Methods and monitoring of treatment with a Wnt pathway inhibitor
Methods for treating diseases such as cancer comprising administering a Wnt pathway inhibitor, either alone or in combination with other anti-cancer agents, and monitoring for skeletal-related side effects and/or toxicity.
1. A method for reducing a skeletal-related side effect and/or toxicity in a human subject having cancer and receiving treatment with a Wnt pathway inhibitor for the cancer, comprising:
(a) administering a therapeutically effective amount of a Wnt pathway inhibitor to the subject;
(b) determining the level of collagen type 1 cross-linked C-telopeptide (β-CTX) in a sample from the subject after the administration of the Wnt pathway inhibitor; and
(c) administering to the subject a therapeutically effective amount of a bisphosphonate if the level of β-CTX in the sample is higher than a predetermined level of the β-CTX; and
wherein the Wnt pathway inhibitor is:
(i) an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7, and FZD8 and comprises a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6); or
(ii) a soluble receptor comprising a Fri domain of human FZD8 and a human Fc region.
2. The method of claim 1 , wherein the Wnt pathway inhibitor is an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7, and FZD8 and comprises a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6).
3. The method of claim 2 , wherein the antibody is a monoclonal antibody, a recombinant antibody, a chimeric antibody, a bispecific antibody, a human antibody, or an antibody fragment comprising an antigen-binding site.
4. The method of claim 2 , wherein the antibody is OMP-18R5.
5. The method of claim 1 , wherein the antibody comprises a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:8.
6. The method of claim 1 , wherein the Wnt pathway inhibitor is a soluble receptor comprising a Fri domain of human FZD8 and a human Fc region.
7. The method of claim 6 , wherein the soluble receptor comprises SEQ ID NO:41.
8. The method of claim 6 , wherein the soluble receptor is OMP-54F28.
9. The method of claim 1 , wherein the sample is blood, serum, or plasma.
10. The method of claim 1 , wherein the predetermined level of β-CTX is determined at an earlier timepoint, at an initial screening, and/or prior to treatment.
11. The method of claim 1 , wherein the level of β-CTX in the sample is at least two-fold higher than the predetermined level of the β-CTX.
12. The method of claim 1 , wherein the skeletal-related side effect and/or toxicity is an increased risk of bone fracture, osteopenia, or osteoporosis.
13. The method of claim 1 , wherein the bisphosphonate is zoledronic acid.
14. The method of claim 1 , wherein the subject is treated with the Writ pathway inhibitor in combination with one or more additional therapeutic agents.
15. A method of selecting a human subject having cancer for treatment with a Wnt pathway inhibitor for the cancer, comprising:
(a) determining the level of β-CTX in a sample from the subject;
(b) selecting the subject for treatment with the Wnt pathway inhibitor if the level of β-CTX is below a predetermined level; and
(c) administering a therapeutically effective dose of the Wnt pathway inhibitor to the subject;
wherein the Wnt pathway inhibitor is:
(i) an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7, and FZD8 and comprises a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6); or
(ii) a soluble receptor comprising a Fri domain of human FZD8 and a human Fc region.
16. The method of claim 15 , wherein the sample is blood, serum, or plasma.
17. The method of claim 15 , wherein the pre-determined level of β-CTX sample is a level of β-CTX determined at an initial screening.
18. The method of claim 15 , wherein the predetermined level of β-CTX is 1000 pg/ml.
19. The method of claim 15 , wherein the antibody is OMP-18R5.
20. The method of claim 15 , wherein the soluble receptor is OMP-54F28.
21. A method of preventing or attenuating the development of a skeletal-related side effect and/or toxicity in a human subject having cancer, comprising:
(a) determining the level of β-CTX in a sample from the subject prior to treatment for cancer;
(b) administering to the subject a therapeutically effective amount of a bisphosphonate if the level of β-CTX in the sample is higher than a predetermined level of β-CTX; and
(c) administering to the subject a Wnt pathway inhibitor;
wherein steps (b) and (c) are performed in any order after step (a); and
wherein the Wnt pathway inhibitor is:
(i) an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7 and FZD8 and comprises a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6); or
(ii) a soluble receptor comprising a Fri domain of human FZD8 and a human Fc region.
22. The method of claim 21 , wherein the antibody is OMP-18R5.
23. The method of claim 21 , wherein the soluble receptor is OMP-54F28.
24. A method of preventing or attenuating the development of a skeletal-related side effect and/or toxicity in a human subject having cancel and receiving treatment with a Wnt pathway inhibitor, comprising administering to the subject a therapeutically effective amount of a bisphosphonate;
wherein the Wnt pathway inhibitor is:
(i) an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7, and FZD8 and comprises a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6); or
(ii) a soluble receptor comprising a Fri domain of human FZD8 and a human Fc region.
25. The method of claim 24 , wherein the antibody is OMP-18R5.
26. The method of claim 24 , wherein the soluble receptor is OMP-54F28.
27. A method of treating cancer in a human subject having cancer, comprising:
(a) administering to the subject a therapeutically effective amount of a Wnt pathway inhibitor; and
(b) determining the level of β-CTX in a sample from the subject;
wherein the Wnt pathway inhibitor is:
(i) an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7, and FZD8 and comprises a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO:1), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), and a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), and a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6); or
(ii) a soluble receptor comprising a Fri domain of human FZD8 and a human Fc region.
28. The method of claim 27 , wherein the antibody is OMP-18R5.
29. The method of claim 27 , wherein the soluble receptor is OMP-54F28.