Methods of treating cancer by administering an Axl ligand-binding portion of an Axl tyrosine kinase receptor extracellular domain
View Patent ↗Disclosed are novel inhibitors of the Axl receptor tyrosine kinase (RTK) and methods of using such inhibitors in a variety of therapeutic approaches in the areas of cancer therapy and anti-thrombosis (anti-clotting) therapy.
1. A method of treating cancer in an individual, comprising administering to the individual an Axl fusion protein comprising:
a) a first protein comprising at least a portion of the extracellular domain of an Axl receptor tyrosine kinase (Axl RTK) that binds to an Axl ligand; and
b) a second protein that is an immunoglobulin Fc domain, wherein the second protein is fused to the first protein.
2. The method of claim 1 , wherein the first protein comprises an Axl domain selected from the group consisting of:
a) the Ig1 domain and the Ig2 domain of Axl; and,
b) entire Axl RTK extracellular domain of Axl.
3. The method of claim 1 , wherein the first protein comprises an Axl domain selected from the group consisting of:
a) positions 1-445 of Axl RTK, with respect to SEQ ID NO:2;
b) positions 1-325 of Axl RTK, with respect to SEQ ID NO:2;
c) positions 1-225 of Axl RTK, with respect to SEQ ID NO:2;
d) positions 10-222 of Axl RTK with respect to SEQ ID NO:2;
e) positions 20-222 of Axl RTK with respect to SEQ ID NO:2;
f) positions 30-222 of Axl RTK with respect to SEQ ID NO:2;
g) positions 40-222 of Axl RTK with respect to SEQ ID NO:2;
h) positions 50-222 of Axl RTK with respect to SEQ ID NO:2;
i) positions 60-222 of Axl RTK with respect to SEQ ID NO:2;
j) positions 10-225 of Axl RTK with respect to SEQ ID NO:2;
k) positions 20-225 of Axl RTK with respect to SEQ ID NO:2; and
m) positions 30-225 of Axl RTK with respect to SEQ ID NO:2.
4. The method of claim 1 , wherein the Axl RTK comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:2 or SEQ ID NO:4.
5. The method of claim 1 , wherein the Axl RTK comprises an amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4.
6. The method of claim 1 , wherein the immunoglobulin Fc domain consists essentially of or consists of a heavy chain hinge region, a CH 2 domain and a CH 3 domain.
7. The method of claim 1 , wherein the immunoglobulin Fc domain is from an IgG immunoglobulin protein.
8. The method of claim 1 , wherein the cancer is an Axl-positive cancer.
9. The method of claim 1 , wherein the cancer is a Mer-positive cancer.
10. The method of claim 1 , wherein the cancer is a Tyro-3-positive cancer.
11. The method of claim 1 , wherein the cancer is selected from the group consisting of: lung cancer, myeloid leukemia, lymphoma, uterine cancer, ovarian cancer, gliomas, melanoma, prostate cancer, breast cancer, gastric cancer, osteosarcoma, renal cell carcinoma, and thyroid cancer.
12. The method of claim 11 , wherein the cancer is a leukemia or lymphoma.
13. The method of claim 11 , wherein the cancer is myeloid leukemia.
14. The method of claim 11 , wherein the cancer is non-small cell lung cancer (NSCLC).
15. The method of claim 1 , wherein the Axl fusion protein is administered to a subject in need of such treatment as a pharmaceutical composition.