DKK-1 antibodies
The invention provides human engineered antibodies, antigen-binding fragments thereof, that bind to, and inhibit the activity of, human DKK-1, and which are effective in treating diseases in which pathogenesis is mediated by DKK-1.
1. A human engineered DKK-1 antibody or antigen binding fragment thereof, comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3, wherein LCDR1 has the amino sequence of SEQ ID NO:5, LCDR2 has the amino sequence of SEQ ID NO:47, LCDR3 has the amino sequence of SEQ ID NO:49, HCDR1 has the amino sequence of SEQ ID NO:1, HCDR2 has the amino sequence of SEQ ID NO:2, and an HCDR3 has the amino sequence of SEQ ID NO:44.
2. The human engineered DKK-1 antibody of claim 1 , wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 52 and the HCVR comprises the amino acid sequence of SEQ ID NO: 51.
3. The human engineered DKK-1 antibody of claim 2 , wherein the LCVR and HCVR comprise amino acid sequences selected from the group consisting of:
(i) a LCVR comprising the amino acid sequence of SEQ ID NO: 13 and a HCVR comprising the amino acid sequence of SEQ ID NO: 11;
(ii) a LCVR comprising the amino acid sequence of SEQ ID NO: 14 and a HCVR comprising the amino acid sequence of SEQ ID NO: 12;
(iii) a LCVR comprising the amino acid sequence of SEQ ID NO: 15 and a HCVR comprising the amino acid sequence of SEQ ID NO: 11;
(iv) a LCVR comprising the amino acid sequence of SEQ ID NO: 16 and a HCVR comprising the amino acid sequence of SEQ ID NO: 11.
4. The human engineered DKK-1 antibody of claim 3 , wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 14 and the HCVR comprises the amino acid sequence of SEQ ID NO: 12.
5. The human engineered DKK-1 antibody of claim 3 , wherein the human engineered DKK-1 antibody comprises a heavy chain and a light chain amino acid sequence selected from the group consisting of
a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and light chain comprising the amino acid sequence of SEQ ID NO: 19,
b. a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20,
c. a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 21, and
d. a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
6. A human engineered DKK-1 antibody comprising two light chains wherein each light chain comprises the amino acid sequence of SEQ ID NO: 20, and two heavy chains wherein each heavy chain comprises the amino acid sequence of SEQ ID NO: 18.
7. A pharmaceutical composition comprising the human engineered DKK-1 antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.
8. A method of healing bone comprising administering to a patient in need thereof an effective amount of the human engineered DKK-1 antibody or antigen-binding fragment thereof, of claim 1 .
9. A method of treating cancer comprising administering to a patient in need thereof an effective amount of the human engineered DKK-1 antibody or antigen-binding fragment thereof of claim 1 .
10. The method of claim 9 , wherein the cancer is selected from the group consisting of multiple myeloma, breast cancer and non-small cell lung cancer.
11. A pharmaceutical composition comprising the human engineered DKK-1 antibody or antigen-binding fragment thereof of claim 6 , and a pharmaceutically acceptable carrier, diluent, or excipient.
12. A method of healing bone comprising administering to a patient in need thereof an effective amount of the human engineered DKK-1 antibody or antigen-binding fragment thereof, of claim 6 .
13. A method of treating cancer comprising administering to a patient in need thereof an effective amount of the human engineered DKK-1 antibody or antigen-binding fragment thereof of claim 6 .
14. The method of claim 13 , wherein the cancer is selected from the group consisting of multiple myeloma, breast cancer and non-small cell lung cancer.