Methods of screening for neoplastic disease states
The present invention provide purified Flt4 receptor tyrosine kinase polypeptides and fragments thereof, polynucleotides encoding such polypeptides, antibodies that specifically bind such polypeptides, and uses therefor.
1. A method of screening for a neoplastic disease state, comprising the steps of:
(a) contacting tissue from a mammalian organism suspected of having a neoplastic disease state with a composition comprising a compound that binds Flt4 receptor tyrosine kinase, wherein the compound comprises a member selected from the group consisting of (i) an anti-Flt4 antibody; (ii) a polypeptide comprising an antigen-binding fragment of an anti-Flt4 antibody; and (iii) a polypeptide comprising an Flt4 ligand selected from the group consisting of Vascular Endothelial Growth Factor-C (VEGF-C) and Vascular Endothelial Growth Factor-D (VEGF-D);
(b) detecting said compound bound to cells in said mammalian organism; and
(c) screening for a neoplastic disease from the quantity or distribution of said compound bound to cells in said mammalian organism; wherein the detection of the compound bound to blood vessel endothelial cells is correlated with the presence of a neoplastic disease.
2. The method of claim 1 , wherein the compound comprises a Flt4 ligand that is selected from the group consisting of Vascular Endothelial Growth Factor-C (VEGF-C) and Vascular Endothelial Growth Factor-D (VEGF-D).
3. The method of claim 1 , wherein the compound is an anti-Flt4 antibody.
4. The method of claim 3 , wherein the antibody is a human or humanized antibody.
5. The method of claim 3 , wherein the compound further comprises a detectable label.
6. The method according to claim 1 , wherein said tissue comprises mammary tissue.
7. The method of claim 6 , wherein the neoplastic disease is breast cancer.
8. The method of claim 1 , wherein the mammalian organism is human.
9. A method of screening for a disease characterized by a change in neovascular endothelial cells, comprising the steps of:
(a) obtaining a tissue sample from a vertebrate organism suspected of being in a diseased state characterized by changes in neovascular endothelial cells;
(b) exposing said tissue sample to a composition comprising a compound that binds Flt4 receptor tyrosine kinase expressed by cells in said organism, wherein the compound comprises a member selected from the group consisting of (i) an anti-Flt4 antibody; (ii) a polypeptide comprising an antigen-binding fragment of an anti-Flt4 antibody; and (iii) a polypeptide comprising an Flt4 ligand selected from the group consisting of Vascular Endothelial Growth Factor-C (VEGF-C) and Vascular Endothelial Growth Factor-D (VEGF-D); and
(c) screening for said disease by detecting the presence, quantity, or distribution of said compound in said tissue sample, wherein the detection of the compound bound to neovascular endothelial cells is correlated with the presence of a disease characterized by a change in neovascular endothelial cells in the organism.
10. The method of claim 9 , wherein the compound comprises a Flt4 ligand that is selected from the group consisting of Vascular Endothelial Growth Factor-C (VEGF-C) and Vascular Endothelial Growth Factor-D (VEGF-D).
11. The method of claim 9 , wherein the compound is an anti-Flt4 antibody.
12. The method of claim 11 , wherein the compound further comprises a detectable label.
13. A method for detecting neovascular endothelial cells in a mammal, comprising the steps of:
(a) administering to said mammal a composition comprising a first compound that binds a mammalian Flt4 receptor tyrosine kinase, wherein the first compound comprises a member selected from the group consisting of (i) an anti-Flt4 antibody; (ii) a polypeptide comprising an antigen-binding fragment of an anti-Flt4 antibody; and (iii) a polypeptide comprising an Flt4 ligand selected from the group consisting of Vascular Endothelial Growth Factor-C (VEGF-C) and Vascular Endothelial Growth Factor-D (VEGF-D); and
(b) detecting said first compound bound to neovascular endothelial cells, thereby detecting neovascular endothelial cells in said organism.
14. The method of claim 13 , wherein the first compound comprises a Flt4 ligand that is selected from the group consisting of Vascular Endothelial Growth Factor-C (VEGF-C) and Vascular Endothelial Growth Factor-D (VEGF-D).
15. The method of claim 13 , wherein the first compound is an anti-Flt4 antibody.
16. The method of claim 15 , wherein the first compound further comprises a detectable label.
17. The method according to claim 13 , further comprising administering to said mammal a second compound that specifically binds to a blood vessel endothelial marker; and wherein said detecting step comprises detection of said first compound and said second compound bound to neovascular endothelial cells.
18. The method of claim 17 , wherein the blood vessel endothelial marker is selected from the group consisting of PAL-E, VEGFR-1, and VEGFR-2.