Human Notch1 decoys
Provided herein are Notch1 fusion proteins. These fusion proteins comprise consecutive amino acids the sequence of which, commencing at the N-terminus of the fusion protein, is identical to the sequence of the amino acids in an extracellular domain of a human Notch1 receptor protein and an Fc portion of an antibody. The amino acid sequence of the extracellular domain (ECD) of the human Notch1 receptor protein commences with the amino acid present at the N-terminus of EGF-like repeat 10 and extends at least through the C-terminal amino acid of EGF-like repeat 23. The N-terminal portion of the ECD of the human Notch1 receptor protein may extend up to the C-terminal amino acid of EGF-like repeat 24 or may extend up to the C-terminal amino acid of EGF-like repeat 36. Compositions of these fusion proteins are also provided. Also provided are methods of treating age-related macular degeneration (AMD), diabetic retinopathy and cancer using the fusion proteins described herein.
1. A method of treating a subject suffering from cancer which comprises administering to the subject a fusion protein in an amount effective to treat the subject's cancer, wherein the fusion protein comprises consecutive amino acids the sequence of which, commencing at the N-terminus of the fusion protein, is identical to the sequence of amino acids in:
(a) an extracellular domain of a human Notch1 receptor protein, followed by
(b) an Fc portion of an antibody,
wherein the extracellular domain of the human Notch1 receptor protein
(i) commences with the amino acid present at the N-terminus of EGF-like repeat 10 and
(ii) extends at least through the C-terminal amino acid of EGF-like repeat 24.
2. The method of claim 1 , wherein the cancer is pancreatic cancer.
3. The method of claim 2 , further comprising administering an inhibitor of Vascular Endothelial Growth Factor (VEGF).
4. The method of claim 3 , wherein the inhibitor of VEGF is an inhibitor of VEGF-A, PGIF, VEGF-B, VEGF-C, or VEGF-D.
5. The method of claim 2 , further comprising administering a VEGF receptor inhibitor.
6. The method of claim 5 , wherein the VEGF receptor inhibitor is a VEGFR-1 or a VEGFR-2 inhibitor.
7. The method of claim 2 , wherein the Fc portion of an antibody is the Fc portion of a human antibody.
8. The method of claim 1 , wherein the cancer is breast cancer.
9. The method of claim 8 , further comprising administering an inhibitor of Vascular Endothelial Growth Factor (VEGF).
10. The method of claim 9 , wherein the inhibitor of VEGF is an inhibitor of VEGF-A, PGIF, VEGF-B, VEGF-C, or VEGF-D.
11. The method of claim 8 , further comprising administering a VEGF receptor inhibitor.
12. The method of claim 11 , wherein the VEGF receptor inhibitor is a VEGFR-1 or a VEGFR-2 inhibitor.
13. The method of claim 8 , wherein the Fc portion of an antibody is the Fc portion of a human antibody.
14. The method of claim 1 , further comprising administering an inhibitor of Vascular Endothelial Growth Factor (VEGF).
15. The method of claim 14 , wherein the inhibitor of VEGF is an inhibitor of VEGF-A, PGIF, VEGF-B, VEGF-C, or VEGF-D.
16. The method of claim 1 , further comprising administering a VEGF receptor inhibitor.
17. The method of claim 16 , wherein the VEGF receptor inhibitor is a VEGFR-1 or a VEGFR-2 inhibitor.
18. The method of claim 1 , wherein the Fc portion of an antibody is the Fc portion of a human antibody.
19. The method of claim 1 , wherein the fusion protein comprises the sequence of the consecutive amino acids set forth in SEQ ID NO: 3, commencing with cystine at position 24 and ending with lysine at position 833.