Antibodies binding RANKL and uses thereof
An isolated monoclonal antibody that specifically binds human RANKL, or the antigen-binding portion thereof. A nucleic acid molecule encoding the antibody or the antigen-binding portion thereof, an expression vector, a host cell and a method for expressing the antibody or the antigen-binding portion thereof are also provided. A treatment method using an anti-RANKL antibody or the antigen-binding portion is provided.
1 . An antibody, or an antigen-binding portion thereof comprising a heavy chain variable region comprising a VH-CDR1 region, a VH-CDR2 region and a VH-CDR3 region, and a light chain variable region comprising a VL-CDR1 region, a VL-CDR2 region and a VL-CDR3 region, wherein the VH-CDR1 region, the VH-CDR2 region, the VH-CDR3 region, the VL-CDR1 region, the VL-CDR2 region and the VL-CDR3 region comprise amino acid sequences of SEQ ID NOs: 1, 5, 10, 14, 18 and 21, respectively.
2 . The antibody, or the antigen-binding portion thereof, of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence having at least 85% identity to SEQ ID NOs: 25 or 26,
wherein 49 th , 76 th and 114 th amino acid residues in SEQ ID NO: 26 are A, R and T respectively; S, K and K respectively; or A, K and K respectively.
3 . The antibody, or antigen binding portion thereof, of claim 2 , wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to SEQ ID NOs: 25 or 26.
4 . The antibody, or antigen binding portion thereof, of claim 2 , wherein the heavy chain variable region comprises an amino acid sequence having at least 95% identity to SEQ ID NOs: 25 or 26.
5 . The antibody, or antigen binding portion thereof, of claim 2 , wherein the heavy chain variable region comprises an amino acid sequence having 100% identity to SEQ ID NOs: 25 or 26.
6 . The antibody, or the antigen-binding portion thereof, of claim 1 , wherein the light chain variable region comprises an amino acid sequence having at least 85% identity to SEQ ID NOs: 30 or 31,
wherein 43 rd and 83 rd amino acid residues in SEQ ID NO: 31 are A and I respectively; or S and L respectively.
7 . The antibody, or antigen binding portion thereof, of claim 6 , wherein the light chain variable region comprises an amino acid sequence having at least 90% identity to SEQ ID NOs: 30 or 31.
8 . The antibody, or antigen binding portion thereof, of claim 6 , wherein the light chain variable region comprises an amino acid sequence having at least 95% identity to SEQ ID NOs: 30 or 31.
9 . The antibody, or antigen binding portion thereof, of claim 6 , wherein the light chain variable region comprises an amino acid sequence having 100% identity to SEQ ID NOs: 30 or 31.
10 . The antibody, or the antigen-binding portion thereof, of claim 2 , wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences of
(1) SEQ ID NOs: 25 and 30, respectively;
(2) SEQ ID NOs: 26 and 31, respectively,
wherein 49 th , 76 th and 114 th amino acid residues in SEQ ID NO: 26 are A, R and T respectively; S, K and K respectively; or A, K and K respectively,
wherein 43 rd and 83 rd amino acid residues in SEQ ID NO: 31 are A and I respectively; or
(3) SEQ ID NOs: 26, respectively,
wherein 49 th , 76 th and 114 th amino acid residues in SEQ ID NO: 26 are A, R and T respectively; S, K and K respectively; or A, K and K respectively,
wherein 43 rd and 83 rd amino acid residues in SEQ ID NO: 31 are S and L respectively.
11 . The antibody, or the antigen-binding portion thereof, of claim 10 , comprising a heavy chain constant region having the amino acid sequence of SEQ ID NOs: 35 or 36, linked to the heavy chain variable region, and a light chain constant region having the amino acid sequence of SEQ ID NO: 37, linked to the light chain variable region.
12 . The antibody, or antigen binding portion thereof, of claim 1 which binds to Receptor activator of nuclear factor kappa-B ligand (RANKL).
13 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , which is able to (a) bind human or monkey RANKL; and (b) block RANKL-RANK interaction.
14 . The antibody, or the antigen-binding portion thereof, of claim 1 , which is a mouse, chimeric or humanized antibody or antigen-binding portion thereof.
15 . The antibody, or the antigen-binding portion thereof, of claim 1 , which is an IgG1, IgG2 or IgG4 isotype.
16 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody, or the antigen-binding portion thereof, of claim 1 , and a pharmaceutically acceptable carrier.
17 . The pharmaceutical composition of claim 16 , further comprising an additional anti-tumor agent or an anti-bone loss agent.
18 . A method for treating a disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the antibody, or the antigen-binding portion thereof of claim 12 and a pharmaceutically acceptable carrier, wherein the disease is bone loss, breast cancer or prostate carcinoma.
19 . The method of claim 8 , wherein the bone loss is bone loss in hormone therapy, postmenopausal osteoporosis, bone loss in bone metastasis, or bone loss in multiple myeloma.