Human Anti-OPGL Neutralizing Antibodies As Selective OPGL Pathway Inhibitors
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.
1 - 4 . (canceled)
5 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human osteoprotegerin ligand (OPGL) and comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises any of SEQ ID NO: 6, SEQ ID NO: 14, SEQ ID NO: 22, or SEQ ID NO: 26.
6 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises either SEQ ID NO: 10 or SEQ ID NO: 18.
7 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises any of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 24, or SEQ ID NO: 28.
8 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises either SEQ ID NO: 12 or SEQ ID NO: 20.
9 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the heavy chain comprises any of SEQ ID NO: 30, SEQ ID NO: 38, SEQ ID NO: 46, or SEQ ID NO: 50.
10 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the heavy chain comprises either SEQ ID NO: 34 or SEQ ID NO: 42.
11 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the light chain comprises any of SEQ ID NO: 32, SEQ ID NO: 40, SEQ ID NO: 48, or SEQ ID NO: 52.
12 . The method of any of claim 5 , 7 , 9 , or 11 , wherein the human antibody or antigen-binding fragment specifically binds the D-E loop region of human OPGL.
13 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the light chain comprises either of SEQ ID NO: 36 or SEQ ID NO: 44.
14 . The method of any of claim 6 , 8 , 10 , or 13 , wherein the human antibody or antigen-binding fragment specifically binds to:
(a) a region of human OPGL that is outside the D-E loop region; or
(b) both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.
15 . The method of claim 14 , wherein the antibody or antigen-binding fragment binding to both a region of human 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 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain variable region comprising SEQ ID NO: 6 and a light chain variable region comprising SEQ ID NO: 8, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6 and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;
(b) a heavy chain variable region comprising SEQ ID NO: 14 and a light chain variable region comprising SEQ ID NO: 16, or wherein antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 14 and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;
(c) a heavy chain variable region comprising SEQ ID NO: 22 and a light chain variable region comprising SEQ ID NO: 24, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 22 and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or
(d) a heavy chain variable region comprising SEQ ID NO: 26 and a light chain variable region comprising SEQ ID NO: 28, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 26 and CDR1, CDR2, and CDR3 of SEQ ID NO: 28.
17 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a in need thereof patient a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain comprising SEQ ID NO: 30 and a light chain comprising SEQ ID NO: 32, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6 and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;
(b) a heavy chain comprising SEQ ID NO: 38 and a light chain comprising SEQ ID NO: 40, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 14 and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;
(c) a heavy chain comprising SEQ ID NO: 46 and a light chain comprising SEQ ID NO: 48, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 22 and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or
(d) a heavy chain comprising SEQ ID NO: 50 and a light chain comprising SEQ ID NO: 52, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 26 and CDR1, CDR2, and CDR3 of SEQ ID NO: 28.
18 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain variable region comprising SEQ ID NO: 10 and a light chain variable region comprising SEQ ID NO: 12, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 10 and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or
(b) a heavy chain variable region comprising SEQ ID NO: 18 and a light chain variable region comprising SEQ ID NO: 20, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 18 and CDR1, CDR2, and CDR3 of SEQ ID NO: 20.
19 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain comprising SEQ ID NO: 34 and a light chain comprising SEQ ID NO: 36, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 10 and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or
(b) a heavy chain comprising SEQ ID NO: 42 and a light chain comprising SEQ ID NO: 44, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 18 and CDR1, CDR2, and CDR3 of SEQ ID NO: 20.
20 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
(a) CDR1, CDR2, and CDR3 of SEQ ID NO: 6, and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;
(b) CDR1, CDR2, and CDR3 of SEQ ID NO: 14, and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;
(c) CDR1, CDR2, and CDR3 of SEQ ID NO: 22, and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or
(d) CDR1, CDR2, and CDR3 of SEQ ID NO: 26, and CDR1, CDR2, and CDR3 of SEQ ID NO: 28.
21 . The method of any of claim 16 , 17 or 20 , wherein the antibody or antigen-binding fragment thereof specifically binds the D-E loop region of human osteoprotegerin ligand (OPGL).
22 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
(a) CDR1, CDR2, and CDR3 of SEQ ID NO: 10, and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or
(b) CDR1, CDR2, and CDR3 of SEQ ID NO: 18, and CDR1, CDR2, and CDR3 of SEQ ID NO: 20.
23 . The method of any of claim 18 , 19 or 22 wherein the antibody or antigen-binding fragment thereof, specifically binds to:
(a) a region of human OPGL that is outside the D-E loop region; or
(b) both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.
24 . The method claim 23 , wherein binding to both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous.
25 . The method of any of claim 16 - 20 or 22 , wherein the antibody or antigen-binding fragment thereof is a single-chain antibody.
26 . The method of claim 25 wherein antibody or antigen-binding fragment is a single-chain Fv antibody.
27 . The method of any of claim 16 - 20 or 22 , wherein the antigen-binding fragment thereof is a Fab antibody fragment.
28 . The method of any of claim 16 - 20 or 22 , wherein the antigen-binding fragment thereof is a Fab′ antibody fragment.
29 . The method of any of claim 16 - 20 or 22 , wherein the antigen-binding fragment thereof is a (Fab′) 2 antibody fragment.
30 . The method of any of claim 16 - 20 or 22 , wherein the antibody or antigen-binding fragment thereof inhibits binding of OPGL to an osteoclast differentiation and activation receptor (ODAR).
31 . The method of any of claim 16 - 20 or 22 , wherein the antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.
32 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL, and comprises:
(a) a heavy chain variable region comprising SEQ ID NO: 6, and a light chain variable region comprising SEQ ID NO: 8;
(b) a heavy chain variable region comprising SEQ ID NO: 14, and a light chain variable region comprising SEQ ID NO: 16;
(c) a heavy chain variable region comprising SEQ ID NO: 22, and a light chain variable region comprising SEQ ID NO: 24; or
(d) a heavy chain variable region comprising SEQ ID NO: 26, and a light chain variable region comprising SEQ ID NO: 28.
33 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises:
(a) a heavy chain variable region comprising SEQ ID NO: 10, and a light chain variable region comprising SEQ ID NO: 12; or
(b) a heavy chain variable region comprising SEQ ID NO: 18, and a light chain variable region comprising SEQ ID NO: 20.
34 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human osteoprotegerin ligand OPGL and comprises:
(a) a heavy chain comprising SEQ ID NO: 30, and a light chain comprising SEQ ID NO: 32;
(b) a heavy chain comprising SEQ ID NO: 34, and a light chain comprising SEQ ID NO: 36; or
(c) a heavy chain comprising SEQ ID NO: 38, and a light chain comprising SEQ ID NO: 40.
35 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody that specifically binds human OPGL and comprises:
(a) a heavy chain comprising SEQ ID NO: 42, and a light chain comprising SEQ ID NO: 44;
(b) a heavy chain comprising SEQ ID NO: 46, and a light chain comprising SEQ ID NO: 48; or
(c) a heavy chain comprising SEQ ID NO: 50, and a light chain comprising SEQ ID NO: 52.
36 . The method of any one of claim 5 - 11 , 13 , 16 - 20 , 22 , or 32 - 35 wherein the cancer is selected from breast cancer, prostate cancer and multiple myeloma.