Compositions comprising angiogenic factors and methods of use thereof
The present invention provides recombinant Listeria strains comprising an angiogenic factor, recombinant polypeptides comprising an angiogenic factor operatively linked to a polypeptide comprising a PEST-like sequence, recombinant nucleotide molecules encoding same, related vaccines, and immunogenic and therapeutic methods utilizing same.
1. A method of inducing an immune response against a tumor vasculature of a tumor growth or cancer in a subject, the method comprising the step of administering to said subject a recombinant Listeria strain expressing an angiogenic factor for targeting said tumor vasculature of a tumor growth or cancer in said subject, wherein said angiogenic factor is a vascular endothelial growth factor receptor-2 (VEGFR2) polypeptide or a fragment thereof, wherein said VEGFR2 fragment is a fetal liver kinase-1 (Flk-1)-E1, a Flk-1-E2, a Flk-1-I1, or a combination thereof, wherein said subject mounts an immune response against said angiogenic factor.
2. The method of claim 1 , wherein said immune response is a therapeutic immune response useful in treating, inhibiting or suppressing said tumor growth or cancer in said subject.
3. The method of claim 1 , wherein said angiogenic factor is fused to an additional polypeptide, wherein said additionally polypeptide is a) a non-hemolytic LLO, b) an N-terminal ActA, or c) a PEST sequence.
4. The method of claim 1 , wherein said VEGFR2 fragment is selected from SEQ ID NO: 5-7.
5. The method of claim 1 , wherein said angiogenic factor is expressed from an hly promoter, a prfA promoter, an actA promoter, or a p60 promoter.
6. The method of claim 1 , wherein said angiogenic factor is expressed from an episomal vector or from the Listeria chromosome.
7. The method of claim 1 , wherein said additional polypeptide enhances the immunogenicity of said fragment or factor.
8. The method of claim 1 , wherein said recombinant Listeria strain is a recombinant Listeria monocytogenes strain.
9. The method of claim 1 , wherein said recombinant Listeria strain has been passaged through an animal host.
10. The method of claim 1 , wherein said recombinant Listeria strain induces the release of one or more anti-angiogenic factors.
11. The method of claim 1 , wherein said anti-angiogenic factor is interferon-gamma, pigment epithelium-derived factor (PEDF); angiostatin; endostatin; fms-like tyrosine kinase (sFlt)-1; or soluble endoglin (sEng).
12. The method of claim 1 , wherein said cancer is breast cancer, gastric cancer, ovarian cancer, brain cancer or metastases, or an Her-2/neu-expressing cancer.
13. The method of claim 1 , wherein the method allows preventing the recurrence of said tumor or said cancer, or allows inhibiting metastases of said tumor or said cancer in a subject.
14. The method of claim 1 , wherein said tumor is a breast tumor, a brain metastasis or an Her-2/neu-expressing tumor.
15. The method of claim 1 , wherein said subject mounts an immune response against a tumor antigen expressed by said tumor or cancer, and wherein said immune response against said tumor antigen occurs via epitope spreading.