Vegf-activated fas ligands
AssigneeThe Regents of the University of California
InventorTimothy P. Quinn
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Abstract
The present invention provides fusion proteins comprising an extracellular domain of a VEGF receptor and a death ligand. The fusion proteins bind to VEGF and to death receptors on tumor cells thereby inhibiting VEGF activation of VEGF receptors and inducing apoptosis in the tumor cells. Fusion proteins of the present invention are useful for inducing apoptosis and cytotoxic effects in cells, treating cancer and diseases or disorders related to unregulated angiogenesis and/or vasculogenesis. Thus, this invention further provides methods for treating angiogenesis related diseases using the fusion proteins, polynucleotides encoding the fusion proteins, vectors containing the polynucleotides, pharmaceutical compositions and kits containing the fusion proteins or the polynucleotides encoding the fusion proteins.
Claims43
A fusion protein which binds to a death receptor, the fusion protein comprising:
- (i) a vascular endothelial growth factor receptor (VEGFR) polypeptide that binds a vascular endothelial growth factor (VEGF) polypeptide;
- and
- (ii) a death ligand comprising an oligomerization domain and a death receptor recognition moiety,
- wherein the C-terminus of the VEGFR polypeptide is linked to the N-terminus of the death ligand.
A nucleic acid comprising the nucleotide sequence shown in SEQ ID NO:14.
A method of modulating a death receptor-mediated pathway comprising the step of:
- contacting a death receptor expressing cell with a fusion protein comprising:
- (i) a VEGFR polypeptide that binds a VEGF protein;
- (ii) a death ligand comprising an oligomerization domain and a death receptor recognition moiety;
- wherein the VEGFR polypeptide has bound a VEGF protein and wherein the amount of the fusion protein is effective to modulate the death receptor-mediated pathway.
A pharmaceutical composition comprising:
- (i) a fusion protein comprising:
- (1) a VEGFR polypeptide that binds a VEGF protein;
- (2) a Fas ligand comprising an oligomerization domain and a Fas receptor recognition moiety of the extracellular domain of a Fas ligand protein;
- and
- (ii) a pharmaceutically acceptable excipient, carrier and/or diluent.
A composition comprising:
- (i) a vector comprising a nucleic acid having a nucleotide sequence as shown in SEQ ID NO:14;
- and
- (ii) a pharmaceutically acceptable excipient, carrier and/or diluent.
A pharmaceutical composition comprising:
- (i) a fusion protein comprising:
- (1) a VEGFR polypeptide that binds a VEGF protein;
- (2) a TRAIL ligand comprising an oligomerization domain and a TRAIL receptor recognition moiety of the extracellular domain of a TRAIL ligand protein;
- and
- (ii) a pharmaceutically acceptable excipient, carrier and/or diluent.
A pharmaceutical composition comprising:
- (i) a fusion protein comprising:
- (1) a VEGFR polypeptide that binds a VEGF protein;
- (2) a TNF ligand comprising an oligomerization domain and a TNF receptor recognition moiety of the extracellular domain of a TNF ligand protein;
- and
- (ii) a pharmaceutically acceptable excipient, carrier and/or diluent.
A pharmaceutical composition comprising:
- (i) a fusion protein comprising:
- (1) a VEGFR polypeptide that binds a VEGF protein;
- (2) a LT ligand comprising an oligomerization domain and a LT receptor recognition moiety of the extracellular domain of a LT ligand protein;
- and
- (ii) a pharmaceutically acceptable excipient, carrier and/or diluent.
Dependencies are inferred from the claim text.