim 21 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 30, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 32, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         32 . The antibody of  claim 21 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 38, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 40, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         33 . The antibody of  claim 21 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 46, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 48, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         34 . The antibody of  claim 21 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 50, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 52, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         35 . An isolated human antibody that specifically binds osteoprotegerin ligand (OPGL), wherein the antibody comprises:
 a. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 10, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 12, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   b. a heavy chain having a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 18, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain having a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 20, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof;   c. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 34, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 36, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof; or   d. a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 42, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 44, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof.   
     
     
         36 . The antibody of  claim 35 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.   
     
     
         37 . The antibody of  claim 36 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         38 . The antibody of  claim 35 , wherein the heavy chain comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 10, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 12, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         39 . The antibody of  claim 38 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 10, and wherein the light chain variable region comprises an amino acid sequence that has as least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 12, wherein the antibody specifically binds to an osteoprotegerin ligand (OPGL). 
     
     
         40 . The antibody of  claim 35 , wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 18, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 20, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         41 . The antibody of  claim 40 , wherein the heavy chain variable region comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 18, and wherein the light chain variable region comprises an amino acid sequence that has as least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 20, wherein the antibody specifically binds to an osteoprotegerin ligand (OPGL). 
     
     
         42 . The antibody of  claim 35 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 34, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 36, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         43 . The antibody of  claim 35 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 42, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 44, an antigen-binding fragment thereof, or an immunologically functional immunoglobulin fragment thereof. 
     
     
         44 . The antibody of  claim 21  or  35 , wherein the heavy chain and light chain are connected by a flexible linker to form a single-chain antibody. 
     
     
         45 . The antibody of  claim 44 , which is a single-chain Fv antibody. 
     
     
         46 . The antibody of  claim 21  or  35 , which is a Fab antibody. 
     
     
         47 . The antibody of  claim 21  or  35 , which is Fab′ antibody. 
     
     
         48 . The antibody of  claim 21  or  35 , which is a (Fab′) 2  antibody. 
     
     
         49 . The antibody of  claim 21  or  35 , wherein the antibody is fully human. 
     
     
         50 . The antibody of  claim 21  or  35 , wherein the antibody inhibits binding of OPGL to an osteoclast differentiation and activation receptor (ODAR). 
     
     
         51 . A method of treating an osteopenic disorder in a patient, comprising administering to a patient a pharmaceutically effective amount of the antibody of  claim 50 . 
     
     
         52 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody of  claim 50 . 
     
     
         53 . A method of treating an osteopenic disorder in a patient, comprising administering to a patient the pharmaceutical composition of  claim 52 . 
     
     
         54 . A method for detecting OPGL in a biological sample comprising:
 a. contacting the sample with the antibody of  claim 21  or  35 , under conditions that allow for binding of the antibody to OPGL;   b. and measuring the level of bound antibody in the sample.   
     
     
         55 . A heavy chain comprising a variable region and a constant region, wherein the variable region comprises an amino acid sequence as set forth in any of SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, or SEQ ID NO: 26, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         56 . A heavy chain comprising an amino acid sequence as set forth in any of SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 46, or SEQ ID NO: 50, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         57 . A light chain comprising a variable region and a constant region, wherein the variable region comprises an amino acid sequence as set forth in any of SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, or SEQ ID NO: 28, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         58 . A light chain comprising an amino acid sequence as set forth in any of SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, or SEQ ID NO: 52, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof. 
     
     
         59 . An isolated human antibody comprising:
 a. human heavy chain framework regions, a human heavy chain CDR1 region, a human heavy chain CDR2 region, and a human heavy chain CDR3 region, wherein the human heavy chain CDR3 region is the heavy chain CDR3 region of 16E1, 2D8, 22B3, or 9H7 as shown in  FIG. 15 ; and   b. human light chain framework regions, a human light chain CDR1 region, a human light chain CDR2 region, and a human light chain CDR3 region, wherein the human light chain CDR3 region is the light chain CDR3 region of 16E1, 2D8, 22B3, or 9H7 as shown in  FIG. 16 ;   wherein the antibody specifically binds to osteoprotegerin ligand (OPGL).   
     
     
         60 . The antibody of  claim 59 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         61 . The isolated human antibody of  claim 59 , wherein the human heavy chain CDR2 region is the heavy chain CDR2 region of 16E1, 2D8, 22B3, or 9H7 as shown in  FIG. 15  and the human light chain CDR2 region is the light chain CDR2 region of 16E1, 2D8, 22B3, or 9H7 as shown in  FIG. 16 . 
     
     
         62 . The antibody of  claim 61 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         63 . The isolated human antibody of  claim 59 , wherein the human heavy chain CDR1 region is the heavy chain CDR1 region of 16E1, 2D8, 22B3, or 9H7 as shown in  FIG. 15  and the human light chain CDR1 region is the light chain CDR1 region of 16E1, 2D8, 22B3, or 9H7 as shown in  FIG. 16 . 
     
     
         64 . The antibody of  claim 63 , wherein the antibody specifically binds the D-E loop region of osteoprotegerin ligand (OPGL). 
     
     
         65 . An isolated human antibody comprising:
 a. human heavy chain framework regions, a human heavy chain CDR1 region, a human heavy chain CDR2 region, and a human heavy chain CDR3 region, wherein the human heavy chain CDR3 region is the heavy chain CDR3 region of 2E11 or 18B2, as shown in  FIG. 15 ; and   b. human light chain framework regions, a human light chain CDR1 region, a human light chain CDR2 region, and a human light chain CDR3 region, wherein the human light chain CDR3 region is the light chain CDR3 region of 2E11 or 18B2 as shown in  FIG. 16 ;   wherein the antibody specifically binds to osteoprotegerin ligand (OPGL).   
     
     
         66 . The antibody of  claim 65 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region, wherein binding is consecutive or simultaneous.   
     
     
         67 . The antibody of  claim 66 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         68 . The isolated human antibody of  claim 65 , wherein the human heavy chain CDR2 region is the heavy chain CDR2 region of 2E11 or 18B2 as shown in  FIG. 15  and the human light chain CDR2 region is the light chain CDR2 region of 2E11 or 18B2 as shown in  FIG. 16 . 
     
     
         69 . The antibody of  claim 68 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region, wherein binding is consecutive or simultaneous.   
     
     
         70 . The antibody of  claim 69 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         71 . The isolated human antibody of  claim 65 , wherein the human heavy chain CDR1 region is the heavy chain CDR1 region of 2E11 or 18B2 as shown in  FIG. 15  and the human light chain CDR1 region is the light chain CDR1 region of 2E11 or 18B2 as shown in  FIG. 16 . 
     
     
         72 . The antibody of  claim 71 , wherein the antibody specifically binds to:
 a. a region of osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or   b. both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region, wherein binding is consecutive or simultaneous.   
     
     
         73 . The antibody of  claim 72 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous.