DNA composition encoding an immunogenic VEGF receptor peptide and methods of use thereof
A DNA composition effective for inhibiting endothelial cell proliferation comprises a DNA construct operably encoding a vascular endothelial growth factor (VEGF) receptor polypeptide, which can be a full length VEGF receptor protein or an immunogenic fragment thereof. This invention provides DNA compositions that encode VEGF receptor-2 (KDR), VEGF receptor-1 (Flt-1), or Flk-1 (the murine homolog of KDR), as well as methods of using such a DNA composition to inhibit vascular endothelial cell proliferation in the tumor micro-environment. Angiogenesis inhibition and subsequent decrease in tumor growth and dissemination is achieved.
1. A DNA composition comprising a DNA construct encoding at least one immunogenic fragment of a VEGF receptor capable of eliciting an immune response against vascular endothelial cells, which is expressible in immune cells, and is incorporated in a pharmaceutically acceptable carrier;
wherein the DNA construct is incorporated in an attenuated bacterial vector.
2. The DNA composition of claim 1 wherein the attenuated bacterial vector is selected from attenuated Salmonella typhimurium, Salmonella typhi, Shigella, Bacillus, Lactobacillus, BCG, Escherichia coli, Vibrio cholerae , and Campylobacter.
3. A DNA composition comprising a DNA construct encoding at least one immunogenic fragment of a VEGF receptor capable of eliciting an immune response against vascular endothelial cells, which is expressible in immune cells, and is incorporated in a pharmaceutically acceptable carrier wherein the DNA construct is incorporated in an attenuated bacterial vector, AroA − , dam − Salmonella typhimurium.
4. A DNA composition comprising a DNA construct encoding at least one immunogenic fragment of a VEGF receptor capable of eliciting an immune response against vascular endothelial cells, which is expressible in immune cells, and is incorporated in a pharmaceutically acceptable carrier wherein the composition further comprises a DNA construct encoding an immune effector protein expressible in immune cells.
5. The DNA composition of claim 4 wherein the immune effector protein is a cytokine.
6. The DNA composition of claim 5 wherein the cytokine is CCL21, IL-2, or CD40LT.
7. The DNA composition of claim 1 wherein the immunogenic fragment of a VEGF receptor comprises at least one immunogenic VEGF receptor fragment consisting of about 8 to 10 consecutive amino acid residues of Flk-1 (SEQ ID NO: 6).